Wednesday, July 29, 2009

Low-dose atypical antipsychotics for treating non-psychotic anxiety or mood symptoms

Atypical antipsychotics are frequently prescribed to treat symptoms of anxiety and depression. They can be used in the treatment of generalized anxiety, panic disorder, OCD, major depressive disorder, PTSD, bipolar disorder, personality disorders, etc. At this point, such use could be considered "off-label", since the primary use of antipsychotics is treating schizophrenia or major mood disorders with psychotic features.

But there is an expanding evidence base showing that atypicals can be useful in "off-label" situations. Here is a brief review of some of the studies:
{this is a good recent study comparing low-dose risperidone -- about 0.5 mg -- with paroxetine, for treating panic disorder over 8 weeks. The risperidone group did well, with equal or better symptom relief, also possibly faster onset. But 8 weeks is very brief -- it would be important to look at results over a year or more, and to assess the possibility of withdrawal or rebound symptoms if the medication is stopped. Also is would be important to determine if the medication is synergistic with psychological therapies, or whether it could undermine psychological therapy (there is some evidence that benzodiazepines may undermine the effectiveness of psychological therapies) }
{an open study from 2006 showing significant improvements in anxiety when low doses of risperidone, of about 1 mg, were added to an antidepressant, over an 8 week trial}
{this 2008 study shows significant improvement in generalized anxiety with 12 weeks of adjunctive quetiapine. It was not "low-dose" though -- the average dose was almost 400 mg per day. There is potential bias in this study due to conflict-of-interest, also there was no adjunctive placebo group}
{in this 2006 study. patients with a borderline personality diagnosis were given quetiapine 200-400 mg daily, for a 12 week trial. As I look at the results in the article itself, I see that the most substantial improvement was in anxiety symptoms, without much change in other symptom areas. The authors state that patients with prominent impulsive or aggressive symptoms responded best}
{in this large 2006 study (the BOLDER II study), quetiapine alone was used to treat bipolar depression. Doses were 300 mg/d, 600 mg/d, or placebo. There was significant, clinically relevant improvement in the quetiapine groups, with the 300 mg group doing best. Improvements were in anxiety symptoms, depressive symptoms, suicidal ideation, sleep, and overall quality of life.}

Here's a reference to a lengthy and detailed report from the FDA about quetiapine safety when used to treat depression or anxiety:

In summary, I support the use of atypical antipsychotics as adjuncts for treating various symptoms including anxiety, irritability, etc. But as with any treatment (or non-treatment), there needs to be a close review of benefits vs. risks. The risks of using antipsychotics for treating anxiety are probably underestimated, because the existing studies are of such short duration. Also the benefits over long-term use are not clearly established either.

For risk data, it would be relevant to look at groups who have taken antipsychotics for long periods of time. In this group, antipsychotic use is associated with reduced mortality rates (see the following 2009 reference from Lancet:, which looks at a cohort of over 60 000 schizophrenic patients, showing reduced mortality rates in those who took antipsychotics long-term, compared to those taking shorter courses of antipsychotics, or none at all--the mortality rate was most dramatically reduced in those taking clozapine. Overall, the life expectancy of schizophrenic patients was shown to have increased over a 10-year period, alongside substantial increases in atypical antipsychotic use)

It is certainly clear to me that all other treatments for anxiety (especially behavioural therapies, lifestyle changes, other forms of psychotherapy) be optimized, in an individualized way, before medication adjuncts be used.

But I recognize that suffering from anxiety or other psychiatric symptoms can be severely debilitating, can delay or obstruct progress in relationships, work, school, quality of life, etc. The risks of non-treatment should be taken very seriously. My view of the existing evidence is that adjunctive low-dose antipsychotics can have significant benefits, which can outweigh risks for many patients with non-psychotic disorders. As with any medical treatment decision, it is important for you and your physician to regularly monitor or discuss risks vs. benefits of ongoing medication therapies, and be open to discuss new evidence which is coming out.


Anonymous said...

Thank you very much for your helpful entry on low-dose antipsychotics. It is clear from the studies you noted that these medications can be useful adjunctives to SSRIs for anxiety/mood problems, or useful as the sole medicine for treatment of serious illnesses such as schizophrenia.

Thank you for citing relevant research.

I have yet to find quality studies on side-effects of low-dose antipsychotics when taken long-term. In particular I like to know how frequent and pervasive are extrapyramidal symptoms, weight gain/diabetes, etc.

Surely in most cases of schizophrenia the balance of benefits vs. side-effects leans in the direction of use. However, in anxiety/mood illnesses, a clear picture of drug's effects on the body must be evaluated. Hence switching to another SSRI instead may be more beneficial in the long term given the side-effects such as dysphoria, diabetes, extrapyramidal symptom, not to mention the rare but dangerious side effects associated with certain antipsychotics like Clozapine.

My best.

Long time reader.

GK said...

You're right.

I can think of examples, though, of cases of depression or anxiety where SSRI treatments (sometimes several different trials) don't help much. Or, the side-effects of the antidepressant are worse than the side-effects of a low-dose antipsychotic. Sometimes the combination of SSRI+antipsychotic helps reduce the side effects of both.

Also, in many individual cases of mood or anxiety disorder, I have concerns about subtle "bipolarity": in some of these cases I have seen people develop agitated, psychotic, or manic states while on antidepressants alone. In these cases, I find that low-dose atypicals are much safer.

Conversely, the side-effects of non-treatment of various anxiety or depressive states could at times include dysphoria or diabetes (via behavioural withdrawal or unhealthy diet). I would not expect movement disorder as a side-effect of non-treatment of anxiety though. Mind you, the incidence of EPS or tardive movement disorders due to atypical antipsychotics is low, even with chronic, high doses in schizophrenia treatment.

But given the lack of clear, specific long-term evidence, the standard of practice has to be reserved about using atypical antipsychotics for anxiety routinely, especially over the longer term.