Reviews

A mood disorder is a chronic illness, associated with episodic recurrence over time^1,2; when a patient experiences a new mood episode, explore possible underlying causes of that recurrence. The mnemonic RELAPSE can help you take an informed approach to treatment, instead of making reflexive medication changes (Table).

Rhythm disturbances. Seasonal changes, shift work, jet lag, and sleep irregularity can induce a mood episode in a vulnerable patient. Failure of a patient’s circadian clock to resynchronize itself after such disruption in the dark–light cycle can trigger mood symptoms.

Ending treatment. Intentional or unintentional non-adherence to a prescribed medication or psychotherapy can trigger a mood episode. Likewise, switching from a brand-name medication to a generic equivalent can induce a new episode because the generic drug might be as much as 20% less bioavailable than the brand formulation.³

Life change. Some life events, such as divorce or job loss, can be sufficiently overwhelming—despite medical therapy and psychotherapy—to induce a new episode in a vulnerable patient.

Additional drugs. Opiates, interferon, steroids, reserpine, and other drugs can be depressogenic; on the other hand, steroids, anticholinergic agents, and antidepressants can induce mania. If another physician, or the patient, adds a medication or supplement that causes an interaction with the patient’s current psychotropic prescription, the result might be increased metabolism or clearance of the psychotropic—thus decreasing its efficacy and leading to a new mood episode.

Physical health changes. Neurologic conditions (epilepsy, multiple sclerosis, stroke), autoimmune illnesses (eg, lupus), primary sleep disorders (eg, obstructive sleep apnea), and hormone changes (eg, testosterone, estrogen, and thyroid) that can occur over the lifespan of a patient with a mood disorder can trigger a new episode.

Substance use and withdrawal. Chronic use of alcohol and opiates and withdrawal from cocaine and stimulants in a patient with a mood disorder can induce a depressive episode; use of cocaine, stimulants, and caffeine can induce a manic state.

End of drug response. Some patients experience a loss of drug response over time (tachyphylaxis) or a depressive recurrence while taking an antidepressant.⁴ These phenomena might be caused by brain changes over time. These are a diagnosis of exclusion after other possibilities have been ruled out.

A mood disorder is a chronic illness, associated with episodic recurrence over time^1,2; when a patient experiences a new mood episode, explore possible underlying causes of that recurrence. The mnemonic RELAPSE can help you take an informed approach to treatment, instead of making reflexive medication changes (Table).

Rhythm disturbances. Seasonal changes, shift work, jet lag, and sleep irregularity can induce a mood episode in a vulnerable patient. Failure of a patient’s circadian clock to resynchronize itself after such disruption in the dark–light cycle can trigger mood symptoms.

Ending treatment. Intentional or unintentional non-adherence to a prescribed medication or psychotherapy can trigger a mood episode. Likewise, switching from a brand-name medication to a generic equivalent can induce a new episode because the generic drug might be as much as 20% less bioavailable than the brand formulation.³

Life change. Some life events, such as divorce or job loss, can be sufficiently overwhelming—despite medical therapy and psychotherapy—to induce a new episode in a vulnerable patient.

Additional drugs. Opiates, interferon, steroids, reserpine, and other drugs can be depressogenic; on the other hand, steroids, anticholinergic agents, and antidepressants can induce mania. If another physician, or the patient, adds a medication or supplement that causes an interaction with the patient’s current psychotropic prescription, the result might be increased metabolism or clearance of the psychotropic—thus decreasing its efficacy and leading to a new mood episode.

Physical health changes. Neurologic conditions (epilepsy, multiple sclerosis, stroke), autoimmune illnesses (eg, lupus), primary sleep disorders (eg, obstructive sleep apnea), and hormone changes (eg, testosterone, estrogen, and thyroid) that can occur over the lifespan of a patient with a mood disorder can trigger a new episode.

Substance use and withdrawal. Chronic use of alcohol and opiates and withdrawal from cocaine and stimulants in a patient with a mood disorder can induce a depressive episode; use of cocaine, stimulants, and caffeine can induce a manic state.

End of drug response. Some patients experience a loss of drug response over time (tachyphylaxis) or a depressive recurrence while taking an antidepressant.⁴ These phenomena might be caused by brain changes over time. These are a diagnosis of exclusion after other possibilities have been ruled out.

A mood disorder is a chronic illness, associated with episodic recurrence over time^1,2; when a patient experiences a new mood episode, explore possible underlying causes of that recurrence. The mnemonic RELAPSE can help you take an informed approach to treatment, instead of making reflexive medication changes (Table).

Rhythm disturbances. Seasonal changes, shift work, jet lag, and sleep irregularity can induce a mood episode in a vulnerable patient. Failure of a patient’s circadian clock to resynchronize itself after such disruption in the dark–light cycle can trigger mood symptoms.

Ending treatment. Intentional or unintentional non-adherence to a prescribed medication or psychotherapy can trigger a mood episode. Likewise, switching from a brand-name medication to a generic equivalent can induce a new episode because the generic drug might be as much as 20% less bioavailable than the brand formulation.³

Life change. Some life events, such as divorce or job loss, can be sufficiently overwhelming—despite medical therapy and psychotherapy—to induce a new episode in a vulnerable patient.

Additional drugs. Opiates, interferon, steroids, reserpine, and other drugs can be depressogenic; on the other hand, steroids, anticholinergic agents, and antidepressants can induce mania. If another physician, or the patient, adds a medication or supplement that causes an interaction with the patient’s current psychotropic prescription, the result might be increased metabolism or clearance of the psychotropic—thus decreasing its efficacy and leading to a new mood episode.

Physical health changes. Neurologic conditions (epilepsy, multiple sclerosis, stroke), autoimmune illnesses (eg, lupus), primary sleep disorders (eg, obstructive sleep apnea), and hormone changes (eg, testosterone, estrogen, and thyroid) that can occur over the lifespan of a patient with a mood disorder can trigger a new episode.

Substance use and withdrawal. Chronic use of alcohol and opiates and withdrawal from cocaine and stimulants in a patient with a mood disorder can induce a depressive episode; use of cocaine, stimulants, and caffeine can induce a manic state.

End of drug response. Some patients experience a loss of drug response over time (tachyphylaxis) or a depressive recurrence while taking an antidepressant.⁴ These phenomena might be caused by brain changes over time. These are a diagnosis of exclusion after other possibilities have been ruled out.

A crescendo of paranoid fear sharply increases the likelihood that a person will kill his (her) misperceived persecutor. Persecutory delusions are more likely to lead to homicide than any other psychiatric symptom.1 If people define a delusional situation as real, the situation is real in its consequences.

Based on my experience performing more than 100 insanity evaluations of paranoid persons charged with murder, I have identified 4 paranoid motives for homicide.

Self-defense. The most common paranoid motive for murder is the misperceived need to defend one’s self.

A steel worker believed that there was a conspiracy to kill him. His wife insisted that he go to a hospital emergency room for an evaluation. He then concluded that his wife was in on the conspiracy and stabbed her to death.

Defense of one’s manhood. Homosexual panic occurs in men who think of themselves as heterosexual.

A man with paranoid schizophrenia developed a delusion that his former high school football coach was having the entire team rape him at night. He shot the coach 6 times in front of 22 witnesses.

Defense of one’s children. A parent may kill to save her (his) children’s souls.

A deeply religious woman developed persecutory delusions that her 9-year-old son and 3-year-old daughter were going to be kidnapped and forced to make child pornography. To save her children’s souls, she stabbed her children more than 100 times.

Defense of the world. Homicide may be seen as a way to protect all humankind.

A woman developed a delusion that her father was Satan and would kill her. She believed that if she could kill her father (Satan) and his family she would save herself and bring about world peace. After killing her father, she thrust the sharp end of a tire iron into her grandmother’s umbilicus and vagina because those body parts were involved in “birthing Satan.”

Questioning to determine risk
I have found that, when evaluating a paranoid, delusional person for potential violence, it is better to present that person with a hypothetical question about encountering his perceived persecutor than with a generic question about homicidality.² For example, a delusional person who reports that he was afraid of being killed by the Mafia could be asked, “If you were walking down an alley and encountered a man dressed like a Mafia hit man with a bulge in his jacket, what would you do?” One interviewee might reply, “The Mafia has so much power there is nothing I could do.” Another might answer, “As soon as I got close enough I would blow his head off with my .357 Magnum.” Although both people would be reporting honestly that they have no homicidal ideas, the latter has a much lower threshold for killing in misperceived self-defense.

Summing up
Persecutory delusions are more likely than any other psychiatric symptom to lead a psychotic person to commit homicide. The killing might be motivated by misperceived self-defense, defense of one’s manhood, defense of one’s children, or defense of the world.

A crescendo of paranoid fear sharply increases the likelihood that a person will kill his (her) misperceived persecutor. Persecutory delusions are more likely to lead to homicide than any other psychiatric symptom.1 If people define a delusional situation as real, the situation is real in its consequences.

Based on my experience performing more than 100 insanity evaluations of paranoid persons charged with murder, I have identified 4 paranoid motives for homicide.

Self-defense. The most common paranoid motive for murder is the misperceived need to defend one’s self.

A steel worker believed that there was a conspiracy to kill him. His wife insisted that he go to a hospital emergency room for an evaluation. He then concluded that his wife was in on the conspiracy and stabbed her to death.

Defense of one’s manhood. Homosexual panic occurs in men who think of themselves as heterosexual.

A man with paranoid schizophrenia developed a delusion that his former high school football coach was having the entire team rape him at night. He shot the coach 6 times in front of 22 witnesses.

Defense of one’s children. A parent may kill to save her (his) children’s souls.

A deeply religious woman developed persecutory delusions that her 9-year-old son and 3-year-old daughter were going to be kidnapped and forced to make child pornography. To save her children’s souls, she stabbed her children more than 100 times.

Defense of the world. Homicide may be seen as a way to protect all humankind.

A woman developed a delusion that her father was Satan and would kill her. She believed that if she could kill her father (Satan) and his family she would save herself and bring about world peace. After killing her father, she thrust the sharp end of a tire iron into her grandmother’s umbilicus and vagina because those body parts were involved in “birthing Satan.”

Questioning to determine risk
I have found that, when evaluating a paranoid, delusional person for potential violence, it is better to present that person with a hypothetical question about encountering his perceived persecutor than with a generic question about homicidality.² For example, a delusional person who reports that he was afraid of being killed by the Mafia could be asked, “If you were walking down an alley and encountered a man dressed like a Mafia hit man with a bulge in his jacket, what would you do?” One interviewee might reply, “The Mafia has so much power there is nothing I could do.” Another might answer, “As soon as I got close enough I would blow his head off with my .357 Magnum.” Although both people would be reporting honestly that they have no homicidal ideas, the latter has a much lower threshold for killing in misperceived self-defense.

Summing up
Persecutory delusions are more likely than any other psychiatric symptom to lead a psychotic person to commit homicide. The killing might be motivated by misperceived self-defense, defense of one’s manhood, defense of one’s children, or defense of the world.

A crescendo of paranoid fear sharply increases the likelihood that a person will kill his (her) misperceived persecutor. Persecutory delusions are more likely to lead to homicide than any other psychiatric symptom.1 If people define a delusional situation as real, the situation is real in its consequences.

Based on my experience performing more than 100 insanity evaluations of paranoid persons charged with murder, I have identified 4 paranoid motives for homicide.

Self-defense. The most common paranoid motive for murder is the misperceived need to defend one’s self.

A steel worker believed that there was a conspiracy to kill him. His wife insisted that he go to a hospital emergency room for an evaluation. He then concluded that his wife was in on the conspiracy and stabbed her to death.

Defense of one’s manhood. Homosexual panic occurs in men who think of themselves as heterosexual.

A man with paranoid schizophrenia developed a delusion that his former high school football coach was having the entire team rape him at night. He shot the coach 6 times in front of 22 witnesses.

Defense of one’s children. A parent may kill to save her (his) children’s souls.

A deeply religious woman developed persecutory delusions that her 9-year-old son and 3-year-old daughter were going to be kidnapped and forced to make child pornography. To save her children’s souls, she stabbed her children more than 100 times.

Defense of the world. Homicide may be seen as a way to protect all humankind.

A woman developed a delusion that her father was Satan and would kill her. She believed that if she could kill her father (Satan) and his family she would save herself and bring about world peace. After killing her father, she thrust the sharp end of a tire iron into her grandmother’s umbilicus and vagina because those body parts were involved in “birthing Satan.”

Questioning to determine risk
I have found that, when evaluating a paranoid, delusional person for potential violence, it is better to present that person with a hypothetical question about encountering his perceived persecutor than with a generic question about homicidality.² For example, a delusional person who reports that he was afraid of being killed by the Mafia could be asked, “If you were walking down an alley and encountered a man dressed like a Mafia hit man with a bulge in his jacket, what would you do?” One interviewee might reply, “The Mafia has so much power there is nothing I could do.” Another might answer, “As soon as I got close enough I would blow his head off with my .357 Magnum.” Although both people would be reporting honestly that they have no homicidal ideas, the latter has a much lower threshold for killing in misperceived self-defense.

Summing up
Persecutory delusions are more likely than any other psychiatric symptom to lead a psychotic person to commit homicide. The killing might be motivated by misperceived self-defense, defense of one’s manhood, defense of one’s children, or defense of the world.

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

A complex relationship and a daunting clinical challenge
Chronic pain enhances the risk of MDD by 2-fold to 5-fold. The risk appears to be mediated by the number of pain conditions rather than by the severity of pain.²³ Some authors have noted a kind of dose-response relationship among pain, depression, and anxiety. Among patients who experienced chronic pain that affected 1 body region, the prevalence of generalized anxiety disorder (GAD) and MDD was 30% and 20%, respectively; in patients who experienced pain in ≥2 regions, the prevalence of GAD and MDD was elevated to 54% and 32%.²⁵ Moreover, patients with fibromyalgia were 4.3 times more likely than healthy controls to develop MDD at some point in their lives and 4.7 times more likely to develop an anxiety disorder.²⁶

Although women are more likely to suffer from fibromyalgia, the risk for people of either sex of developing subsequent MDD is comparable once the condition has developed.²⁷ Overall, depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence ranging from 20% to 80% and 13% to 63.8%, respectively.²⁸

High comorbidity between depression and pain also is relevant for patients with neuropathic pain. A survey from Australia reported depression in 34% and anxiety in 25% of patients with neuropathic pain.²⁹ Pain severity tended to be enduring and associated with significantly impaired functioning. A significant percentage of patients suffering from rheumatoid arthritis and systemic lupus erythematosus tend to manifest anxiety and depression (93% to 94%), cognitive impairment (66%), fatigue (40%), and sleep disorders (72%).²²

The relationship between depression and pain appears to be bidirectional. For example, recent studies demonstrate that 30% to 60% of depressed patients also suffer from a painful condition.⁵

The complex history of patients presenting with concomitant complaints of depression, anxiety, chronic pain, sleep disturbance, cognitive impairment, and fatigue present a daunting diagnostic task. Pain tends to be associated with greater fatigue and sleep disturbance, which in turn depletes a patient’s ability to enjoy life and enhances negative affect.^19,20,30 The take-home message might be to screen all chronic pain patients for MDD, anxiety, and sleep disorders, and vice versa.

Furthermore, comorbidity among chronic pain, MDD, anxiety, and sleep disorders can introduce specific intricacies into our treatment approach. Although, in general, comorbidities tend to have a negative impact on treatment outcomes, many pharmacotherapeutic and non-drug interventions targeting chronic pain might ameliorate sleep problems, low energy, anxiety, depression, and anhedonia.^18,20,30-32 On the other hand, we should consider that opioid treatment for chronic pain might represent a risk factor for subsequent depression. It is conceivable that chronic opioid treatment and associated sedation can erode self-efficacy and social relationships, thereby compromising sources of support.^33,34 It is equally important to keep in mind that, even if we are successful in attaining remission when treating depression and pain, residual pain symptoms might persist, requiring more specific interventions.²⁴

MDD and chronic pain each have, on their own, a well-established association with suicide attempts and completion. Researchers are investigating whether a pathophysiologic suicide-promoting synergy between the 2 disorders exists when they are comorbid (Box^35-37).

Shared genetics and pathophysiology
Several candidate genes have been identified as risk genes for chronic pain, depression, and anxiety. One of those studied the most is 5-HTTLPR, involved in regulating synthesis of serotonin transporter. The short form of this gene has been implicated in a diverse set of conditions, including MDD, anxiety disorders, and substance abuse—and fibromyalgia. Other genes associated with the risk of MDD and pain disorders are ones that code for:

• serotonin 5-HT2A and 5-HT1A receptors
• catechol-O-methyltransferase, an enzyme involved in catecholamine metabolism
• dopamine D4 receptor
• proinflammatory cytokines interleukin-1 and interleukin-6.⁴

Both monoamines and inflammatory cytokines play a role in modulating γ-aminobutyric acid (GABA) and glutamate neurons, as well as glia cells constituting peripheral pain pathways and central circuits that participate in the pain response and regulation of mood.^4,17,38

The ‘pain matrix’
Brain circuitry that is involved in processing pain stimuli—often referred to as the pain matrix—shares many structural components with circuitry involved in the stress response and emotional modulation.⁴ Emerging evidence indicates that the pain matrix might not be pain-specific but, instead, a complex aggregate of interconnected brain structures involved in evoking defensive responses to a number of offending stimuli, including pain, threat, danger, loss, and social rejection or isolation.

It is remarkable, in this regard, that imaging studies show that the dorsal anterior cingulate, central to experiencing negative affect in response to physical pain, also mediates distress in response to the “pain” of social exclusion.³⁹ Emerging functional and structural imaging provides evidence of continuous reorganization of prefrontal cortices as a consequence of enduring chronic pain.¹ Of particular interest are findings of (1) a reduction of gray matter in the dorsolateral prefrontal cortex (DLPFC) and (2) functional activation of the medial prefrontal cortex (mPFC), both of which correlate with the duration and experience of chronic back pain.¹ It is tempting to speculate that structural decline of the DLPFC, observed in MDD and chronic pain, is linked to cognitive and executive function deficits, which are readily observed in patients with either disorder—given that DLPFC is a “hub” of the so-called “cognitive-executive functional network.”^1,4

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

A complex relationship and a daunting clinical challenge
Chronic pain enhances the risk of MDD by 2-fold to 5-fold. The risk appears to be mediated by the number of pain conditions rather than by the severity of pain.²³ Some authors have noted a kind of dose-response relationship among pain, depression, and anxiety. Among patients who experienced chronic pain that affected 1 body region, the prevalence of generalized anxiety disorder (GAD) and MDD was 30% and 20%, respectively; in patients who experienced pain in ≥2 regions, the prevalence of GAD and MDD was elevated to 54% and 32%.²⁵ Moreover, patients with fibromyalgia were 4.3 times more likely than healthy controls to develop MDD at some point in their lives and 4.7 times more likely to develop an anxiety disorder.²⁶

Although women are more likely to suffer from fibromyalgia, the risk for people of either sex of developing subsequent MDD is comparable once the condition has developed.²⁷ Overall, depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence ranging from 20% to 80% and 13% to 63.8%, respectively.²⁸

High comorbidity between depression and pain also is relevant for patients with neuropathic pain. A survey from Australia reported depression in 34% and anxiety in 25% of patients with neuropathic pain.²⁹ Pain severity tended to be enduring and associated with significantly impaired functioning. A significant percentage of patients suffering from rheumatoid arthritis and systemic lupus erythematosus tend to manifest anxiety and depression (93% to 94%), cognitive impairment (66%), fatigue (40%), and sleep disorders (72%).²²

The relationship between depression and pain appears to be bidirectional. For example, recent studies demonstrate that 30% to 60% of depressed patients also suffer from a painful condition.⁵

The complex history of patients presenting with concomitant complaints of depression, anxiety, chronic pain, sleep disturbance, cognitive impairment, and fatigue present a daunting diagnostic task. Pain tends to be associated with greater fatigue and sleep disturbance, which in turn depletes a patient’s ability to enjoy life and enhances negative affect.^19,20,30 The take-home message might be to screen all chronic pain patients for MDD, anxiety, and sleep disorders, and vice versa.

Furthermore, comorbidity among chronic pain, MDD, anxiety, and sleep disorders can introduce specific intricacies into our treatment approach. Although, in general, comorbidities tend to have a negative impact on treatment outcomes, many pharmacotherapeutic and non-drug interventions targeting chronic pain might ameliorate sleep problems, low energy, anxiety, depression, and anhedonia.^18,20,30-32 On the other hand, we should consider that opioid treatment for chronic pain might represent a risk factor for subsequent depression. It is conceivable that chronic opioid treatment and associated sedation can erode self-efficacy and social relationships, thereby compromising sources of support.^33,34 It is equally important to keep in mind that, even if we are successful in attaining remission when treating depression and pain, residual pain symptoms might persist, requiring more specific interventions.²⁴

MDD and chronic pain each have, on their own, a well-established association with suicide attempts and completion. Researchers are investigating whether a pathophysiologic suicide-promoting synergy between the 2 disorders exists when they are comorbid (Box^35-37).

Shared genetics and pathophysiology
Several candidate genes have been identified as risk genes for chronic pain, depression, and anxiety. One of those studied the most is 5-HTTLPR, involved in regulating synthesis of serotonin transporter. The short form of this gene has been implicated in a diverse set of conditions, including MDD, anxiety disorders, and substance abuse—and fibromyalgia. Other genes associated with the risk of MDD and pain disorders are ones that code for:

• serotonin 5-HT2A and 5-HT1A receptors
• catechol-O-methyltransferase, an enzyme involved in catecholamine metabolism
• dopamine D4 receptor
• proinflammatory cytokines interleukin-1 and interleukin-6.⁴

Both monoamines and inflammatory cytokines play a role in modulating γ-aminobutyric acid (GABA) and glutamate neurons, as well as glia cells constituting peripheral pain pathways and central circuits that participate in the pain response and regulation of mood.^4,17,38

The ‘pain matrix’
Brain circuitry that is involved in processing pain stimuli—often referred to as the pain matrix—shares many structural components with circuitry involved in the stress response and emotional modulation.⁴ Emerging evidence indicates that the pain matrix might not be pain-specific but, instead, a complex aggregate of interconnected brain structures involved in evoking defensive responses to a number of offending stimuli, including pain, threat, danger, loss, and social rejection or isolation.

It is remarkable, in this regard, that imaging studies show that the dorsal anterior cingulate, central to experiencing negative affect in response to physical pain, also mediates distress in response to the “pain” of social exclusion.³⁹ Emerging functional and structural imaging provides evidence of continuous reorganization of prefrontal cortices as a consequence of enduring chronic pain.¹ Of particular interest are findings of (1) a reduction of gray matter in the dorsolateral prefrontal cortex (DLPFC) and (2) functional activation of the medial prefrontal cortex (mPFC), both of which correlate with the duration and experience of chronic back pain.¹ It is tempting to speculate that structural decline of the DLPFC, observed in MDD and chronic pain, is linked to cognitive and executive function deficits, which are readily observed in patients with either disorder—given that DLPFC is a “hub” of the so-called “cognitive-executive functional network.”^1,4

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

A complex relationship and a daunting clinical challenge
Chronic pain enhances the risk of MDD by 2-fold to 5-fold. The risk appears to be mediated by the number of pain conditions rather than by the severity of pain.²³ Some authors have noted a kind of dose-response relationship among pain, depression, and anxiety. Among patients who experienced chronic pain that affected 1 body region, the prevalence of generalized anxiety disorder (GAD) and MDD was 30% and 20%, respectively; in patients who experienced pain in ≥2 regions, the prevalence of GAD and MDD was elevated to 54% and 32%.²⁵ Moreover, patients with fibromyalgia were 4.3 times more likely than healthy controls to develop MDD at some point in their lives and 4.7 times more likely to develop an anxiety disorder.²⁶

Although women are more likely to suffer from fibromyalgia, the risk for people of either sex of developing subsequent MDD is comparable once the condition has developed.²⁷ Overall, depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence ranging from 20% to 80% and 13% to 63.8%, respectively.²⁸

High comorbidity between depression and pain also is relevant for patients with neuropathic pain. A survey from Australia reported depression in 34% and anxiety in 25% of patients with neuropathic pain.²⁹ Pain severity tended to be enduring and associated with significantly impaired functioning. A significant percentage of patients suffering from rheumatoid arthritis and systemic lupus erythematosus tend to manifest anxiety and depression (93% to 94%), cognitive impairment (66%), fatigue (40%), and sleep disorders (72%).²²

The relationship between depression and pain appears to be bidirectional. For example, recent studies demonstrate that 30% to 60% of depressed patients also suffer from a painful condition.⁵

The complex history of patients presenting with concomitant complaints of depression, anxiety, chronic pain, sleep disturbance, cognitive impairment, and fatigue present a daunting diagnostic task. Pain tends to be associated with greater fatigue and sleep disturbance, which in turn depletes a patient’s ability to enjoy life and enhances negative affect.^19,20,30 The take-home message might be to screen all chronic pain patients for MDD, anxiety, and sleep disorders, and vice versa.

Furthermore, comorbidity among chronic pain, MDD, anxiety, and sleep disorders can introduce specific intricacies into our treatment approach. Although, in general, comorbidities tend to have a negative impact on treatment outcomes, many pharmacotherapeutic and non-drug interventions targeting chronic pain might ameliorate sleep problems, low energy, anxiety, depression, and anhedonia.^18,20,30-32 On the other hand, we should consider that opioid treatment for chronic pain might represent a risk factor for subsequent depression. It is conceivable that chronic opioid treatment and associated sedation can erode self-efficacy and social relationships, thereby compromising sources of support.^33,34 It is equally important to keep in mind that, even if we are successful in attaining remission when treating depression and pain, residual pain symptoms might persist, requiring more specific interventions.²⁴

MDD and chronic pain each have, on their own, a well-established association with suicide attempts and completion. Researchers are investigating whether a pathophysiologic suicide-promoting synergy between the 2 disorders exists when they are comorbid (Box^35-37).

Shared genetics and pathophysiology
Several candidate genes have been identified as risk genes for chronic pain, depression, and anxiety. One of those studied the most is 5-HTTLPR, involved in regulating synthesis of serotonin transporter. The short form of this gene has been implicated in a diverse set of conditions, including MDD, anxiety disorders, and substance abuse—and fibromyalgia. Other genes associated with the risk of MDD and pain disorders are ones that code for:

• serotonin 5-HT2A and 5-HT1A receptors
• catechol-O-methyltransferase, an enzyme involved in catecholamine metabolism
• dopamine D4 receptor
• proinflammatory cytokines interleukin-1 and interleukin-6.⁴

Both monoamines and inflammatory cytokines play a role in modulating γ-aminobutyric acid (GABA) and glutamate neurons, as well as glia cells constituting peripheral pain pathways and central circuits that participate in the pain response and regulation of mood.^4,17,38

The ‘pain matrix’
Brain circuitry that is involved in processing pain stimuli—often referred to as the pain matrix—shares many structural components with circuitry involved in the stress response and emotional modulation.⁴ Emerging evidence indicates that the pain matrix might not be pain-specific but, instead, a complex aggregate of interconnected brain structures involved in evoking defensive responses to a number of offending stimuli, including pain, threat, danger, loss, and social rejection or isolation.

It is remarkable, in this regard, that imaging studies show that the dorsal anterior cingulate, central to experiencing negative affect in response to physical pain, also mediates distress in response to the “pain” of social exclusion.³⁹ Emerging functional and structural imaging provides evidence of continuous reorganization of prefrontal cortices as a consequence of enduring chronic pain.¹ Of particular interest are findings of (1) a reduction of gray matter in the dorsolateral prefrontal cortex (DLPFC) and (2) functional activation of the medial prefrontal cortex (mPFC), both of which correlate with the duration and experience of chronic back pain.¹ It is tempting to speculate that structural decline of the DLPFC, observed in MDD and chronic pain, is linked to cognitive and executive function deficits, which are readily observed in patients with either disorder—given that DLPFC is a “hub” of the so-called “cognitive-executive functional network.”^1,4

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

A number of new advances have occurred in the management of chemotherapy-related nausea and vomiting (CINV). A new neurokinin-1 receptor antagonist (NK1RA), netupitant, has been combined with palonosetron in a single oral tablet for treating the effects of moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC). Rolapitant, another NK1RA, unlike aprepitant, has a long half-life and does not block CYP-3A4 and therefore has fewer drug interactions. Olanzapine reduces nausea more effectively than aprepitant in patients who are receiving HEC and is a better rescue antiemetic than is metoclopramide. Ginger lacks efficacy as an antiemetic agent for CINV. Although there was some evidence in a pilot study of gabapentin as an antiemetic, it was no better in reducing CINV than was placebo. Compliance to guidelines in multiple settings ranges from 50%-60% but is improved by computerized order entry of antiemetics and recommendations displayed with chemotherapy.

Click on the PDF icon at the top of this introduction to read the full article.

A number of new advances have occurred in the management of chemotherapy-related nausea and vomiting (CINV). A new neurokinin-1 receptor antagonist (NK1RA), netupitant, has been combined with palonosetron in a single oral tablet for treating the effects of moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC). Rolapitant, another NK1RA, unlike aprepitant, has a long half-life and does not block CYP-3A4 and therefore has fewer drug interactions. Olanzapine reduces nausea more effectively than aprepitant in patients who are receiving HEC and is a better rescue antiemetic than is metoclopramide. Ginger lacks efficacy as an antiemetic agent for CINV. Although there was some evidence in a pilot study of gabapentin as an antiemetic, it was no better in reducing CINV than was placebo. Compliance to guidelines in multiple settings ranges from 50%-60% but is improved by computerized order entry of antiemetics and recommendations displayed with chemotherapy.

Click on the PDF icon at the top of this introduction to read the full article.

A number of new advances have occurred in the management of chemotherapy-related nausea and vomiting (CINV). A new neurokinin-1 receptor antagonist (NK1RA), netupitant, has been combined with palonosetron in a single oral tablet for treating the effects of moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC). Rolapitant, another NK1RA, unlike aprepitant, has a long half-life and does not block CYP-3A4 and therefore has fewer drug interactions. Olanzapine reduces nausea more effectively than aprepitant in patients who are receiving HEC and is a better rescue antiemetic than is metoclopramide. Ginger lacks efficacy as an antiemetic agent for CINV. Although there was some evidence in a pilot study of gabapentin as an antiemetic, it was no better in reducing CINV than was placebo. Compliance to guidelines in multiple settings ranges from 50%-60% but is improved by computerized order entry of antiemetics and recommendations displayed with chemotherapy.

Click on the PDF icon at the top of this introduction to read the full article.

Primary care physicians are playing a bigger role in evaluating the incidental finding of interstitial lung diseases since the recent publication of guidelines recommending computed tomography (CT) to screen for lung cancer.

In August 2011, the National Cancer Institute published its findings from the National Lung Screening Trial, which demonstrated a 20% reduction in mortality from lung cancer in patients at high risk screened with low-dose CT.¹ Based on these results, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommended annual screening for lung cancer with low-dose CT in adults ages 55 to 74 who have a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years.² In December 2013, the US Preventive Services Task Force published similar guidelines but increased the age range to include high-risk patients ages 55 to 80.³

Bach et al⁴ estimated that, in 2010 in the United States, 8.6 million people met the criteria used in the National Lung Screening Trial for low-dose CT screening. These are the same criteria as in the multisociety recommendations cited above.² With such large numbers of patients eligible for CT screening, internists and other primary care physicians are undoubtedly encountering the incidental discovery of nonmalignant pulmonary diseases such as interstitial lung disease.

This article reviews the radiographic characteristics of the most common interstitial lung diseases the internist may encounter on screening CT in long-term smokers.

Referral to a specialist has been associated with lower rates of morbidity and death,⁵ and a diagnosis of interstitial lung disease should be confirmed by a pulmonologist and a radiologist specializing in differentiating the subtypes. But the primary care physician now plays a critical role in recognizing the need for further evaluation.

HOW COMMON IS INTERSTITIAL LUNG DISEASE IN SMOKERS?

Several studies have published data on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening.

A trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 participants.⁶

A trial in Ireland identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who underwent low-dose CT screening for lung cancer.⁷

Sverzellati et al⁸ evaluated 692 participants in the Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 (15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial pneumonia in 26 (3.8%).

The National Lung Screening Trial reported that the frequency of “clinically significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%.¹ A retrospective analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities in 86 participants (9.7%).⁹ These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884.

Follow-up CT at 2 years in this trial demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were more common in those who currently smoked and in those with more pack-years of cigarette smoking.⁹

In sum, these trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung disease in this at-risk population and can characterize them as fibrotic or nonfibrotic, a distinction important for prognosis and subsequent management.

NONFIBROTIC VS FIBROTIC DISEASE

It is important to distinguish between nonfibrotic and fibrotic interstitial lung disease, as fibrotic disease carries a worse prognosis and is treated differently.

Features of nonfibrotic interstitial lung disease:

• Ground-glass opacities
• Nodules
• Mosaic attenuation or consolidation.

Features of fibrotic interstitial lung disease:

• Combination of ground-glass opacities and reticulation
• Reticulation by itself
• Traction bronchiectasis
• Honeycombing
• Loss of lung volume.

NONFIBROTIC INTERSTITIAL LUNG DISEASES

Given the strong likelihood that a patient undergoing screening CT is either a current or former smoker, physicians may encounter, in addition to emphysema and lung cancer, the following smoking-related interstitial lung diseases, which are primarily nonfibrotic and which frequently coexist (Table 1):

• Respiratory bronchiolitis
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Pulmonary Langerhans cell histiocytosis.

Respiratory bronchiolitis

Respiratory bronchiolitis occurs mostly in smokers and does not necessarily lead to respiratory symptoms in all patients.¹⁰ It cannot always be identified radiographically but occasionally appears as predominantly upper-lobe, patchy ground-glass opacities or ill-defined centrilobular nodules without evidence of fibrosis (Figure 1).

Respiratory bronchiolitis-interstitial lung disease

In rare cases, respiratory bronchiolitis leads to peribronchial fibrosis invading the alveolar walls, which is then classified as respiratory bronchiolitis-interstitial lung disease.¹¹ The CT findings in respiratory bronchiolitis-interstitial lung disease are upper-lobe-predominant centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening (Figure 2).¹⁰ Occasionally, mild reticulation is noted without honeycombing. Mild air trapping can be seen in the lower lobes, with centrilobular emphysema in the upper lobes.¹²

The only successful therapy for respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease is smoking cessation. Finding either of these diseases should prompt aggressive counseling by the internist and consideration of referral to a specialist in interstitial lung disease.

Desquamative interstitial pneumonia

Although pathologically different from respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia has a similar clinical and radiographic presentation. Because their features significantly overlap, they are considered a pathomorphologic continuum, representing degrees of severity of the same disease process caused by prolonged tobacco inhalation.^10,13

Widespread ground-glass opacities are the predominant CT finding. These are bilateral and symmetric in distribution in 86%, basal and peripheral in 60%, patchy in 20%, and diffuse in 20% (Figure 3).¹⁴ Other frequent findings are mild reticulation with traction bronchiectasis and coexistent emphysema (Figure 4).¹⁵ The small peripheral cystic spaces noted in this disease most likely represent dilated bronchioles and alveolar ducts rather than honeycombing.¹⁶

No additional treatment beyond elimination of smoking has been proven effective for desquamative interstitial pneumonia, and patients who manage to quit smoking generally have a favorable prognosis.^17,18

Pulmonary Langerhans cell histiocytosis

The combination of upper-lobe-predominant cysts and nodules in a young heavy smoker are diagnostic of pulmonary Langerhans cell histiocytosis. The cysts are bizarrely shaped, thin- or thick-walled, and nonuniform in size (Figure 5). The irregular cavitary nodules are centrilobular. The disease characteristically spares the costophrenic angles.

Spontaneous pneumothorax is the initial clinical presentation in 15% of patients.¹⁶ In the early stages of the disease (nodule-predominant disease without cysts), infection and metastatic disease need to be excluded (Figure 6). In the later stages, the cysts become coalescent, making the distinction between this disease and “burned-out” lymphangioleiomyomatosis or severe emphysema extremely difficult (Figure 7).¹⁷ Smoking cessation and corticosteroids are the mainstay of medical therapy for pulmonary Langerhans cell histiocytosis, and about 50% of patients who quit smoking and receive corticosteroids demonstrate partial or complete clearing of the radiographic abnormalities and symptoms (Figure 8).

FIBROTIC INTERSTITIAL LUNG DISEASES

If CT identifies a diffuse fibrotic pattern, the two most common possibilities (Table 2) are:

• Nonspecific interstitial pneumonia
• Usual interstitial pneumonia.

As noted above, these carry a worse prognosis than the nonfibrotic interstitial lung diseases.

Nonspecific interstitial pneumonia

While most frequently idiopathic, the nonspecific interstitial pneumonia pattern can often be seen in connective tissue diseases. It has also been associated with chronic hypersensitivity pneumonitis, drug toxicity, and slowly resolving diffuse alveolar damage.¹⁹ Although it is not the only pathologic pattern in interstitial lung disease associated with connective tissue disease, it is the most common pattern in systemic sclerosis, systemic lupus erythematosus, dermatomyositis-polymyositis, and mixed connective tissue disease.²⁰

The parenchymal changes are typically subpleural and symmetric in distribution (Figure 9). In about one-third of cases, there is a peribronchovascular distribution of the abnormalities (Figure 10).

Ground-glass opacities are the dominant imaging findings, seen in 80% of cases.¹⁸ In advanced disease (also referred to as fibrotic nonspecific interstitial pneumonia), patients have accompanying fine or coarse reticular opacities, traction bronchiectasis, and consolidation (Figure 11). Honeycombing is seen in 1% to 5% of patients.²¹

The most specific sign of nonspecific interstitial pneumonia is sparing of the immediate subpleural lung, apparent in 30% to 50% of patients (Figure 12).²² Subpleural sparing with a peribronchovascular distribution of abnormalities, absence of lobular areas with decreased attenuation, and lack of honeycombing are imaging features that increase the diagnostic confidence of nonspecific interstitial pneumonia (Table 3).²³ Clinically, compared with those who have usual interstitial pneumonia (see below), patients are younger and more of them are female. These patients also present with extrapulmonary manifestations such as joint involvement, rash, and Raynaud phenomenon. Therefore, these associated symptoms on presentation can help distinguish nonspecific interstitial pneumonia or usual interstitial pneumonia related to connective tissue disease from the idiopathic forms.

The first step in managing nonspecific interstitial pneumonia is to remove all potential exposure to inhaled substances or to drugs. Although immunosuppressive therapy has never been studied in a randomized controlled trial in this disease, numerous reports suggest that patients may respond to prednisone and to steroid-sparing immunosuppressants.²⁴

In several studies, survival rates in nonspecific interstitial pneumonia were significantly greater than in usual interstitial pneumonia independent of the treatment strategy. In long-term follow-up of patients with idiopathic nonspecific interstitial pneumonia treated with immunosuppressive therapy, two-thirds remained stable or improved.^25–27

Although most connective tissue diseases cause a lung pattern of nonspecific interstitial pneumonia, some (eg, rheumatoid arthritis) may present with a pattern of usual interstitial pneumonia. In these cases and in those of advanced fibrotic nonspecific interstitial pneumonia, the prognosis is worse, as the disease is less responsive to immunosuppressive therapy.²⁰

Usual interstitial pneumonia

Usual interstitial pneumonia is the most severe form of lung fibrosis. Most cases are idio­pathic and are termed idiopathic pulmonary fibrosis. Other causes of the usual interstitial pneumonia pattern include domestic and occupational environmental exposures, connective tissue disease, and drug toxicity.²⁸ An epidemiologic association between smoking and usual interstitial pneumonia is well documented.²⁸

Idiopathic pulmonary fibrosis typically affects men ages 50 to 70. Because its risk factors coincide with those of lung cancer, there is a high likelihood of detecting idiopathic pulmonary fibrosis early in this screening population. It has an especially poor prognosis, with a mean survival of 2 to 5 years from the time of diagnosis.¹⁸

The distribution of disease in usual interstitial pneumonia is characteristically subpleural and basal. CT features include coarse subpleural reticulation and honeycombing combined with traction bronchiectasis or bronchiolectasis and architectural distortion (Figure 13).¹⁸ Honeycombing is the most specific and key diagnostic CT finding for establishing a definitive diagnosis of usual interstitial pneumonia.²⁹ However, ground-glass opacities are present in most patients, typically in the region of interstitial fibrosis, and are always less extensive than the reticulation.³⁰ The findings demonstrate morphologic heterogeneity, with areas of fibrosis adjacent to areas of normal lung (Figure 14).

In addition to the aforementioned imaging features, the 2011 American Thoracic Society and European Respiratory Society joint guidelines for the CT diagnosis of usual interstitial pneumonia patterns require the absence of atypical features that suggest an alternative diagnosis, including those seen in nonspecific interstitial pneumonia, such as an upper, midlung, or peribronchovascular distribution and extensive ground-glass attenuation.²⁸ Mild mediastinal lymphadenopathy (usually < 1.5 cm in the short axis) is common in usual interstitial pneumonia.³¹

Because other chronic interstitial pneumonias that may resemble usual interstitial pneumonia have a more favorable course and may respond to immunosuppressive therapy, establishing an early and accurate diagnosis is of the utmost importance.⁵ Additionally, the emergence of possible new therapies for idiopathic pulmonary fibrosis makes early referral to a specialist paramount in these cases. Recent studies have demonstrated significant slowing of the progression of disease in idiopathic pulmonary fibrosis with both pirfenidone and nintedanib.^32,33

DIAGNOSIS AND MANAGEMENT

The diagnosis of these nonfibrotic and fibrotic lung diseases is complex. In all cases in which interstitial lung disease is detected on screening CT for lung cancer, the internist should strongly consider further evaluation with dedicated high-resolution CT and early referral to a specialist (Figure 15).

Because smoking cessation is the only recommended treatment for nonfibrotic smoking-related interstitial lung diseases, particular emphasis on smoking cessation counseling is essential.

Referral for bronchoscopy with transbronchial lung biopsy is generally not helpful in the diagnosis of the interstitial lung diseases discussed in this article unless there is a need to rule out infection or neoplasm.³⁴ Referral for surgical lung biopsy may be indicated in some cases of suspected pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia if the diagnosis is uncertain (Tables 1 and 2).³⁵

The American Thoracic Society/European Respiratory Society guidelines suggest a multidisciplinary team approach that includes a pathologist, radiologist, and clinician.³⁵ This approach more readily determines the correct diagnosis and relies less on invasive methods such as surgical biopsy and more on noninvasive methods such as radiology and clinical history. Overall, this will promote earlier access to appropriate therapies, clinical trial enrollment, and in more severe cases, lung transplant.

Currently, 23% of all lung transplants worldwide are performed in patients with idiopathic pulmonary fibrosis. Other forms of pulmonary fibrosis account for 3% to 4% of lung transplants performed.³⁶

Evidence suggests that early referral reduces rates of morbidity and death in these patients. The results of a single-center study³⁷ of patients with idiopathic pulmonary fibrosis demonstrated that a longer delay from the onset of symptoms to evaluation by a specialist at a tertiary care referral center was associated with a higher rate of death from this disease independent of disease severity. Those with the longest delay in referral had a multivariable-adjusted death rate 3.4 times higher than those with the shortest delay.^5,37

In summary, with implementation of the new lung cancer screening guidelines, primary care physicians are more often encountering the incidental finding of interstitial lung disease in their patients. Prompt diagnosis of interstitial lung disease helps ensure that patients receive appropriate care and early consideration for clinical trials and lung transplant.

Primary care physicians play a critical role in the initial identification of key characteristics of the interstitial abnormality—namely, whether the pattern is nonfibrotic or fibrotic—and in the correlation of the history and physical findings to expedite the diagnosis. Subsequently, ordering high-resolution CT for more detailed characterization and prompt referral to a specialist in interstitial lung disease allow for a more rapid and accurate diagnosis, specialized therapy, and supportive care.