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Thinking Creatively About Treatment-Resistant Depression
J. Alexander Bodkin, MD
Director of the Clinical Psychopharmacology Research Program at McLean Hospital in Belmont, MA; assistant professor of psychiatry at Harvard Medical School
Dr. Bodkin has disclosed that he has been a principal investigator in a study of brexpiprazole. Dr. Carlat has reviewed his interview and has found no evidence of bias in this educational activity.
TCPR: The term “treatment-resistant depression” is sort of thrown around a bit. I’m sure that there are various formal or informal definitions of it, but how do you think about it?
Dr. Bodkin: The formal definition basically requires 2 failures of distinctly different antidepressants at robust doses for adequate duration. But personally, I think it is important to look at the type of depression before you start talking about whether or not it is treatment resistant. In other words, not just does your patient meet the criteria for depression, but what does the depression look like?
TCPR: How do you think about depression?
Dr. Bodkin: In my opinion, depressive illness is a final common pathway for a number of different brain problems. There are a whole range of ways to have 5 out of the 9 DSM symptoms. Some of them are highly genetic; some of them are less genetic; some of them seem not to be genetic at all; some of them seem to have to do with literal brain injury; some of them have to do with—shall we say—psychological injury, and many of these versions of depression overlap.
TCPR: What are some of the useful large categories of types of depression?
Dr. Bodkin: I ask myself the following questions as I’m evaluating and treating patients:
Does this patient have a bipolar illness? If so, that calls, at least to some extent, for a significantly distinct treatment approach.
Does this patient have melancholia? This is a clear acute-onset medical-looking depressive illness with loss of capacity for any emotional experience at all, reward or otherwise. We see this a relatively small percentage of the time in its pure form, but melancholia is an illness that has one set of best interventions.
Does this patient have a major depression with atypical features? What I mean by this is the capacity to be brought back to an emotionally normal or an undepressed state, at least briefly, by things in life going the right way. A patient might have a wonderful couple of days until a disappointment happens or a perceived affront, rejection, or failure. This is called mood reactivity and it is a requirement as far as a DSM diagnosis. About 15% of patients have atypical features (Seemüller F et al, J Affect Disord 2008;108(3):271–278).
TCPR: What’s the best treatment approach for depression with atypical features?
Dr. Bodkin: These are the patients who also tend to respond better to the monoamine oxidase inhibitors (MAOIs). But these medications are rarely used. In fact, one of the reasons I think we have this troublesome population of so-called treatment-resistant depressives is because by and large, nobody gets tried on MAOIs. And you can’t really be said to be treatment resistant until you’ve been on the standard available treatments.
TCPR: Can you expand upon this?
Dr. Bodkin: Sure. I think that the enormous overgrowth of the treatment resistant category has to do with the hesitancy in using the MAO inhibitors or tricyclics due to their side effects. Tricyclics, in particular, are great uptake inhibitors that cover not only serotonin and norepinephrine, but they are also to some extent antiadrenergic and anticholinergic. We are learning more about how tricyclics may have downstream effects on both the opioid (Onali J et al, Pharmacol Exp Ther 2010;332(1):255–265) and dopamine (Menza M et al, Neurology 2009;72(10):886–892) pathways. The pure serotonin uptake-inhibiting drugs really only take one feature of these wonderful old dirty drugs and therefore are less effective for certain types of depression. In the STAR*D trial, only 28% of people adequately treated with an SSRI achieved remission (Trivedi MH et al, Am J Psychiatry 2006;163(1):28–40). That’s a low rate of remission, and yet SSRIs remain the standard of care. My colleague and I did a review on the extensive published evidence for markedly greater efficacy of the TCAs relative to SSRIs (Bodkin JA and Goren JL, Psychiatric Times 2007; 24(11):20–32). The 2 most famous studies that we looked at were the Danish comparisons of clomipramine with citalopram (Psychopharmacology (Berl) 1986;90(1):131–138), and with paroxetine (J Affect Disord 1990;18(4):289–299). In our 2007 review, we also reviewed published evidence of the superior efficacy of MAOIs compared to SSRIs in 2 subgroups of depression patients: those with atypical features and those showing treatment resistance.
TCPR: Of course SSRIs are quite safe, which may be a reason why standard practice is to start with them.
Dr. Bodkin: This is a standard practice, and I do not think that it is sound. Multiple SSRI trials can be a terrible waste of valuable time for patients who are suffering. In general, the SSRIs are most effective in anxiety disorders. I choose SSRIs first for patients with somatic symptoms of panic, or sometimes for patients with a more generalized anxiety, people who are clearly stewing, worrying, ruminating, fretting, and anticipating problems. SSRIs are somewhat less effective in depressive disorders with prominent anxiety. Now, in patients with psychomotor retardation, deep apathy, anergia, lassitude, loss of drive, if you can ameliorate the anxiety component, these symptoms will get somewhat better in some patients, but you will really not achieve remission.
TCPR: So what do you do in this case?
Dr. Bodkin: If there is a partial response, generally the typical next step is to try to enhance that rather than stop the drug and begin with something else. If the prominent residual symptoms has to do with, let’s say, insomnia or persistent loss of appetite, then you would add something that might ameliorate that, for example, mirtazapine. But if the problem is actually most prominently anergia, bupropion is very helpful (Bodkin J et al, J Clin Psychiatry 1997;58(4):137–145). Similarly, bupropion can help patients with a loss of sexual drive, whether from the depression itself or from an SSRI. Atypical antipsychotics have a place, and they can be remarkably helpful in treating what I call the “turbulent distress” experience, which can be anxiety, or anger, or both. Published evidence in this realm has focused primarily on quetiapine, which has been shown robustly effective in generalized anxiety disorder, a condition featuring “turbulent distress,” both as an SSRI adjunct (Simon NM et al, Psychopharmacology (Berl) 2008;197(4);675–681) and as monotherapy. Of course, people often gain weight on atypical antidepressants; they can develop Type 2 diabetes and experience other problems, so these drugs should not be prescribed without caution. But used appropriately they are often a sensible component of treatment.
TCPR: What about patients who may be in need of a more stimulant-like medicine?
Dr. Bodkin: You can always try psychostimulants like amphetamine or methylphenidate, but doctors are often uncomfortable prescribing them, and patients can be uncomfortable receiving them. There are some alternatives. For patients whose depression is characterized by lethargy, apathy, dragging of the feet, etc. there is the partial agonist strategy of aripiprazole (Abilify) or brexpiprazole (Rexulti). In addition, sometimes pramipexole (Mirapex) is remarkably helpful if you have a patient who ideally should have been started on an MAOI but instead is taking an SNRI and is still lethargic. Pramipexole is a direct dopamine agonist used for Parkinson’s and for restless leg syndrome. It’s sort of a stimulant-like drug without the stimulant-like problems of potential abuse and tolerance.
TCPR: What sort of side effects should I be warning my patient about when I’m using pramipexole?
Dr. Bodkin: Both hypotension and nausea are potential problems, and sometimes people paradoxically get quite sedated. In older patients, especially those who have some degree of dementia, there can be a side effect of impulsivity or excessive initiative. It’s also inconvenient. It’s a t.i.d. drug, occasionally a b.i.d. drug, so dosage has to be titrated with great care.
TCPR: So there are a lot of options out there. It can get confusing. Can you help us with our decision-making?
Dr. Bodkin: I often look at symptoms in terms of a very simple bifurcation: the distress factor vs. the drive factor (Watson D and Tellegen AJ, Pers and Soc Psychol 1988;54(6):1063–1070). The distress factor has to do with anxiety, irritability, rage, panic, etc. These symptoms call for anxiolytic medications—SSRIs, benzodiazepines, many of the atypical antipsychotics. The drive factor has to do with initiative, interest, and energy level. If there is too much of those, we call it hypomania, but patients need at least an average amount of initiative, interest, and gratification from the pursuit of things that are interesting. Diminished drive leads me to reach for dopaminergic interventions, and to a lesser extent to noradrenergic interventions. As we discussed, these include stimulants, bupropion, aripiprazole, pramipexole, but also MAOIs, which among other things inhibit metabolism of dopamine.
TCPR: That is very interesting. Thank you for your time, Dr. Bodkin.
General PsychiatryDr. Bodkin: The formal definition basically requires 2 failures of distinctly different antidepressants at robust doses for adequate duration. But personally, I think it is important to look at the type of depression before you start talking about whether or not it is treatment resistant. In other words, not just does your patient meet the criteria for depression, but what does the depression look like?
TCPR: How do you think about depression?
Dr. Bodkin: In my opinion, depressive illness is a final common pathway for a number of different brain problems. There are a whole range of ways to have 5 out of the 9 DSM symptoms. Some of them are highly genetic; some of them are less genetic; some of them seem not to be genetic at all; some of them seem to have to do with literal brain injury; some of them have to do with—shall we say—psychological injury, and many of these versions of depression overlap.
TCPR: What are some of the useful large categories of types of depression?
Dr. Bodkin: I ask myself the following questions as I’m evaluating and treating patients:
Does this patient have a bipolar illness? If so, that calls, at least to some extent, for a significantly distinct treatment approach.
Does this patient have melancholia? This is a clear acute-onset medical-looking depressive illness with loss of capacity for any emotional experience at all, reward or otherwise. We see this a relatively small percentage of the time in its pure form, but melancholia is an illness that has one set of best interventions.
Does this patient have a major depression with atypical features? What I mean by this is the capacity to be brought back to an emotionally normal or an undepressed state, at least briefly, by things in life going the right way. A patient might have a wonderful couple of days until a disappointment happens or a perceived affront, rejection, or failure. This is called mood reactivity and it is a requirement as far as a DSM diagnosis. About 15% of patients have atypical features (Seemüller F et al, J Affect Disord 2008;108(3):271–278).
TCPR: What’s the best treatment approach for depression with atypical features?
Dr. Bodkin: These are the patients who also tend to respond better to the monoamine oxidase inhibitors (MAOIs). But these medications are rarely used. In fact, one of the reasons I think we have this troublesome population of so-called treatment-resistant depressives is because by and large, nobody gets tried on MAOIs. And you can’t really be said to be treatment resistant until you’ve been on the standard available treatments.
TCPR: Can you expand upon this?
Dr. Bodkin: Sure. I think that the enormous overgrowth of the treatment resistant category has to do with the hesitancy in using the MAO inhibitors or tricyclics due to their side effects. Tricyclics, in particular, are great uptake inhibitors that cover not only serotonin and norepinephrine, but they are also to some extent antiadrenergic and anticholinergic. We are learning more about how tricyclics may have downstream effects on both the opioid (Onali J et al, Pharmacol Exp Ther 2010;332(1):255–265) and dopamine (Menza M et al, Neurology 2009;72(10):886–892) pathways. The pure serotonin uptake-inhibiting drugs really only take one feature of these wonderful old dirty drugs and therefore are less effective for certain types of depression. In the STAR*D trial, only 28% of people adequately treated with an SSRI achieved remission (Trivedi MH et al, Am J Psychiatry 2006;163(1):28–40). That’s a low rate of remission, and yet SSRIs remain the standard of care. My colleague and I did a review on the extensive published evidence for markedly greater efficacy of the TCAs relative to SSRIs (Bodkin JA and Goren JL, Psychiatric Times 2007; 24(11):20–32). The 2 most famous studies that we looked at were the Danish comparisons of clomipramine with citalopram (Psychopharmacology (Berl) 1986;90(1):131–138), and with paroxetine (J Affect Disord 1990;18(4):289–299). In our 2007 review, we also reviewed published evidence of the superior efficacy of MAOIs compared to SSRIs in 2 subgroups of depression patients: those with atypical features and those showing treatment resistance.
TCPR: Of course SSRIs are quite safe, which may be a reason why standard practice is to start with them.
Dr. Bodkin: This is a standard practice, and I do not think that it is sound. Multiple SSRI trials can be a terrible waste of valuable time for patients who are suffering. In general, the SSRIs are most effective in anxiety disorders. I choose SSRIs first for patients with somatic symptoms of panic, or sometimes for patients with a more generalized anxiety, people who are clearly stewing, worrying, ruminating, fretting, and anticipating problems. SSRIs are somewhat less effective in depressive disorders with prominent anxiety. Now, in patients with psychomotor retardation, deep apathy, anergia, lassitude, loss of drive, if you can ameliorate the anxiety component, these symptoms will get somewhat better in some patients, but you will really not achieve remission.
TCPR: So what do you do in this case?
Dr. Bodkin: If there is a partial response, generally the typical next step is to try to enhance that rather than stop the drug and begin with something else. If the prominent residual symptoms has to do with, let’s say, insomnia or persistent loss of appetite, then you would add something that might ameliorate that, for example, mirtazapine. But if the problem is actually most prominently anergia, bupropion is very helpful (Bodkin J et al, J Clin Psychiatry 1997;58(4):137–145). Similarly, bupropion can help patients with a loss of sexual drive, whether from the depression itself or from an SSRI. Atypical antipsychotics have a place, and they can be remarkably helpful in treating what I call the “turbulent distress” experience, which can be anxiety, or anger, or both. Published evidence in this realm has focused primarily on quetiapine, which has been shown robustly effective in generalized anxiety disorder, a condition featuring “turbulent distress,” both as an SSRI adjunct (Simon NM et al, Psychopharmacology (Berl) 2008;197(4);675–681) and as monotherapy. Of course, people often gain weight on atypical antidepressants; they can develop Type 2 diabetes and experience other problems, so these drugs should not be prescribed without caution. But used appropriately they are often a sensible component of treatment.
TCPR: What about patients who may be in need of a more stimulant-like medicine?
Dr. Bodkin: You can always try psychostimulants like amphetamine or methylphenidate, but doctors are often uncomfortable prescribing them, and patients can be uncomfortable receiving them. There are some alternatives. For patients whose depression is characterized by lethargy, apathy, dragging of the feet, etc. there is the partial agonist strategy of aripiprazole (Abilify) or brexpiprazole (Rexulti). In addition, sometimes pramipexole (Mirapex) is remarkably helpful if you have a patient who ideally should have been started on an MAOI but instead is taking an SNRI and is still lethargic. Pramipexole is a direct dopamine agonist used for Parkinson’s and for restless leg syndrome. It’s sort of a stimulant-like drug without the stimulant-like problems of potential abuse and tolerance.
TCPR: What sort of side effects should I be warning my patient about when I’m using pramipexole?
Dr. Bodkin: Both hypotension and nausea are potential problems, and sometimes people paradoxically get quite sedated. In older patients, especially those who have some degree of dementia, there can be a side effect of impulsivity or excessive initiative. It’s also inconvenient. It’s a t.i.d. drug, occasionally a b.i.d. drug, so dosage has to be titrated with great care.
TCPR: So there are a lot of options out there. It can get confusing. Can you help us with our decision-making?
Dr. Bodkin: I often look at symptoms in terms of a very simple bifurcation: the distress factor vs. the drive factor (Watson D and Tellegen AJ, Pers and Soc Psychol 1988;54(6):1063–1070). The distress factor has to do with anxiety, irritability, rage, panic, etc. These symptoms call for anxiolytic medications—SSRIs, benzodiazepines, many of the atypical antipsychotics. The drive factor has to do with initiative, interest, and energy level. If there is too much of those, we call it hypomania, but patients need at least an average amount of initiative, interest, and gratification from the pursuit of things that are interesting. Diminished drive leads me to reach for dopaminergic interventions, and to a lesser extent to noradrenergic interventions. As we discussed, these include stimulants, bupropion, aripiprazole, pramipexole, but also MAOIs, which among other things inhibit metabolism of dopamine.
TCPR: That is very interesting. Thank you for your time, Dr. Bodkin.
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