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Issue 48, Apr 2016
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Which antipsychotics are best for “treatment-resistant” schizophrenia?

Samara et al. Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis. JAMA Psychiatry. 2016 Feb 3. [Epub ahead of print] PubMed PMID: 26842482.

Many persons with schizophrenia fail to respond to initial trials of antipsychotic treatment. This can have very serious consequences for the patient and others.

It has long been recognized that clozapine may work when other antipsychotics have failed to work. But it has many important adverse effects like agranulocytosis, weight gain, etc.

Also, many new studies of second-generation antipsychotics in “treatment-resistant” schizophrenia have been published. These needed to be combined in a meta-analysis to determine which antipsychotics work better than others.

This study received a lot of press. I received several emails from many websites. In each case the title emphasized that the superiority of clozapine has been challenged. This has confused clinicians and I hope that this commentary clarifies the issue.


This study used a meta-analysis to integrate data from all the randomized controlled clinical trials on the use of antipsychotics for “treatment-resistant” schizophrenia.


A comprehensive and systematic search of the literature was done, including unpublished studies, which is good.

Both published and unpublished studies were included, which is also good.

Studies that compared any antipsychotic to another antipsychotic or to placebo in persons with “treatment-resistant schizophrenia” were included.

Because there is no standard, widely accepted definition of “treatment-resistant schizophrenia,” the authors accepted whatever definition was used by each study.

Both single-blind and double-blind studies were included. Single-blind means that only the patient was blinded to what medication s/he was receiving while the treating clinician was not blinded.

Suitable studies were available for only some antipsychotics: chlorpromazine, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, sertindole (ignored in the commentary below because it is not available in the US), ziprasidone.

As is usual and appropriate, at least two independent reviewers selected the studies and extracted the data.

Forty randomized controlled trials with 5172 patients were included in the meta-analysis.


The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. In terms of overall efficacy:

  1. Olanzapine was more efficacious than quetiapine and haloperidol. By how much? The standardized mean difference (same as effect size) was 0.29 for both comparisons. A standardized mean difference of 0.2 is considered to be a small effect size, 0.5 is moderate, and 0.8 is large. So this superiority of olanzapine was relatively small.
  2. Clozapine was more efficacious than haloperidol. By how much? Standardized mean difference 0.22.

That’s it. Two comparisons that showed a small advantage of one antipsychotic. For all other comparisons, the pairs of antipsychotics compared were not different in their efficacy for “treatment-resistant” schizophrenia.

Next, rather than overall efficacy, the meta-analysis also looked specifically at improvement in positive symptoms.

  1. Risperidone was more efficacious than quetiapine (standardized mean difference 0.43)
  2. Clozapine was more efficacious than quetiapine (standardized mean difference 0.40)
  3. Olanzapine was more efficacious than quetiapine (standardized mean difference 0.33)
  4. Risperidone was more efficacious than haloperidol (standardized mean difference 0.29)
  5. Clozapine was more efficacious than haloperidol (standardized mean difference 0.27)

So, risperidone, olanzapine, and clozapine stood out as more efficacious while quetiapine was the antipsychotic that stood out as less efficacious.

What about negative symptoms? Olanzapine was more efficacious than clozapine (very small effect size, though), risperidone, haloperidol, and chlorpromazine.

Bottomline: overall, a general pattern of superiority for olanzapine, clozapine, and risperidone was seen, though these results were not consistent and effect sizes were usually small.

Relatively few studies in “treatment-resistant” schizophrenia were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. Thus, many antipsychotics (e.g., aripiprazole) were not included in this meta-analysis.


There is not enough available data regarding which antipsychotic is more efficacious for patients with “treatment-resistant” schizophrenia.

A major problem with this meta-analysis is that in recent years, the definition of “treatment-resistant” has been softer. So, the studies that are grouped together are actually quite different from each other.

The most surprising and confusing finding of this meta-analysis was that clozapine did not appear to be significantly more efficacious than most other antipsychotics. That is, blinded randomized controlled clinical trials don’t provide clear evidence that clozapine is more efficacious than other second-generation antipsychotics. But see more on this below.

The authors discussed possible reasons for this failure to find clozapine to be more efficacious than other second-generation antipsychotics.

  1. The mean dose of clozapine used in studies comparing clozapine to a second-generation antipsychotic (392 mg/day) was significantly lower than what is clinically recommended and what was used in older studies in which clozapine was compared to first-generation antipsychotics. 
  2. In recent years, we have realized that adequate plasma levels are important for clozapine. But most studies comparing it to a second-generation antipsychotic did not titrate the dose based on plasma levels. Since the dose was low, I suspect that the plasma levels would have been too low for many patients.
  3. Clozapine may be most helpful for illness that is more “treatment-resistant,” but those patients are hard to enroll in blinded clinical trials. This may be an alternative explanation for why clozapine was found to be superior to other antipsychotics in unblinded studies but not in blinded studies. In the important CATIE trial too, the clozapine arm was not blinded. 
  4. Lastly, in recent years, the commercialization of clinical trials seems to have led to enrollment of patients who have high placebo response, making it harder to demonstrate any superiority of a particular antipsychotic.
Clinical Commentary

In a commentary on this paper, Kane and Correll (2016) rightly lament the fact that our field has still not resolved the issue of the efficacy of clozapine for “treatment-resistant” schizophrenia more than 25 years after the publication of the paper by Kane et al. (1988) that showed the greater efficacy of clozapine and led to the introduction of clozapine into clinical practice.

Due to the numerous potential limitations related to clozapine that are discussed above, I think that clinicians should continue to view clozapine as the first choice medication for persons with schizophrenia that is highly treatment-refractory.

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Is combining medication and psychotherapy better for major depression?

Karyotaki et al. Combining pharmacotherapy and psychotherapy or monotherapy for major depression? A meta-analysis on the long-term effects. J Affect Disord. 2016 Apr;194:144-52. PubMed PMID: 26826534.


In short-term treatment of major depression, antidepressant medication and psychotherapy are equally efficacious, but combined treatment with both leads to greater improvement than either one alone.

It is easy to say, as I commonly hear, that all patients with major depressive disorder should get combination treatment with medication and psychotherapy. But this advice, though well meaning, is not realistic to implement.


Why not? Psychotherapy is expensive and well-trained psychotherapists are not readily available to many patients. On the other hand, it is known that the majority of patients do not take their antidepressant medication after the first few months. Also, a considerable number of patients suffer from adverse effects that either lead to discontinuation of treatment or, if the antidepressant is continued despite adverse effects, to impairment in quality of life.


Therefore, the comparison of medication to psychotherapy and of both these treatment options to combination treatment remains an important clinical question. This would allow us to more confidently say for particular patients whether psychotherapy alone is fine, or that antidepressant medication is essential, or that combination therapy is strongly advised.


There is an important detail in looking at studies in which one of the treatments is psychotherapy. Because onset of effect may be slower with psychotherapy than with medication, it is relevant to look at the comparisons not only at 6 or 8 weeks, but also after a few months of treatment.


This study was a meta-analysis that aimed to compare combined medication and psychotherapy to either medication or psychotherapy alone in adults with major depression after at least six months of treatment.

The authors noted that their team was well balanced, they have in the past published meta-analyses on both medication and psychotherapy, and their team does not in advance prefer one type of treatment over the other.


A systematic search of the literature was done to find relevant studies.

The meta-analysis included 23 randomized controlled trials in which a total of 2184 patients participated.

The types of psychotherapy provided in these clinical trials were: cognitive behavior therapy, interpersonal psychotherapy, problem solving therapy, psychodynamic supportive therapy, and social skills training. But most of the studies used cognitive behavior therapy.

The antidepressant medications used in these clinical trials were tricyclic antidepressants and SSRIs.


After at least six months of treatment, combined treatment with medication plus psychotherapy was better than antidepressants alone (odds ratio 2.9).

However, after at least 6 months of treatment, combined treatment was not better than psychotherapy alone.

For studies of the maintenance phase, combined treatment with medication plus psychotherapy was better than antidepressants alone (odds ratio 1.6).


In persons with major depression, combined treatment with medication plus psychotherapy leads to superior results compared to antidepressants alone.

But after 6 months or more, psychotherapy alone is as efficacious as combined treatment with medication plus psychotherapy.

The results of this meta-analysis probably apply only to cognitive behavior therapy that was used in most of the studies included.

Clinical Commentary

This meta-analysis argues for the importance of psychotherapy, either alone or in combination. For persons with major depressive disorder, antidepressant alone is probably suboptimal treatment for many or most patients.

In another meta-analysis of combination treatments with an antidepressant and psychotherapy (Cuijpers et al., 2014. PubMed PMID: 24497254), it was found that combination treatment was more efficacious than medication alone not only in major depression but also in panic disorder and obsessive compulsive disorder. The authors concluded that, “Monotherapy with psychotropic medication may not constitute optimal care for common mental disorders.”

It remains important to identify subgroups of patients are most likely to benefit from one treatment or another. In the studies included in this meta-analysis by Karyotaki et al. (2016), no distinction was made between different severities of depression. The meta-analysis by Cuijpers et al. (2014) found that combination treatment was superior to treatment with medication alone across different severities of depression. What about psychotherapy alone? In persons with severe major depression, it is recommended based on data from other research, that antidepressant should be added to the psychotherapy. 

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An alternative to statins for antipsychotic-induced dyslipidemia

Wu et al. Metformin treatment of antipsychotic-induced dyslipidemia: an analysis of two randomized, placebo-controlled trials. Mol Psychiatry. 2016 Jan 26. PubMed PMID: 26809842.


Second-generation antipsychotics have some advantages over first-generation antipsychotics. However, metabolic adverse effects are perhaps the biggest single problem with second-generation antipsychotics.

There is a great need for effective treatments for the metabolic adverse effects of antipsychotics. These could reduce the morbidity associated with these metabolic adverse effects.


Dyslipidemia can be an adverse effect of many second-generation antipsychotics, especially olanzapine and clozapine, but also others.

Metformin has been used as a treatment for antipsychotic-associated weight gain in persons with schizophrenia. This paper looks at the potential efficacy of metformin for dyslipidemia associated with second-generation antipsychotics.


Data were pooled from two previous randomized, placebo-controlled trials. These clinical trials were originally designed to evaluate the efficacy of metformin in treating antipsychotic-induced weight gain and other metabolic abnormalities.

Persons with schizophrenia (n=201) who had developed dyslipidemia after being treated with an antipsychotic were studied.

Patients were randomly assigned to receive either 1000 mg/day of metformin or placebo for 24 weeks.


The primary outcome measure was the low-density lipoprotein cholesterol (LDL-C) levels.

Patients who received metformin showed a statistically significant reduction in LDL-C levels.

Here you should ask: statistically “significant” (i.e, unlikely to be due to chance alone), yes, but how big a difference was it? After 24 weeks of treatment, LDL-C was above the normal range in 25% of persons taking metformin versus 65% of those on placebo. That’s a big difference.

Persons taking metformin also improved on weight, body mass index, insulin, insulin resistance index, total cholesterol, triglycerides, and HDL cholesterol.


Metformin was efficacious for improving antipsychotic-induced dyslipidemia and insulin resistance.

Improvement in insulin resistance appeared earlier than improvement in dyslipidemia.

Clinical Commentary

It is important to note that the improvement in weight and insulin resistance appeared after 12 weeks of treatment (and then continued to improve), but the improvement in dyslipidemia was only significant after 24 weeks of treatment. Why do I say that it is important to note this? Because we must remember to treat for at least 6 months before deciding whether or not the metformin has been efficacious for reducing dyslipidemia. However, we should see improvement in weight and elevated blood sugar (if present) earlier than that.

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Imagery Rehearsal Therapy: An effective treatment for nightmares

van Schagen et al. Imagery rehearsal therapy in addition to treatment as usual for patients with diverse psychiatric diagnoses suffering from nightmares: a randomized controlled trial. J Clin Psychiatry. 2015 Sep;76(9):e1105-13. doi: 10.4088/JCP.14m09216. PubMed PMID: 26455674.

Nightmares occur at least once a week in two to five percent of the general population but in 30% of those with mental disorders. They cause significant distress and need to be treated.

Off label medications (e.g., prazosin) are sometimes used to treat nightmares, but there is a non-medication alternative.


In Imagery Rehearsal Therapy (IRT), the script of the nightmare is changed into a new dream, which the person is trained to voluntarily imagine during the day.

This Imagery Rehearsal Therapy (IRT) is the treatment of choice for nightmares in persons not identified as having a mental disorder.

But, whether Imagery Rehearsal Therapy (IRT) is helpful in mental health patients is not known.


Ninety patients with different mental disorders were randomized to receive Imagery Rehearsal Therapy (IRT) in addition to treatment-as-usual or only treatment-as-usual.

The Imagery Rehearsal Therapy (IRT) was delivered in 6 sessions of individual therapy.

Various questionnaires were used to systematically assess the frequency of nightmares, distress due to the nightmares, and general psychiatric symptoms.

All the assessments were done before starting treatment, after the Imagery Rehearsal Therapy was completed, and at follow up after 3 months.


Imagery Rehearsal Therapy added to treatment-as-usual led to greater benefit than treatment-as-usual by itself.

There was improvement in all the aspects measured: frequency of nightmares, distress due to nightmares, and general psychopathology.

The effect size for these benefits was 0.5 to 0.7, which indicates a moderate or greater benefit.

Much of these benefits persisted even 3 months after treatment had ended (effect size 0.4 to 0.6).


Imagery Rehearsal Therapy (IRT) is an effective treatment for nightmares in patients with various mental disorders when used along with ongoing mental health treatment.

Clinical Commentary

The American Academy of Sleep Medicine (Aurora et al., 2010. PubMed PMID: 20726290) recommends IRT as a treatment for Nightmare Disorder with the highest level of confidence in the evidence for it. 

Last year, a meta-analysis was published that showed that Imagery Rehearsal Therapy leads to as much benefit as prazosin (Seda et al., PubMed PMID: 25325592). The combination of IRT and CBT for insomnia led to greater improvement than either prazosin alone or IRT alone.

Since nightmares are so common in our patients, we should add this simple intervention to our repertoire of skills.

However, whether and how IRT can be helpful for treatment of nightmares associated with PTSD is beyond the purview of this discussion.

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Can changing our diets lead to better sleep?

St-Onge MP, Roberts A, Shechter A, Choudhury AR. Fiber and Saturated Fat Are Associated with Sleep Arousals and Slow Wave Sleep. J Clin Sleep Med. 2016 Jan 15;12(1):19-24. PubMed PMID: 26156950

Sleep difficulties are extremely common in persons with mental health problems. They may include difficulty falling asleep, repeated awakening, and early morning awakening.

In addition, there is the problem of non-restorative sleep (waking up tired) that can be very difficult to treat.

If lifestyle changes can improve sleep, they will be a valuable adjunct to other measures.


Not much is known about how diet affects sleep.

This study aimed to assess:

  1. Whether sleep is different after a controlled diet vs. an unrestricted diet, and
  2. Whether what the person eats as part of an unrestricted diet affects sleep.

The study enrolled 26 adults (30 to 45 years old) who were of normal weight and who habitually slept 7 to 9 hours per night.

A randomized, crossover inpatient study was conducted. “Crossover” means that each person participated in both types of diets, doing the first type of diet and then crossing over to the other diet. What is the advantage of doing this? The person serves as his/her own control.

Participants were allowed to spend 9 hours in bed.

For the first 4 days, the participants consumed a controlled diet. On day 5, they could eat whatever they wanted. They were given money to buy whatever they wanted to eat (nice!).

A sleep study (polysomnography) was done after 3 days of controlled diet and then after the one day of unrestricted diet.


The duration of sleep was not different after a controlled diet or after the unrestricted diet.

However, after unrestricted eating, the sleep latency (time to fall asleep) was greater and deep (slow wave) sleep was less.

Greater fiber intake was associated with more deep (slow wave) sleep.

A higher percent of energy from saturated fat was associated with less deep (slow wave) sleep.

A higher percent of energy from sugar and from other carbohydrates (excluding fiber, since fiber is a form of indigestible carbohydrate) were both associated with more awakenings from sleep.


High fiber, low saturated fat, low sugar, and low carbohydrate in the diet is associated with deeper sleep and fewer awakenings.

The study has some limitations but is generally consistent with other research on the subject of diet and sleep.

Since this study was on “normal” persons, further research is needed to see whether dietary modification can help in management of persons with sleep disorders.

Clinical Commentary

I am struck by two things about these findings:

  1. This the diet we should all be eating anyway, so there is no downside to recommending this diet to our patients.
  2. I was surprised that the benefit of changing the diet occurs so quickly—within 1 to 3 days.
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Rajnish Mago, MD
Professor of Psychiatry, Thomas Jefferson University

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is Professor of Psychiatry at Thomas Jefferson University and is author of "The Latest Antidepressants and Side Effects of Psychiatric Medications: Prevention, Assessment, and Management." Dr. Mago selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry.

We are always carefully evaluating which research papers to discuss in GME Research Review. Have you come across a research paper published in the last 6 months that you think is clinically relevant? If you would like to ask Dr. Mago to consider analyzing it, please email him the citation at: [email protected]

To contact GME, email us at [email protected]

GME does not provide medical advice. The website and articles are intended for informational purposes only. They are not a substitute for professional medical advice, diagnosis or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on the GME Website. If you think you may have a medical emergency, immediately call your doctor or dial 911.

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