Can Antipsychotics help Depression?

[Short take: Not first-line for most people with depression. Newer antipsychotics help 1 out of 10 takers achieve remission. They have a number of potentially serious side effects.]

Major depression affects between 10% and 20% of people in the US at some point in their lifetime. Though there are many antidepressants available, from a number of different classes of medication, the majority of people that take an antidepressant do not get a complete response to the first, or even second medication they take. As each new treatment is tried, and fails, the likelihood of a good response decreases. As a result, many with depression are left with no response or only a partial response  and are unsure what to do next. Psychotherapy, particularly the evidence based forms (such s Cognitive Behavior Therapy (CBT), Commitment and Acceptance Therapy (ACT), Interpersonal Therapy (IPT), and probably mindfulness based therapies founded on CBT), are successful as first-line treatments and good alternatives to medication. They should also be tried in treatment resistant depression. Finding a well-trained therapist can sometimes be difficult, though perhaps no more difficult than finding someone up to date in psycho-pharmacology. Both medications and psychotherapies have benefits and risks.

In recent years, in an effort to expand the market for their medications, pharmaceutical companies have funded a number of large, well-done studies to assess the usefulness of adding the newer antipsychotics to antidepressants for treating major depression. The FDA has approved 2 of these medications, quetiapine and aripiprazole, for major depression that is not responding adequately to antidepressants (olanzapine has been approved in a fixed-dose combination with fluoxetine, but not as an add-on to any antidepressant). Unlike T3 and Lithium, which have been studied primarily with older antidepressants, the second generation* antipsychotics have been studied as an add-on to SSRI’s (sertaline, fluoxetine, paroxetine, citalopram, escitalopram) and SNRI’s (venlafaxine, duloxetine).

Do the atypical* anti-psychotics help decrease symptoms of depression when added to an antidepressant? Given the size of the studies and their statistical power, it is clear that they do help. When compared to adding a placebo, quetiapine and aripiprazole help more people respond (meaning that the symptoms decrease by at least 50%) and achieve remission. And the experts all agree, remission is what counts. When a person is in remission from depression they are back to normal, or at least almost completely back to their non-depressed baseline. And this is very important, since even mild residual symptoms of depression increase the risk of depression coming back, and each episode of depression increases the risk of another episode and the risk of entering a state of chronic depression.

How well do they work? Simply put, not very well, particularly given the potential side effect burden associated with them. The NNT (number needed to treat) is 10. This means that compared to placebo, the addition of an SGA to an antidepressant will help 1 in 10 people achieve remission. NNT is one of simplest ways of looking at the clinical meaningfulness of a treatment. Studies frequently report results that are statistically significant, but statistically significant is not the same as clinically meaningful. A large study may have a very strong finding in a statistical sense, but the treatment may not help very many people, or not help them very much. An NNT of 2 or 3 indicates a very useful treatment. NNT’s of 4-7 are helpful.

Partial or non-response to antidepressants is a big problem, and reasonable and effective treatment options are badly needed. The SGA’s are effective, but helping only 1 in 10 is on the borderline of usefulness. An NNT of 10 is considered marginal, and though a completely benign treatment might be looked at favorably, these medications are not free of side effects.

What are the side effects of the atypical antipsychotics? The side effects vary somewhat between medications, but can be substantial. Aripiprazole (Abilify) is less likely to cause sedation, weight gain, increased triglycerides and increased blood sugar than quetiapine (Seroquel XR), but more likely to cause restlessness and inability to stay still (akathisia). Long-term side effects have not been systematically studied for either of them, and it is unclear how much risk of tardive dyskinesia (abnormal muscle movements that can be permanent) is associated with their use. Since these medications can cause increased weight, blood sugar and lipids, they likely put people at risk of developing diabetes and cardiovascular disease.

Should SGA’s be used in treating depression? Yes, they definitely have a role. Following the recommendations of Connolly and Thase as stated in Management Of Treatment-Resistant Major Psychiatric Disorders, SGA’s should be considered as first-line add-on options when the antidepressant is well-tolerated enough to be continued, and there is some urgency in decreasing symptoms. The evidence supports them as having a fairly rapid effect, with some improvement seen within 1-2 weeks. The other situation in which they are first-line and clearly indicated is when psychotic symptoms are present along with depression.

To sum up: Lack of a complete response to an antidepressant is the norm. There are many options, but not a lot of information to guide the selection of treatments, or the best sequence to use them in. If a person has taken just one antidepressant and not had a good response, and the situation is not urgent, then adding an antipsychotic is not likely to be the next step. On the other hand, if someone has had several antidepressants, and their depression is not getting better, then an antipsychotic could be a very helpful option. Unanswered is the question of how long the antipsychotic should be taken, and monitoring of side effects is important, particularly weight gain, metabolic and muscular ones.

* Several terms are used in referring to a group of medications that were initially used in treating schizophrenia, and which now are commonly used in treating Bipolar Disorder, Major Depression, and other conditions; these include atypical antipsychotics, second-generation antipsychotics (SGA’s), and newer antipsychotics. This is to distinguish them from the older, or typical, antipsychotics such as Thorazine, Haldol, Stelazine and Prolixin. Though the SGA’s all block dopamine, and hence share the ability to decrease psychotic symptoms, there is a lot of variability among them, and antipsychotic may not be a very good term for them. They are effective at treating manic episodes, preventing recurrence of manic episodes and decreasing depressive symptoms, among other things.

References for Treatment Resistant Depression

1) Connolly,K.R., Thase,M.E. (2012) Systematic Approach to Treatment-Resistant Depression: Psychopharmacology and Psychotherapy. In C.B.Nemereoff, Management Of Treatment-Resistant Major Psychiatric Disorders(pp. 23-48). New York: Oxford University Press.

2)Phillip,S.P.,Pharmacologic Approaches to Treatment Resistant Depression:A re-examination for the Modern Era. Expert Opin Pharmacother. 2010 April;11(5):709-722. doi:1517/1465651003614781.

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