EVIDENCE BASED MEDICINE:

Acute and maintenance effects of non-pharmacologic interventions for

antipsychotic associated weight gain and metabolic abnormalities: a metaanalytic comparison of randomized controlled trials.
Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road,
Orangeburg, NY 10962, USA.

Abstract
OBJECTIVE: To evaluate the efficacy of non-pharmacological interventions for
antipsychotic-associated weight gain.

METHODS: Systematic literature search and meta-analysis of randomized

controlled trials comparing behavioral interventions with control groups to
ameliorate antipsychotic-associated weight gain.

RESULTS:
Across 17 studies (n=810, mean age: 38.8 years, 52.7% male, 40.8% White, 85.6%
with schizophrenia-spectrum disorders), non-pharmacological interventions led to
a significant reduction in weight (-3.12 kg; CI: -4.03, -2.21, p<0.0001) and body
mass index (BMI) (-0.94 kg/m; CI: -1.45, -0.43, p=0.0003) compared with control
groups. Intervention benefits extended to all secondary outcomes, except for high
density-lipoprotein-cholesterol and systolic blood pressure. Compared to controls,
intervention patients experienced significant decreases in waist circumference
(WMD=-3.58 cm, CI: -5.51, -1.66, p=0.03), percent body fat (WMD=-2.82%, CI:
-5.35, -0.30, p=0.03), glucose (WMD=-5.79 mg/dL, CI: -9.73, -1.86, p=0.004),
insulin (WMD=-4.93 uIU/mL, CI: -7.64, -2.23, p=0.0004), total cholesterol (WMD=20.98 mg/dL, CI: -33.78, -8.19; p=0.001), low density-lipoprotein-cholesterol
(WMD=-22.06 mg/dL, CI: -37.80, -6.32, p=0.006) and triglycerides (WMD=-61.68
mg/dL, CI: -92.77, -30.59, p=0.0001), and less weight gain >7% (29.7% vs. 61.3%;
RR=-0.52, CI: -0.35, -0.78, p=0.002; number-needed-to-treat=4). Up to 12 months
after the intervention ended (mean=3.6 months), benefits endured regarding
weight (WMD=-3.48 kg, CI: -6.37, -0.58, p=0.02), but not BMI (p=0.40). Subgroup
analyses showed superiority of non-pharmacological interventions irrespective of
treatment duration, individual or group, cognitive behavioral or nutritional
interventions, or prevention versus intervention trials. However, weight and BMI
were significantly improved only in outpatient trials (p<0.0001), but not in
inpatient or mixed samples (p=0.09-0.96).

CONCLUSION:
Behavioral interventions effectively prevented and reduced antipsychoticassociated weight gain and cardiometabolic perturbations, at least in outpatients
agreeing to participate in trials aimed at improving physical health. Effective
treatments ranged from nutritional interventions to cognitive behavioral therapy.

How antipsychotic medications cause metabolic side effects such as obesity

and diabetes
Sanford-Burnham study suggests that many antipsychotics affect metabolism
because they activate the TGFbeta pathway -- a finding that could lead to
safer therapeutics for bipolar disorder and schizophrenia patients
LA JOLLA, Calif. -- In 2008, roughly 14.3 million Americans were taking
antipsychoticstypically prescribed for bipolar disorder, schizophrenia, or a
number of other behavioral disordersmaking them among the most
prescribed drugs in the U.S. Almost all of these medications are known to
cause the metabolic side effects of obesity and diabetes, leaving patients with
a difficult choice between improving their mental health and damaging their
physical health. In a paper published January 31 in the journal Molecular
Psychiatry, researchers at Sanford-Burnham Medical Research Institute
(Sanford-Burnham) reveal how antipsychotic drugs interfere with normal
metabolism by activating a protein called SMAD3, an important part of the
transforming growth factor beta (TGFbeta) pathway.
The TGFbeta pathway is a cellular mechanism that regulates many biological
processes, including cell growth, inflammation, and insulin signaling. In this
study, all antipsychotics that cause metabolic side effects activated SMAD3,
while antipsychotics free from these side effects did not. What's more, SMAD3
activation by antipsychotics was completely independent from their
neurological effects, raising the possibility that antipsychotics could be
designed that retain beneficial therapeutic effects in the brain, but lack the
negative metabolic side effects.
"We now believe that many antipsychotics cause obesity and diabetes
because they trigger the TGFbeta pathway. Of all the drugs we tested, the
only two that didn't activate the pathway were the ones that are known not to
cause metabolic side effects," said Fred Levine, M.D., Ph.D., director of the
Sanford Children's Health Research Center at Sanford-Burnham and senior
author of the study.
In a previous study aimed at developing new insights into diabetes, Dr. Levine
and his team used Sanford-Burnham's high-throughput screening capabilities
to search a collection of known drugs for those that alter the body's ability to
generate insulin, the pancreatic hormone that helps regulate glucose. That's
when they first noticed that many antipsychotics alter the activity of the
insulin gene. In this current study, the researchers set out to connect the dots
between antipsychotics and insulin. In doing so, experiments in laboratory
cell-lines showed that antipsychotics known to cause metabolic side effects
also activated the TGFbeta pathwaya mechanism that controls many cellular
functions, including the production of insulinwhile the drugs without these
side effects did not.

Wondering whether their initial laboratory observations were relevant to the

human experience, the researchers reanalyzed previously published gene
expression patterns in brain tissue from schizophrenic patients treated with
antipsychotics. What they found supported their earlier findingsTGFbeta
signaling was activated only in those patients receiving antipsychotic
treatment. Looking further, they found that the extent to which each
antipsychotic drug activated the TGF beta.