Metformin Effective for Treating Antipsychotic-Induced Amenorrhea, Weight Gain, and Insulin Resistance in Women

May 24, 2013 · Posted in Potential Treatments · Comment 

scaleTreatment with antipsychotics often has side effects such as amenorrhea (loss of the menstrual period) and weight gain that make sticking to a treatment regimen difficult for some patients. A 2012 study by Wu et al. in the American Journal of Psychiatry suggests that the drug metformin, often used to treat diabetes, can reverse these changes. The 84 female patients recruited for the study were being treated for a first episode schizophrenia, were on one antipsychotic, and had experienced amenorrhea for several months. They received either placebo or 1000mg/day of metformin in addition to their antipsychotic treatment for six months. Seventy-six women completed the trial.

Metformin was able to reverse the side effects in many of the women. Menstruation returned in 28 of the patients taking metformin compared to only two patients taking placebo. Among those on metformin, body mass index (BMI) decreased by a mean of 0.93, compared to a mean increase in those on placebo (0.85). Insulin resistance improved in the women on metformin as well.

Editor’s Note: Metformin can also delay the onset of type II diabetes in those in the borderline diabetic range. The weight loss on metformin was not spectacular and other options include the combination of the antidepressant bupropion (Wellbutrin) and the opiate antagonist naltrexone (Revia, 50mg/day), monotherapy with topiramate (Topamax), the fixed combination of topiramate and phentermine (Qsymia), or monotherapy with zonisamide (Zonegran).

Adjunctive Topiramate Is Effective In Schizophrenia

May 17, 2013 · Posted in Potential Treatments · Comment 

topiramateMany patients with schizophrenia do not reach full remission on antipsychotic drugs alone. The anticonvulsant drug topiramate (Topamax) has shown some promise as an adjunctive treatment for schizophrenia. To clarify the results of studies of topiramate, researcher Christoph Correll and colleagues performed a meta-analysis of nine randomized, placebo-controlled clinical trials of the drug. They found that when topiramate was added to antipsychotic treatment, it improved both positive and negative symptoms of schizophrenia, and it also led to reduced weight.

Editor’s Note: Topiramate might also be useful for patients with schizophrenia who have the common comorbidities of alcohol and cocaine abuse, since in other studies of patients with these primary disorders, topiramate was helpful.

 

New Data Support the Efficacy of Lurasidone for Bipolar Depression

August 24, 2012 · Posted in Potential Treatments · Comment 

depressed man

In two recent clinical trials that were presented at the annual meeting of the American Psychiatric Association in May 2012, the atypical antipsychotic lurasidone (Latuda), which is currently used to treat schizophrenia, was associated with significant improvement in bipolar depression compared to placebo. The studies, known as PREVAIL (or Program to Evaluate the Antidepressant Impact of Lurasidone), assessed lurasidone’s efficacy as an adjunctive treatment and as a monotherapy.

PREVAIL 1 assessed lurasidone’s efficacy and safety when the drug was added to treatment with lithium or valproate in bipolar patients who became depressed.  In this 6-week study, scores on the Montgomery-Asberg Depression Rating Scale (MADRS) improved significantly more in patients taking lurasidone (20 – 120mg/day; N=183) in addition to their mood stabilizer compared to those who received placebo (N=165) in addition to their mood stabilizer.

In PREVAIL 2, patients received lurasidone at either 20-60mg/day (N=166) or 80-120mg/day (N=169) or placebo (N=170) as a monotherapy for bipolar depression. As measured by MADRS scores, lurasidone was significantly more effective in improving bipolar depression than placebo was by the end of the 6-week study period.

In both studies lurasidone showed significant effects on other measures and endpoints including: improvement in Clinical Global Impressions severity of depression (CGI-BP-S) scores, reductions in anxiety symptoms, and improvement in social or occupational functioning. Lurasidone also produced higher rates of response (50% improvement on the MADRS). The CGI-BP-S improved in patients on lurasidone significantly more than in those on placebo as early as week one.

Editor’s Note: These two trials in bipolar depression suggest new possibilities for treating the depressed phase of bipolar disorder.

In studies of patients with schizophrenia, lurasidone has had an excellent safety and tolerability profile; it is relatively weight neutral and does not increase metabolic indices such cholesterol, triglycerides, or blood sugar.  

Lurasidone also has an unusual mechanism of action, blocking serotonin 5HT 7 receptors, that may be related to its antidepressant effects. Antagonism of 5HT 7 receptors has been closely linked to antidepressant effects in studies of animal models of depression by two different investigators, Stephen Stahl and Herb Meltzer. It remains to be seen whether this or some other mechanism of lurasidone accounts for its antidepressant effects.

As we have noted before, since all antipsychotic drugs used in the treatment of schizophrenia (which block dopamine D2 receptors) also show efficacy in mania, it is likely that lurasidone will show the same effects. Studies of the drug in mania have not yet been presented. Lurasidone is not yet FDA-approved for bipolar depression, but the PREVAIL studies may be sufficient for an application for FDA approval of lurasidone for this additional indication.

Currently quetiapine (Seroquel) is the only monotherapy approved for bipolar depression. Studies of two other atypical antipsychotics, ziprasidone (Geodon) and aripiprazole (Abilify), failed to show efficacy in bipolar depression when compared with placebo. Ziprasidone’s effects were similar to those of placebo, while aripiprazole showed evidence of significant improvement in the first weeks of treatment compared to placebo, but these failed to last, perhaps because of overly high doses that led to a high drop-out rate.

Antidepressants used for the treatment of unipolar depression are not FDA-approved for bipolar depression and did not appear to be beneficial compared to placebo in recent meta-analyses by Sidor and MacQueen. These antidepressants include the selective serotonin reuptake inhibitors (SSRIs), mixed serotonin and norepinephrine reuptake inhibitors (SNRIs), the dopamine active drug bupropion, and the older tricyclic antidepressants. Not only are these antidepressants not effective in bipolar depression, but some (especially the tricyclics and the SNRIs) appear to increase risk of switching into mania.

None of the mood stabilizers are FDA-approved for bipolar depression; these include lithium, valproate, carbamazepine, and lamotrigine. Thus, quetiapine has had the unique position of being FDA-approved to treat both phases of bipolar disorder—mania and depression—and for prevention of both mania and depression when used as an adjunct to lithium or valproate.  

If the lurasidone data lead to FDA approval of this drug as a monotherapy, it will be only the second monotherapy (after quetiapine) approved for bipolar depression. (The combination of olanzapine and fluoxetine is also approved for this indication.) Since bipolar depression can take a serious toll on patients’ health, cognition, and life expectancy, the prospect of having another effective drug for this phase of the illness is especially promising.

Weight Gain and Metabolic Risks of Antipsychotic Drugs in Children and Adolescents

May 14, 2012 · Posted in Peer-Reviewed Published Data, Risk Factors · Comment 

doctor weighing a patientA study published in the Journal of Child and Adolescent Psychopharmacology in late 2011 reviewed the various weight and metabolic side effects of drugs like olanzapine, clozapine, risperidone, quetiapine, and aripiprazole.

Across 34 published head-to-head and placebo-controlled studies in youth with psychotic and bipolar disorders, weight gain ranged from 3.8 to 16.2 kg with olanzapine (n=353), 0.9-9.5 kg with clozapine (n=97), 1.9-7.2 kg with risperidone (n=571), 2.3-6.1 kg with quetiapine (n=133), and 0-4.4 kg with aripiprazole (n=451).

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