Consider four factors in refractory MDD

LAS VEGAS – Despite your best efforts at treating patients newly diagnosed with major depressive disorder, only about 1 in 3 patients achieves remission on the first antidepressant and almost 50% subsequently relapse.

"Our work is cut out for is," Dr. Jonathan E. Alpert said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Factors associated with nonremission in major depressive disorder (MDD) include a history of chronic or recurrent depression; anxious, melancholic, or psychotic features; psychiatric or general medical comorbidity; minority ethnic/racial status; and lower quality of life and function prior to treatment. When a patient fails to remit, Dr. Alpert recommends a checklist of four basic factors to consider before rushing to the next medication or to the next form of psychotherapy.

"It’s important to step back for a moment and recheck what you think you know about that particular patient," said Dr. Alpert, associate chief of psychiatry for clinical services at Massachusetts General Hospital (MGH), Boston.

One factor on the checklist is adherence. Some patients – and sometimes their significant others – are ambivalent about pursuing depression treatment, which could interfere with adherence. "Other patients are confused about the instructions we’ve given them, or they might have cognitive problems that make it difficult for them to stick with the complex regimens we might be prescribing," he explained. "Access to health care and cost of medications can also play a role."

Another factor on the checklist is to be sure of your primary diagnosis. Is it MDD, or is it MDD with psychotic features? Is it bipolar disorder or mood dysregulation in the context of personality disorder? "It can be difficult to separate these," he said.

A third factor on the checklist is to assess for comorbidities such as substance abuse; obsessive-compulsive disorder; posttraumatic stress disorder; and general medical conditions that can mimic MDD symptoms, such as hypothyroidism.

A fourth factor to consider is drug-drug interactions and pharmacokinetics. For example, rapid/fast metabolizers and smokers "may require high doses of medication to achieve a benefit," said Dr. Alpert, who also serves as associate director of the MGH Depression Clinical and Research Program.

After you’ve run through the checklist and you’re confident that a patient has MDD, consider switch, augmentation, and combination strategies to improve response. "Typically we switch from one antidepressant to another in the setting of nonresponse or intolerance to the first agent," he said. "It’s been difficult to see differential effects of different classes of antidepressants. There are some limited data that show the inferiority of tricyclic antidepressants compared with monoamine oxidase inhibitors in patients with atypical features – the kind of depression characterized by pronounced rejection, sensitivity, and mood reactivity."

Dr. Alpert noted that some data support selective norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants as being superior to selective serotonin reuptake inhibitors (SSRIs) in MDD complicated by comorbid pain syndrome such as fibromyalgia. "Bupropion is clearly better than SSRIs and SNRIs for MDD with antidepressant-related sexual dysfunction, nicotine dependence, or ADHD," he said. "Consider broad-spectrum agents such as clomipramine in the setting of persistent refractory depression."

For patients who have only achieved partial response to an antidepressant, consider augmenting with a nonantidepressant such as atypical antipsychotics; dopamine agonists and psychostimulants; lithium; thyroid (T3); buspirone; and natural agents such as l-methylfolate, S-adenosyl-l-methionine (SAMe), creatinine, and omega-3 fatty acids.

Another strategy is to combine antidepressants together in the context of partial response and tolerability of the initial agent. Examples of combination therapy include an SSRI or SNRI plus bupropion, or an SNRI plus mirtazapine.

As for future directions in the psychopharmacology of depression, important recent targets in drug development include mitochondrial function, inflammation processes, and neurogenesis. "Non-monoaminergic mechanisms including kappa and NK1 antagonists and a range of glutamatergic agents are a continued and growing focus," Dr. Alpert concluded. "Rapid-acting antidepressants such as intravenous ketamine and scopolamine promise novel strategies for jump-starting treatment."

Dr. Alpert said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

LAS VEGAS – Despite your best efforts at treating patients newly diagnosed with major depressive disorder, only about 1 in 3 patients achieves remission on the first antidepressant and almost 50% subsequently relapse.

"Our work is cut out for is," Dr. Jonathan E. Alpert said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Factors associated with nonremission in major depressive disorder (MDD) include a history of chronic or recurrent depression; anxious, melancholic, or psychotic features; psychiatric or general medical comorbidity; minority ethnic/racial status; and lower quality of life and function prior to treatment. When a patient fails to remit, Dr. Alpert recommends a checklist of four basic factors to consider before rushing to the next medication or to the next form of psychotherapy.

"It’s important to step back for a moment and recheck what you think you know about that particular patient," said Dr. Alpert, associate chief of psychiatry for clinical services at Massachusetts General Hospital (MGH), Boston.

One factor on the checklist is adherence. Some patients – and sometimes their significant others – are ambivalent about pursuing depression treatment, which could interfere with adherence. "Other patients are confused about the instructions we’ve given them, or they might have cognitive problems that make it difficult for them to stick with the complex regimens we might be prescribing," he explained. "Access to health care and cost of medications can also play a role."

Another factor on the checklist is to be sure of your primary diagnosis. Is it MDD, or is it MDD with psychotic features? Is it bipolar disorder or mood dysregulation in the context of personality disorder? "It can be difficult to separate these," he said.

A third factor on the checklist is to assess for comorbidities such as substance abuse; obsessive-compulsive disorder; posttraumatic stress disorder; and general medical conditions that can mimic MDD symptoms, such as hypothyroidism.

A fourth factor to consider is drug-drug interactions and pharmacokinetics. For example, rapid/fast metabolizers and smokers "may require high doses of medication to achieve a benefit," said Dr. Alpert, who also serves as associate director of the MGH Depression Clinical and Research Program.

After you’ve run through the checklist and you’re confident that a patient has MDD, consider switch, augmentation, and combination strategies to improve response. "Typically we switch from one antidepressant to another in the setting of nonresponse or intolerance to the first agent," he said. "It’s been difficult to see differential effects of different classes of antidepressants. There are some limited data that show the inferiority of tricyclic antidepressants compared with monoamine oxidase inhibitors in patients with atypical features – the kind of depression characterized by pronounced rejection, sensitivity, and mood reactivity."

Dr. Alpert noted that some data support selective norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants as being superior to selective serotonin reuptake inhibitors (SSRIs) in MDD complicated by comorbid pain syndrome such as fibromyalgia. "Bupropion is clearly better than SSRIs and SNRIs for MDD with antidepressant-related sexual dysfunction, nicotine dependence, or ADHD," he said. "Consider broad-spectrum agents such as clomipramine in the setting of persistent refractory depression."

For patients who have only achieved partial response to an antidepressant, consider augmenting with a nonantidepressant such as atypical antipsychotics; dopamine agonists and psychostimulants; lithium; thyroid (T3); buspirone; and natural agents such as l-methylfolate, S-adenosyl-l-methionine (SAMe), creatinine, and omega-3 fatty acids.

Another strategy is to combine antidepressants together in the context of partial response and tolerability of the initial agent. Examples of combination therapy include an SSRI or SNRI plus bupropion, or an SNRI plus mirtazapine.

As for future directions in the psychopharmacology of depression, important recent targets in drug development include mitochondrial function, inflammation processes, and neurogenesis. "Non-monoaminergic mechanisms including kappa and NK1 antagonists and a range of glutamatergic agents are a continued and growing focus," Dr. Alpert concluded. "Rapid-acting antidepressants such as intravenous ketamine and scopolamine promise novel strategies for jump-starting treatment."

Dr. Alpert said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

LAS VEGAS – Despite your best efforts at treating patients newly diagnosed with major depressive disorder, only about 1 in 3 patients achieves remission on the first antidepressant and almost 50% subsequently relapse.

"Our work is cut out for is," Dr. Jonathan E. Alpert said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Factors associated with nonremission in major depressive disorder (MDD) include a history of chronic or recurrent depression; anxious, melancholic, or psychotic features; psychiatric or general medical comorbidity; minority ethnic/racial status; and lower quality of life and function prior to treatment. When a patient fails to remit, Dr. Alpert recommends a checklist of four basic factors to consider before rushing to the next medication or to the next form of psychotherapy.

"It’s important to step back for a moment and recheck what you think you know about that particular patient," said Dr. Alpert, associate chief of psychiatry for clinical services at Massachusetts General Hospital (MGH), Boston.

One factor on the checklist is adherence. Some patients – and sometimes their significant others – are ambivalent about pursuing depression treatment, which could interfere with adherence. "Other patients are confused about the instructions we’ve given them, or they might have cognitive problems that make it difficult for them to stick with the complex regimens we might be prescribing," he explained. "Access to health care and cost of medications can also play a role."

Another factor on the checklist is to be sure of your primary diagnosis. Is it MDD, or is it MDD with psychotic features? Is it bipolar disorder or mood dysregulation in the context of personality disorder? "It can be difficult to separate these," he said.

A third factor on the checklist is to assess for comorbidities such as substance abuse; obsessive-compulsive disorder; posttraumatic stress disorder; and general medical conditions that can mimic MDD symptoms, such as hypothyroidism.

A fourth factor to consider is drug-drug interactions and pharmacokinetics. For example, rapid/fast metabolizers and smokers "may require high doses of medication to achieve a benefit," said Dr. Alpert, who also serves as associate director of the MGH Depression Clinical and Research Program.

After you’ve run through the checklist and you’re confident that a patient has MDD, consider switch, augmentation, and combination strategies to improve response. "Typically we switch from one antidepressant to another in the setting of nonresponse or intolerance to the first agent," he said. "It’s been difficult to see differential effects of different classes of antidepressants. There are some limited data that show the inferiority of tricyclic antidepressants compared with monoamine oxidase inhibitors in patients with atypical features – the kind of depression characterized by pronounced rejection, sensitivity, and mood reactivity."

Dr. Alpert noted that some data support selective norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants as being superior to selective serotonin reuptake inhibitors (SSRIs) in MDD complicated by comorbid pain syndrome such as fibromyalgia. "Bupropion is clearly better than SSRIs and SNRIs for MDD with antidepressant-related sexual dysfunction, nicotine dependence, or ADHD," he said. "Consider broad-spectrum agents such as clomipramine in the setting of persistent refractory depression."

For patients who have only achieved partial response to an antidepressant, consider augmenting with a nonantidepressant such as atypical antipsychotics; dopamine agonists and psychostimulants; lithium; thyroid (T3); buspirone; and natural agents such as l-methylfolate, S-adenosyl-l-methionine (SAMe), creatinine, and omega-3 fatty acids.

Another strategy is to combine antidepressants together in the context of partial response and tolerability of the initial agent. Examples of combination therapy include an SSRI or SNRI plus bupropion, or an SNRI plus mirtazapine.

As for future directions in the psychopharmacology of depression, important recent targets in drug development include mitochondrial function, inflammation processes, and neurogenesis. "Non-monoaminergic mechanisms including kappa and NK1 antagonists and a range of glutamatergic agents are a continued and growing focus," Dr. Alpert concluded. "Rapid-acting antidepressants such as intravenous ketamine and scopolamine promise novel strategies for jump-starting treatment."

Dr. Alpert said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com