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Our review describes potential weight-altering effects of psychotropic medications (antipsychotics, antidepressants, anti-anxiety medications, mood stabilizers, sedative-hypnotics, medications for attention-deficit/hyperactivity disorder, and other psychotropic medications) and offers guidance on switching a medication if its weight-altering effect becomes problematic. For second-generation antipsychotics, the risk of weight gain is high with clozapine and olanzapine, low with amisulpride, aripiprazole, and ziprasidone, and medium with other second-generation antipsychotics. Switching from a high-risk antipsychotic to a low-risk antipsychotic usually mitigates or reverses weight gain. For second-generation antidepressants, there may be modest weight loss with bupropion and modest weight gain with mirtazapine and paroxetine. Other second-generation antidepressants are weight neutral but individual variations can occur. If significant change in weight occurs, switching to or adding a low-risk second-generation antidepressant should be considered. Mood stabilizers include lithium, valproate, carbamazepine, lamotrigine, oxcarbazepine, and most second-generation antipsychotics. Risk of weight gain is high with lithium and valproate and low with carbamazepine, lamotrigine, and oxcarbazepine. Given the complexity of bipolar disorder and its management, a switch of a mood stabilizer would be best done by a psychiatrist. Benzodiazepines, non-benzodiazepine and melatonergic hypnotics, doxepin, and trazodone are weight neutral. Diphenhydramine may cause weight-gain and can be switched to a weight-neutral hypnotic if needed. Stimulants can cause varying degrees of weight loss and switching to atomoxetine or bupropion may reverse this problem. If that fails, switching to clonidine or guanfacine can be tried. Switching must be evidence-based and take into account status of the condition being treated, efficacy, side effect profile, potential drug-drug interactions, required laboratory monitoring and cost of the drug(s) being considered, and patient's pregnancy status or plan. Non-pharmacological interventions both for mental disorders and overweight/obesity must be fully availed.
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CLINICAL FEATURES
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Weight Considerations in Psychotropic Drug
Prescribing and Switching
Mehrul Hasnain, MD1
W. Victor R. Vieweg, MD2
1Department of Psychiatry, Memorial
University, St John’s, Newfoundland,
Canada; 2Departments of Psychiatry
and Internal Medicine, Virginia
Commonwealth University, Richmond,
VA
Correspondence: Mehrul Hasnain, MD,
Waterford Hospital,
Waterford Bridge Road,
St. John’s, NL, A1E 4J8,
Canada.
Tel: 709-777-3311
Fax: 709-777-3011
E-mail: mehrul_hasnain@yahoo.com
DOI: 10.3810/pgm.2013.09.2706
Abstract: Our review describes potential weight-altering effects of psychotropic medications
(antipsychotics, antidepressants, anti-anxiety medications, mood stabilizers, sedative-hypnotics,
medications for attention-decit/hyperactivity disorder, and other psychotropic medications) and
offers guidance on switching a medication if its weight-altering effect becomes problematic. For
second-generation antipsychotics, the risk of weight gain is high with clozapine and olanzapine,
low with amisulpride, aripiprazole, and ziprasidone, and medium with other second-generation
antipsychotics. Switching from a high-risk antipsychotic to a low-risk antipsychotic usually
mitigates or reverses weight gain. For second-generation antidepressants, there may be modest
weight loss with bupropion and modest weight gain with mirtazapine and paroxetine. Other
second-generation antidepressants are weight neutral but individual variations can occur. If
signicant change in weight occurs, switching to or adding a low-risk second-generation anti-
depressant should be considered. Mood stabilizers include lithium, valproate, carbamazepine,
lamotrigine, oxcarbazepine, and most second-generation antipsychotics. Risk of weight gain is
high with lithium and valproate and low with carbamazepine, lamotrigine, and oxcarbazepine.
Given the complexity of bipolar disorder and its management, a switch of a mood stabilizer
would be best done by a psychiatrist. Benzodiazepines, non-benzodiazepine and melatonergic
hypnotics, doxepin, and trazodone are weight neutral. Diphenhydramine may cause weight-
gain and can be switched to a weight-neutral hypnotic if needed. Stimulants can cause varying
degrees of weight loss and switching to atomoxetine or bupropion may reverse this problem.
If that fails, switching to clonidine or guanfacine can be tried. Switching must be evidence-
based and take into account status of the condition being treated, efcacy, side effect prole,
potential drug-drug interactions, required laboratory monitoring and cost of the drug(s) being
considered, and patient’s pregnancy status or plan. Non-pharmacological interventions both for
mental disorders and overweight/obesity must be fully availed.
Keywords: antidepressants; antipsychotics; mood stabilizers; obesity; psychotropics; weight
gain
Introduction
The responsibility for providing mental health care is falling increasingly on primary
care physicians (PCPs). Between 11% and 36% of primary care patients have a mental
disorder and more than one-third of mental health patients accessing health care systems
are cared for solely by PCPs.1 Even when under the care of a psychiatrist, metabolic
and other medical problems of these patients are managed by PCPs.
Obesity, obesity-related metabolic problems, and subsequent cardiovascular
complications are more common in patients with mental illness than individuals in
the general population. Patients with major mental illness (schizophrenia, schizoaf-
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Mehrul Hasnain and W. Victor R. Vieweg
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fective disorder, and bipolar disorder) die approximately 25
years sooner than those free of such an illness, mostly due
to cardiovascular diseases.2 Obesity and depression increase
the odds for each other by approximately 1.5 times.3 Anxiety
disorders are also prevalent in obese individuals but their
association is less well studied.4
Mechanisms linking common mental disorders and obe-
sity are quite complex and involve an interplay of genetic,
lifestyle, and iatrogenic factors. Psychotropic drugs vary
widely in their potential to alter appetite and weight. Knowl-
edge about these differences will enable PCPs to minimize
the potential effect of psychotropic drug-induced weight gain
by monitoring weight closely, and by switching to a safer
medication if weight gain or loss is problematic.
Scope and Methodology of Review
We summarize weight effects of commonly used psycho-
tropic medications and explain how to switch among such
medications if weight change (gain or loss) is problematic.
Discussion on other metabolic complications (glucose and
lipid dysregulation, metabolic syndrome) is beyond the
scope of this article; however, these complications parallel
the weight gain associated with these medications. We have
extensively reviewed literature on the weight effects (and
other metabolic complications) of psychotropic medications
over last few years.5–7 In this review, we searched for more
recent literature to update our previous reviews with a focus
on literature to guide medication switching.
Psychotropic Medications Included in
Our Review
Psychotropic medications include antipsychotics (APs), anti-
depressants (ADs), anti-anxiety medications (AAMs), mood
stabilizers (MSTs), sedative/hypnotics, and medications used
to treat attention-decit/hyperactivity disorder (ADHD). Our
review includes commonly used medications from all these
categories, as well as a few others under the “miscellaneous”
category. Table 1 lists the medications reviewed in this paper.
Measures Used to Report Weight Change
Antipsychotic medications have been best studied for their
potential to cause weight gain. Weight gain with use of APs
has been reported as short term (between 8 to 16 weeks),
long term (several months to over a year), and percentage
of patients gaining signicant weight, generally considered
as $ 7% weight increase compared with pre-drug state. The
rst 2 (short and long term weight change) denote the extent
of weight change and the third is an estimate of likelihood
of signicant weight change. We have attempted to provide
information in these terms when describing the weight effects
of psychotropic drugs.
Literature Used to Guide on Switching
Medications
A switch from one psychotropic medication to another one
may be indicated when change in weight (weight gain in most
cases) is a concern and non-pharmacological interventions
are ineffective. The switch must be evidence-based to mini-
mize decompensation (relapse, remission) or other potential
complications such as withdrawal, drug-drug interactions,
and adverse effects. Medication switching recommendations
made in this review are based on pertinent recent literature,
which is cited in the relevant sections below. A general
approach to switching medications and commonly used
methods to make the switch are noted in Figure 1.
Weight Change Liability of APs and
Switching Options
For APs, we included all second-generation APs (SGAPs)
available in the United States as well as an SGAP not avail-
able in United States (amisulpride), and 2 rst-generation APs
(FGAPs) (perphenazine and molindone) that were included
in the major recent clinical effectiveness studies of patients
receiving these medications.8–10
Weight Change Liability of APs
Several APs are associated with weight gain. Medication-
specic approximated information is provided in Table 2.
Note that there are a greater extent and likelihood of weight
gain in rst-episode psychosis patients observed in recent
studies,11,12 which is not reected in Table 2. However, this is
discussed further in this section below. It is well established
that the extent and likelihood of weight gain is high with
clozapine and olanzapine; low with amisulpride, aripiprazole,
and ziprasidone; and medium with paliperidone, quetiapine,
and risperidone.6,13,14 Preliminary ndings suggest that ase-
napine and lurasidone have low liability and iloperidone has
medium liability to cause weight gain.15–19
In the Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE; AP treatment up to 18 months),8
perphenazine was associated with a slight (, 1 kg) mean
weight loss though 12% of patients gained signicant
weight. In a study of rst-episode psychosis patients,10
mean weight gain with perphenazine over a 1-year period
was 1.6 kg and 10% gained signicant weight. In the
Treatment of Early-Onset Schizophrenia Spectrum Dis-
Weight Changes With Psychotropic Drugs
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orders (TEOSS) study,9 molindone was weight neutral
over the 8-week study period. The number of patients
gaining signicant weight was not reported. Older stud-
ies reviewed by Stanton20 have also reported weight loss
with molindone.
Both the extent and likelihood of weight gain is 3- to
4-fold greater in young, rst-episode psychosis patients
with limited previous exposure to APs than in older patients
with chronic psychosis in both short-term and long-term
studies.21 The European First-Episode Schizophrenia Trial
(EUFEST)11 was a 1-year multicenter, open, randomized
trial of 498 patients aged 18 to 40 years, with rst-episode
schizophrenia or schizoaffective disorder. In the trial, mean
weight gain/% gaining $ 7% at study end was 9.7 kg/63%
for amisulpride, 13.9 kg/86% for olanzapine, 10.5 kg/45%
for quetiapine, and 4.8 kg/37% for ziprasidone. In another
trial of early-onset psychosis,12 80% of patients in the olan-
zapine group had gained $ 7% of their baseline weight at
week 52, compared with 50% and 58% of the quetiapine and
risperidone groups, respectively.
Young patients with bipolar disorder and non-psychotic
disorders are as vulnerable to weight gain with SGAPs as
are those with schizophrenia and other forms of psychosis.22
There appears to be an inverse relationship between baseline
body mass index and weight gain with SGAP treatment, but
the data are not convincing.23 Preliminary evidence suggests a
dose-response relationship between clozapine and olanzapine
serum concentrations and metabolic outcomes, although the
association between administered daily dose and metabolic
outcomes is not clear.24 First-episode psychosis patients
compared with chronic patients are more responsive to APs
regarding positive symptoms of psychosis (hallucinations,
delusions, agitation) and require lower doses.25
Switching an AP Due to Weight-Gain
Concerns
The benecial effects of exchanging an SGAP with high
metabolic liability for one with a low liability are well
established. In an open-label, rater-blinded study of patients
with schizophrenia and schizoaffective disorder,26 switch-
ing from olanzapine to risperidone signicantly improved
anthropometric measures. In another open-label study,27 84
patients with schizophrenia or schizoaffective disorder who
experienced various metabolic side effects with olanzapine
(n = 40, mean treatment duration 29 months) or risperidone
(n = 20, mean treatment duration 36 months) were switched to
ziprasidone. Anthropometric measures and metabolic param-
eters improved signicantly after 6 months of ziprasidone
treatment. Switching to aripiprazole may also be benecial.2 8
When considering switching an AP, take into account the
condition for which it is being used. Common established
uses of APs are schizophrenia and related psychoses, bipolar
disorder, schizoaffective disorder, and psychosis associated
Table 1. Psychotropic Medications and Weight-Change
Potential in Patients
Antipsychotics (APs) Second-generation APs
aripiprazole, asenapine, clozapine,
iloperidone, lurasidone,
olanzapine, quetiapine,
risperidone, ziprasidone
First-generation APs
molindone, perphenazine
Antidepressants (ADs) Second-generation ADs
SSRIs: citalopram, escitalopram,
uoxetine, uvoxamine,
paroxetine, sertraline
SNRIs: desvenlafaxine,
duloxetine, venlafaxine
Other SGADs: bupropion,
mirtazapine, nefazodone,
vilazodone
Mood Stabilizers (MSTs) Carbamazepine, lamotrigine,
lithium, oxcarbazepine, valproate,
various SGAPs
Anti-Anxiety Medicationsa
(AAMs)
Buspirone
Sedative/Hypnotics Benzodiazepines: clonazepam,
diazepam, lorazepam, nitrazepam,
oxazepam, temazepam
Non-benzodiazepines:
eszopiclone, zaleplon, zolpidem,
zopiclone
Melatonin agonists:
agomelatine, melatonin,
ramelteon
Others: diphenhydramine,
doxepin, trazodone
Medications for ADHD Stimulants: dexmethylphenidate,
dextroamphetamine,
dextroamphetamine-
amphetamine, lisdexamfetamine,
methylphenidate
Non-stimulants: Atomoxetine,
clonidine, guanfacine
Miscellaneous Medications
(Atypical)
naltrexone, prazosin, varenicline
Medications for Dementia:
cholinesterase inhibitors (ChEIs:
donepezil, galantamine and
rivastigmine), memantine
aIn addition to ADs and sedatives.
Abbreviations: AAMs, anti-anxiety medications; ADs, anti-depressants; ADHD,
attention-decit/hyperactivity disorder; APs, antipsychotics; ChEIs, cholinesterase
inhibitors; MSTs, mood stabilizers; SGADs, second-generation anti-depressants;
SNRI, serotonin-norepinephrine reuptake inhibitors; SSRI; selective serotonin
reuptake inhibitors.
Mehrul Hasnain and W. Victor R. Vieweg
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with mood disorders. Clozapine, reserved for treatment-
resistant schizophrenia and bipolar disorder, is rarely used
by PCPs. Given the marginal differences in efcacy between
other SGAPs, and between SGAPs (excluding clozapine) and
FGAPs for schizophrenia,29–31 initial treatment or medication
switch should be guided by the potential risk for extrapy-
ramidal, anticholinergic, or metabolic side effects and any
warnings issued by the US Food and Drug Administration
(FDA). For patients with schizophrenia, rst-episode psy-
chosis, and schizophreniform psychosis, an AP with high or
medium risk can be exchanged for any AP with low risk of
weight gain (Table 3). Perphenazine and molindone may be
considered keeping in mind side effects of anticholinergic
medication usually required to counter the extrapyramidal
side effects of these APs. Switching to (or initial treatment
with) molindone may be particularly benecial for morbidly
obese patients.32 For best results, make the switch as soon as a
trajectory of rapid and/or signicant weight gain is observed,
which in young, drug-naïve patients may be noted within a
few weeks of initiating the treatment.
For patients receiving an SGAP for bipolar disorder,
switching to another SGAP can be tricky because not all of
them are indicated (or are well studied) for all types (manic,
depressed, or mixed) and phases (acute or maintenance) of
bipolar disorder. For example, iloperidone and lurasidone
are only indicated for schizophrenia, and quetiapine is the
only SGAP indicated for acute bipolar depression. Most of
SGAPs are indicated for maintenance treatment of bipolar
disorder but choice might vary by the symptom pattern. Co-
treatment with MSTs may complicate matters further. Similar
challenges are to be expected in patients with schizoaffective
disorder. We believe switching APs in patients with bipolar or
schizoaffective disorder would be best done by a psychiatrist.
A summary of the approved indication for SGAPs is provided
in Table 1 of a publication by Hasnain et al.6 Complete and
current information can be looked up at the FDA website.33
Patients with psychotic depression respond better to a
combination of an AD and AP than either alone.34 Antipsy-
chotic use is usually short term and a need to switch can be
avoided by initially starting an AP with low weight-gain
liability. If a switch is indicated, any low-risk AP would be
an option. Evidence does not support routine use of APs for
attention-decit/hyperactivity disorder or behavioral dis-
turbances and there is no literature to guide switching. All
patients (irrespective of the diagnosis) receiving APs should
be assessed at baseline and monitored regularly for obesity
and metabolic complications following standard guidelines.35
This care remains poor due to various reasons36,37 and can be
improved via coordinated care by PCPs and psychiatrists.38
Weight Effect of ADs and AAMs and
Switching Options
First-generation ADs (FGADs) (including monoamine
oxidase inhibitors) are rarely used now. Second-generation
ADs (SGADs) are grouped into selective serotonin reuptake
inhibitors (SSRIs; citalopram, escitalopram, uoxetine, u-
voxamine, paroxetine, and sertraline), serotonin–norepineph-
rine reuptake inhibitors (SNRIs; desvenlafaxine, duloxetine,
and venlafaxine), and other SGADs (bupropion, mirtazapine,
nefazodone, and vilazodone). Approximately 60% of the AD
prescriptions are written by PCPs.39 Primary care physicians
should understand the weight effects of these medications and
how to switch among them if needed. Except bupropion and
vilazodone, all other SGADs are also used to treat various
anxiety disorders. Buspirone, a serotonergic 5-HT1A receptor
partial agonist, is specically indicated for generalized anxi-
ety disorder (GAD) and is occasionally used as an adjunct
to AD treatment. Benzodiazepines, indicated for short-term
treatment of anxiety, are discussed later.
Weight Effect of ADs and AAMs
We know less about the weight effects of ADs than APs.
Serretti et al40 performed a meta-analysis of studies docu-
menting weight changes associated with therapeutic doses
Table 2. Weight-Change Risk of Antipsychotic Use6,8–21, a
Medication RR of Weight
Change With
Short-Term
Use
Mean Gain/
Loss During
1 Year, kg
% Patients
Likely to gain
$ 7% from
baselineb
Amisulpride Low 218
Aripiprazole Low 110
Asenapine Low 115
Clozapine High > 5 30–60
IloperidonebMedium 5 13
Lurasidone Low Loss of 17
Molindone Low 0 Not known
Olanzapine High . 5 30–60
Perphenazine Low , 1 12
Paliperidone Medium 2–5 10–30
Quetiapine Medium 2–5 30
Risperidone Medium 2–5 20
Ziprasidone Low 110
aYoung, drug-naïve patients are at a greater risk in terms of risk and extent of
weight gain than adults with previous exposure to antipsychotic drugs.11,12,21 The
greater risk is not reected in Table 2.
bNumbers are from long-term data (mostly 1-year), except for iloperidone (data
from short-term studies)
Weight Changes With Psychotropic Drugs
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of AD monotherapy. In short-term studies (4–12 weeks),
they found a mean weight loss of # 0.5 kg with escitalo-
pram, uvoxamine, paroxetine, and venlafaxine; 0.5 kg–1
kg with citalopram, duloxetine, uoxetine, and sertraline;
and 1.13 kg with bupropion; and a mean weight gain of
1.74 kg with mirtazapine. In studies of $ 4 months, mean
weight loss was: bupropion (1.87 kg), uoxetine (0.31 kg),
and sertraline (0.12 kg). Mean weight gain was: citalopram
(1.69 kg), duloxetine (0.71 kg), escitalopram (0.65 kg), mir-
tazapine (2.59 kg), and paroxetine (2.73 kg). A report on the
comparative effectiveness of SGADs prepared for the Agency
for Healthcare Research and Quality noted that mirtazapine
was more likely to cause weight gain than comparator drugs.41
In a 52-week open-label study,42 duloxetine-treated
patients had a mean weight gain of 1.1 kg at endpoint. Based
on pooled analysis of data from 9 short-term (8-week),
double-blind, placebo-controlled studies and 1 long-term
(6-month) relapse-prevention trial,43 desvenlafaxine was
associated with a small but statistically signicant weight loss
of 0.8 kg both in short- and long-term studies.43 Nefazodone
is weight-neutral.7 Vilazodone did not cause weight change
short term but in an open-label, 1-year study did cause a
mean weight gain of 1.7 kg.44 Agomelatine is a melatonergic-
serotonergic antidepressant available in Europe but not in the
United States. Preliminary evidence suggests it to be free of
any major weight effects.45 Buspirone is weight neutral in
short- and long-term studies.46,47 Table 4 provides approxi-
mate weight changes associated with SGADs and buspirone.
Data on the likelihood of weight changes with SGADs
are very limited. In pooled data from 6 trials48 (3 comparing
nefazodone with uoxetine, paroxetine, and sertraline; and
3 comparing nefazodone with imipramine), 8.3% patients
in the nefazodone group compared with 17.9% in the SSRI
group gained signicant weight during the long-term phase.
In another pooled analysis of 9 studies49 of 6- to 8-weeks
duration, and 1 study of 24-week duration, comparing mir-
tazapine with SSRIs (5 trials of uoxetine, 3 of paroxetine,
and 1 each of citalopram and sertraline), patients taking
mirtazapine were almost 4 times more likely to experience
weight gain than SSRI-treated patients. In placebo-controlled
trials of bupropion SR (slow-release) for depressed patients,50
14% and 19% of patients receiving bupropion SR 300 mg/
day (n = 339) or 400 mg/day (n = 112) reported a weight loss
of . 2.3 kg, respectively, and 3% and 2% of patients receiv-
ing bupropion SR 300 or 400 mg/day experienced a weight
gain of . 2.3 kg. No clinically signicant weight loss was
observed in a 52-week relapse-prevention trial.
Switching an AD or AAM Due to
Weight-Gain Concerns
There are no substantial differences between the efcacy and
effectiveness of SGADs.41,51 Those associated with long-term
weight gain (Table 4) should be avoided in obese patients
or patients at risk of weight gain. Poor appetite and accom-
panying weight loss will improve with successful treatment
of depression and should not be the sole reason to prescribe
an SGAD with a potential to increase appetite. Bupropion
is comparable to other SGADs for depression, including
depression with anxiety symptoms (not to be confused with
depression with comorbid anxiety disorder)51 and may be
preferred for obese depressed patients.
Sussman et al48 pooled data from 3 trials comparing
nefazodone with uoxetine, paroxetine, and sertraline. At
the end of acute-phase treatment (6–8 weeks), 2.1% in the
nefazodone group compared with 1.6% in the SSRI group
gained signicant ($ 7% from baseline) weight; and 1.3%
in the nefazodone group compared with 3.5% in the SSRI
group lost signicant weight. At the end of long-term phase
(16–46 weeks), the number for signicant weight gainers
had increased to 6.9% compared with 13.8%, respectively,
and the number for signicant weight losers had risen 7.3%
and 6.3%, respectively. These data highlight the importance
of ongoing monitoring of weight after initiating any AD.
Table 3. Approximate Patient Weight Changes Associated
With SGADs and AAMs40–50
Medication Mean weight
change, short-
term use (# 12
wks), kg
Mean weight
change, long-term
use ($ 4 mo), kg
Agomelatine NoneaNonea
Bupropion 1.13 1.87
Buspirone NoneaNonea
Citalopram 0.5 – 1 1.69
Desvenlafaxine 0.5 – 1 0.5 – 1
Duloxetine 0.5 – 1 0.5 – 1
Escitalopram # 0.5 0.5 – 1
Fluoxetine 0.5 – 1 # 0.5
Fluvoxamine # 0.5 Limited data
Mirtazapine 1.74 2.59
Nefazodone Minor changesaMinor changesa
Paroxetine # 0.5 2.73
Sertraline 0.5 – 1 # 0.5
Venlafaxine # 0.5 Minor changes
Vilazodone Minor changesa 1.7a
aBased on limited literature.
Abbreviations: AAMs, anti-anxiety medications; SGADs, second-generation
antidepressants.
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Patients gaining (or losing) signicant weight on a SGAD
can be switched to another SGAD with low risk from the
same or a different category. The pros and cons of the switch
must be discussed with the patient before making the switch.
Stage of treatment (initial, middle, maintenance) and status
of depression (response, partial remission, full remission)
should be considered before making the switch. Achieving
remission in depression can be quite challenging with many
patients, requiring sequential treatment steps for best possible
outcome.52 Switching SGAD in difcult-to-treat patients who
are responding well or who are in remission should only be
considered when weight gain is remarkable and non-phar-
macological interventions have failed. A decision to switch
would be much easier to make in patients showing minimal
response to the SGAD. For partial responders, addition of
another appropriate SGAD from a different category (eg,
addition of mirtazapine to an SSRI for patients not able to
regain weight or addition of bupropion to an SSRI who had
gained weight) would be an alternative option.53 Be mind-
ful of the risk of serotonergic withdrawal or serotonergic
syndrome while making the switch (Figure 1).
The approach to switching SGADs in anxiety-disorder
patients is similar to depression-treated patients except that
not all SGADs are indicated for all anxiety disorders. A
summary of the approved indication for SGADs is provided
in Table 3 of a publication by Hasnain et al.6 Complete and
current information can be looked up at the FDA website.33
In clinical practice, all SSRIs and SNRIs are used as rst-
line treatment for most anxiety disorders irrespective of the
approval status. Mirtazapine is often used as a second-line
medication for anxiety disorders. Use of SSRIs is preferred
for initial treatment for obsessive-compulsive disorder.
Bupropion is not routinely used for any anxiety disorder
because its dopaminergic-stimulating effect might worsen
anxiety. Buspirone is specically indicated for and used in
GAD. Benzodiazepines are indicated for short-term use in
Figure 1. Decision process for switching patient psychotropic medications.
Abbreviation: MAO, monoamine oxygenase.
Weight Changes With Psychotropic Drugs
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anxiety disorders. See Hoffman et al54 for review of phar-
macotherapy of anxiety disorders.
Weight Effect of MSTs and
Switching Options
Bipolar and schizoaffective disorders are the primary indi-
cations for MSTs. Commonly used MSTs include lithium,
several antiepileptics (valproate, carbamazepine, oxcar-
bazepine, and lamotrigine) and most of SGAPs (Table 2).
First-generation APs are very rarely used for this indication
except to control acute agitation with injectable preparations
(eg, haloperidol). The MSTs are more effective in control-
ling mood upswings (mania and hypomania) than depression
except lamotrigine and quetiapine. Gabapentin and topira-
mate are not discussed because there is little to suggest they
are effective as MSTs.
Weight Effect of MSTs
We have discussed the weight gain liability of SGAPs previ-
ously (also see Table 2). The weight effects of other MSTs
are less well studied. Overall, the extent and likelihood of
weight gain is high with lithium and valproate, and low
with carbamazepine, lamotrigine, and oxcarbazepine.7 As
reviewed by Torrent et al,55 lithium treatment of bipolar dis-
order can cause weight gain of up to 12 kg (mean gain 2–6
kg) in approximately one-third of patients. Older studies56–58
have reported long-term average weight gain of 10 kg with
lithium with approximately 50% gaining . 5 kg.56 Valproate
is associated with a similar extent of weight gain (average
5 kg) with a likelihood of signicant weight gain in 20% of
patients.55 Women may have a greater likelihood than men; in
a study of patients receiving valproate for epilepsy,57 43.6% of
women compared with 23.5% of men gained $ 5 kg weight
over a mean treatment duration of 1.5 years and 1.8 years,
respectively.57 Children and adolescents appear not to be
overly sensitive to the weight-gaining effect of lithium and
valproate, as they are to APs.58
Limited data for carbamazepine and even less so for
oxcarbazepine suggest that both these agents are unlikely
to cause significant weight change in most patients.55
Lamotrigine is relatively better studied. In an 18-month
study, bipolar-1 depressed patients were initially stabilized
in an open-label phase of several weeks and then random-
ized to lamotrigine, lithium or placebo groups. At the end of
the study, the observed mean changes in body weight from
randomization were -2.2 kg, 4.2 kg, and 1.2 kg, respectively;
and incidence of patients with $ 7% increase in body weight
at the nal visit was 7%, 10%, and 6% for lamotrigine,
lithium, and placebo, respectively. In another 6-month
study59 of olanzapine/uoxetine compared with lamotrigine
for bipolar depression, mean weight change was 4.4 kg in
olanzapine/uoxetine group and -0.9 kg in the lamotrigine
group; $ 7% increase was noted in 33.8% compared with
2.1%, respectively.59
Switching an MST Due to Weight-Gain
Concerns
Bipolar and schizoaffective disorders are cyclic illnesses
with individual variations in the pattern and frequency of the
mood cycles. Comorbidity, polypharmacy, and noncompli-
ance with treatment are common.60 Given these complexities,
along with the fact that MSTs should be tailored according to
their proven efcacy for different types and phases of bipolar
disorder, initiation and switching MSTs would be best done
by a psychiatrist. We have made a few comments below to
familiarize PCPs with some aspects of medication switching
due to weight-gain concern in this population.
Weight-gaining effect of lithium and valproate appear
similar to olanzapine and quetiapine but some recent stud-
ies61,62 suggest that it may be lower than these 2 SGAPs and
comparable to that of risperidone. Patients taking olanzapine
or quetiapine for maintenance of bipolar disorder may be
candidates to be switched to either lithium or valproate.
Patients with bipolar disorder taking risperidone, lithium, or
valproate for maintenance treatment can be considered for
a switch to lamotrigine, carbamazepine, or oxcarbazepine.
Patients with schizoaffective disorder on combination
treatment with olanzapine or quetiapine and a MST could
be switched to an AP with low weight-gain liability while
continuing the MST. If either olanzapine or quetiapine
monotherapy is directed at both psychotic and mood symp-
toms, then switch to an SGAP with low weight-gain liability
appropriate to patient’s mood symptoms and pattern can be
considered. Switching options should be discussed with the
patient (and family if indicated). Patients would be at high
risk of relapse or recurrence during the switch and should
be monitored closely. Rarely, lithium-related subclinical
hypothyroidism can contribute to weight gain.
Weight Effect of Sedative/Hypnotics
and Switching Options
Benzodiazepines are used for symptomatic relief of anxiety
and insomnia. Non-benzodiazepine hypnotics (commonly
referred to as z-drugs) are slightly superior to benzodiaz-
epines. They include eszopiclone, zaleplon, zolpidem and
zopiclone. Both benzodiazepines and non-benzodiazepines
Mehrul Hasnain and W. Victor R. Vieweg
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Table 4. Categorization of Often Prescribed Psychotropic Medications Based on Approximate Long-Term Risk to Cause Patient
Weight Loss or Gaina
Low Risk for Weight
Loss
Minimal Risk of Weight
Gain or Loss
Low Risk for Weight
Gain
Medium Risk for
Weight Gain
High Risk for Weight
Gain
Mean weight loss of 1–3 kg
and/or 10- 25% likelihood
of $ 7% loss from baseline
weight
Mean weight loss or gain
of , 1 kg and/or 10%
likelihood of $ 7% loss or
gain from baseline weight
Mean weight gain of
1–2.5 kg and/or 10-25%
likelihood of $ 7% gain
from baseline weight
Mean weight gain of
2.5–5 kg and/or 25-50%
likelihood of $ 7% gain
from baseline weight
Mean weight gain of . 5
kg and/or . 50% likelihood
of $ 7% gain from baseline
weight
Antidepressant
Bupropion
Medications for ADHD
Atomoxetine
Dexmethylphenidate
Dextroamphetamine
Lisdexamfetamine
Methylphenidate
Dextroamphetamine-
amphetamine mixed salt
Cholinesterase
Inhibitors
Donepezil
Galantamine
Rivastigmine
Antipsychotics
Aripiprazole
Asenapine
Lurasidone
Molindone
Ziprasidone
Antidepressants
and Anti-Anxiety
Medications
Agomelatine
Buspirone
Citalopram
Desvenlafaxine
Fluoxetine
Fluvoxamine
Sertraline
Venlafaxine
Mood Stabilizers
Lamotrigine
Sedative/Hypnotics
Agomelatine
Benzodiazepines
Doxepin
Eszopiclone
Melatonin
Ramelteon
Trazodone
Zaleplon
Zolpidem
Zopiclone
Medications for ADHD
Clonidine
Guanfacine
Others
Memantine
Naltrexone
Prazosin
Varenicline
Antipsychotics
Amisulpride
Perphenazine
Antidepressants
and Anti-Anxiety
Medications
Paroxetine
Vilazodone
Mood Stabilizers
Carbamazepine,
Oxcarbazepine
Sedative/Hypnotics
Diphenhydramine
Antipsychotics
Iloperidone
Paliperidone
Quetiapine
Risperidone
Antidepressants
and Anti-Anxiety
Medications
Mirtazapine
Antipsychotics
Clozapine
Olanzapine
Mood Stabilizers
Lithium
Valproate
aExcept for the “High Risk for Weight Gain category,” boundaries between adjacent categories are not rigid. Signicant individual variations in weight change can occur.
Abbreviation: ADHD, attention-decit/hyperactivity disorder.
are intended for short-term (up to several weeks) use but their
long-term use is common. Melatonergic hypnotics include
over-the-counter melatonin and prescription ramelteon.
Diphenhydramine is available as an over-the-counter sleep-
aid (and as an anti-allergic drug). Doxepin is a tricyclic anti-
depressant with potent histamine-1 (H1) blocking properties.
In 2010, it was approved by FDA for insomnia at very low
doses (3-6 mg at night vs 75-300 mg/day for depression).
Weight Changes With Psychotropic Drugs
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Trazodone 25 mg to 100 mg at night is frequently used as
a hypnotic.
Weight Effect of Sedatives/Hypnotics
Limited data and several decades of anecdotal experience
suggest that benzodiazepines do not have signicant weight
effect.7 Non-benzodiazepine hypnotics are also not known
to alter weight.
Melatonin does not seem to have signicant weight
effects but interesting data are emerging. It limits olan-
zapine-induced adiposity and may curtail fully established
fructose-induced metabolic syndrome in rats.63,64 Ramelteon
prevented age-associated weight gain and hypertension
in spontaneously hypertensive rats.65 In a double-blind,
placebo-controlled, 8-week pilot study66 of patients with
schizophrenia, ramelteon improved some laboratory and
radiologic measures of adiposity but not standard anthropo-
metric measures.
As an H1-receptor blocker, diphenhydramine may
increase appetite and weight but specic literature is lack-
ing. A recent study showed that men taking prescription
H1 blockers weighed 10 kg and women weighed 5 kg
more than matched controls.67 We believe hypnotic doses of
diphenhydramine would have at least “low” risk of weight
gain. Doxepin also has H1-receptor blocking properties.
At the very small dose approved for insomnia, it does not
affect weight.68 Trazodone does not cause signicant weight
changes.7
Switching Sedative/Hypnotics Due to
Weight-Gain Concerns
Sleep problems are prevalent in the community and many
individuals rely on over-the-counter sleep aids and/or alco-
hol to address them.69 Routinely, asking overweight/obese
patients about use of over-the-counter sleep aids should
identify patients taking diphenhydramine and they can be
advised to use a weight-neutral sleep aid (eg, melatonin) or
can be prescribed a hypnotic if indicated. In very rare circum-
stances when a prescription sedative/hypnotic is suspected
to cause weight change, another one can be tried. Be mind-
ful of risk of withdrawal when switching (or discontinuing)
these medications.
Weight Effect of Medications for
ADHD and Switching Options
Medications used to treat ADHD are grouped as stimu-
lants or non-stimulants. Stimulants include a number of
closely related medications (dexmethylphenidate, dextro-
amphetamine, and its predrug form lisdexamfetamine, and
methylphenidate) or their mixture (dextroamphetamine-
amphetamine). Extended-release forms of some of these
agents are available. Transdermal system and osmotic release
oral system (OROS) have been developed to minimize tam-
pering with and abuse of these medications. Non-stimulants
include atomoxetine (a selective norepinephrine reuptake
inhibitor specifically approved for ADHD), adrenergic
α-2 receptor agonists, clonidine, and guanfacine (only the
extended-release form of guanfacine is FDA approved for
ADHD) and bupropion (off-label use).
Weight Effect of Medications for ADHD
To correct for growth, weight (and height) in children and
adolescents is measured in age- and sex-based standard val-
ues (z-scores). All stimulant medications and atomoxetine
are associated with variable but broadly comparable stunt-
ing of growth (height and weight) in youth, which is dose-
dependent and prominent during the initial one to two years
of treatment.70 Clonidine and guanfacine are not associated
with slowing of growth.70,71
Literature on pharmacological treatment of adult ADHD
is relatively scarce. Dose-dependent appetite suppression is
common in adults taking stimulant medications (up to 40%)
and atomoxetine (up to 20%).70 In clinical trials, OROS
methylphenidate was associated with a mean weight loss of
2.3 kg and lisdexamfetamine with a mean weight loss of 1
to 2 kg over long-term.72,73 Atomoxetine can cause a weight
loss of 1 kg in long-term.74 Literature on weight effects of
clonidine and guanfacine in adults is lacking; drawing from
studies in youth they probably are weight-neutral. Weight
effects of bupropion have been discussed above.
Switching ADHD Medications Due to
Weight-Loss Concerns
Evidence of efcacy for ADHD both in youth and adults is
strongest for stimulants followed by atomoxetine and then
other drugs.75,76 Given the high prevalence of overweight/obe-
sity in individuals with ADHD,77 treatment emergent weight
loss is unlikely to be a concern in most cases. Appetite sup-
pression/weight loss (and stunting of growth in youth) may
respond to administering medication after meals, switching
from an immediate-release preparation to an extended/slow-
release preparation, and having drug-holidays (eg, weekends,
summer holidays). The same strategy may be used in adults
who lose weight on stimulants. If concern persists, switch-
ing from one stimulant to another may be tried though this
strategy is unlikely to work in most cases given the modest
Mehrul Hasnain and W. Victor R. Vieweg
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differences in appetite suppression between stimulants.78
Switching from stimulants to atomoxetine is more likely
to address the concern and may be tried as an alternative
to switching between stimulants or as next step. Bupropion
is also effective for ADHD both in youth79 and adults.80 It
would be an option to consider instead of or after atomox-
etine. Patients who continue to lose weight on atomoxetine
or bupropion can be switched to guanfacine or clonidine.
Weight Effect of Miscellaneous
Psychotropic Medications
A few psychotropic medications commonly used by PCPs
could not be included in the categories discussed above.
These include naltrexone, prazosin, varenicline, and medica-
tions used for dementia. Naltrexone is a µ-opioid receptor
antagonist used for opioid and alcohol dependence. It is
associated with minimal weight loss as monotherapy.81 In a
large randomized, double-blind, placebo-controlled study82 of
overweight/obese adults, naltrexone-bupropion combination
(naltrexone 16 mg/day or 32 mg/day plus sustained-release
bupropion 360 mg/day) was found to decrease weight
by $ 5% in 39% and 48%, respectively, over a 56-week
period.
Prazosin is an α1-adrenergic receptor blocker used
originally as an antihypertensive medication. It is effective in
diminishing posttraumatic stress disorder-related nightmares.
Weight change was not identied as a signicant adverse
effect of prazosin.83 Varenicline is a selective α4β2-nicotinic
receptor partial agonist approved for smoking cessation (as
is bupropion). Approximately three-quarters of smokers who
quit smoking gain weight, more than half of them $ 5 kg over
a 1-year period.84 Varenicline and bupropion do not seem to
potentiate or mitigate this weight gain.85,86
Medications used for dementia include cholinesterase
inhibitors (ChEIs; donepezil, galantamine, and rivastig-
mine) and memantine (an uncompetitive antagonist of the
N-methyl-D-aspartate glutamate receptor). Use of ChEIs can
cause signicant gastrointestinal adverse effects, including
nausea, diarrhea, and loss of appetite. In clinical trials,87,88
weight loss was more common among patients taking these
medications than patients taking placebo, affecting 10% to
20% (overall mean, 9%) of patients receiving ChEIs. The
extent of weight loss directly related to the ChEIs is dif-
cult to establish due to disease-related neurobiological and
behavioral factors. Differences between ChEIs appear to be
minimal but switching from one to another can be tried if
weight loss or gastrointestinal adverse effects are prominent.
Memantine does not appear to cause weight loss89 and may be
an alternative in patients with moderate to severe Alzheimer’s
disease not tolerating ChEIs.
Weight Effects of Psychotropic
Combinations and How to Minimize
Risk
Psychiatric comorbidity is very common. Depressive and
anxiety disorders often co-occur with each other and with
alcohol abuse, depression is common in patients with schizo-
phrenia, and ADHD is increasingly being recognized in
patients with mood and anxiety disorders.90,91 Furthermore,
poor or limited response to initial treatment is common in
mental disorders. All these scenarios are likely to lead to
polypharmacy.
Combining medications with weight-gain potential will
increase the risk of weight gain. Kim et al92 evaluated weight
change over 4 weeks in 179 consecutive patients with bipolar
I disorder presenting with acute mania. Combination treat-
ment with APs and MSTs resulted in greater weight gains
than monotherapy with an AP or MST. Augmentation of
SGAD treatment with an SGAP led to signicantly higher
weight gain than SGAD treatment alone.93 Interestingly, in
this study mirtazapine/olanzapine combination induced less
weight than SSRIs/olanzapine combination.
Combining medications provides an opportunity to poten-
tially counter or reverse medication-related adverse weight
effects. For example, addition of a stimulant medication to
treat ADHD comorbid with bipolar disorder might mitigate
the weight-inducing effect of mood stabilizers—but it may
not work.94 Medication combinations can be tailored to suit
a patient’s weight-related need, for example, by combining
mirtazapine and olanzapine to boost appetite in a cachectic
patient with psychotic depression or by starting bupropion
to facilitate weight loss in an obese depressed patient already
on naltrexone for alcohol dependence.
Discussion
The weight-altering effects of psychotropic medications
are based on “mean values” with a broad range for indi-
vidual patients. Medications that are consistently and
commonly associated with weight gain (eg, olanzapine)
or weight loss (eg, stimulants) are very likely to cause
the same weight effect in individual patients. However,
medications with marginal “mean” weight effects, such
as SSRIs and bupropion can cause weight gain or loss,
which can be significant in individual patients. This
underscores the need for individualized monitoring
and care. Table 4 provides approximated “qualitative”
Weight Changes With Psychotropic Drugs
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weight effect categories of all psychotropic medications
discussed above.
Switching medications may limit or counter psychotropic
medication-induced weight gain but can be quite challeng-
ing to implement. The need for this intervention can be
minimized by starting a medication initially that has a low
weight-gain risk. Switching medication is not an alternative
to non-pharmacological interventions including healthy life-
style counselling, which should be offered to all obese and
at-risk patients. Weight gain (or rarely weight loss) is only
one of the reasons to prompt medication switch. A decision
to switch should take a broad clinical perspective. Important
elements to consider include status of the condition being
treated, efcacy, frequency of administration, side effect
prole (including FDA-issued warnings), potential drug-
drug interactions, need for laboratory monitoring and cost of
the alternative drug(s) being considered, previous treatment
history, and pregnancy status/planning. All pros and cons
should be discussed with the patient (and family if needed)
before making the switch.
Psychotherapeutic interventions are essential components
of treatment of mental disorders and in some cases these
interventions may be as effective as medications. They
can improve outcome in treatment-resistant cases, improve
treatment compliance, and improve patent’s psychosocial
functioning. They should be offered to all patients and con-
sidered as an alternative to medication(s) when indicated.
Our review has a several limitations. Its breadth did not
allow specically discussing several studies appearing in our
previous more focused reviews.5–7 Switching among medi-
cations requires understanding of a number of clinical and
pharmacological factors. We discussed those factors briey
in appropriate sections. A detailed discussion of those fac-
tors was beyond the scope of this article. Our review did not
address matters unique to specic populations, such as chil-
dren, older individuals and child-bearing women. The review
also did not specically look for possible racial differences.
Conclusion
Primary care physicians often prescribe or manage patients
receiving psychotropic drugs. These drugs, even when
from the same category or for the same indication, can vary
tremendously in terms of their potential to alter appetite
and weight. Knowledge about the potential weight altering
effects of psychotropic medications and how to switch the
medications if weight change is becoming problematic will
help diminish iatrogenic contribution to weight gain and
obesity. Non-pharmacological interventions both for mental
disorders and overweight/obesity must be fully availed to
optimize patient outcome.
Conict of Interest Statement
Mehrul Hasnain, MD, and W. Victor R. Vieweg, MD, declare
no conicts of interest.
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... Of further note, as weight gain is implicated in the progression of insulin resistance and NAFLD, consideration should be given to the potential weight gain side effects of certain medications for mental health disorders (e.g., certain antidepressants) [10,89]. Indeed, a review by Hasnain and Vieweg [100] highlights the weight changing effects of certain medications used to treat a number of mental health conditions (e.g., mood stabilizers, antidepressants, and anti-anxiety medications), and draws attention to the potential benefits of switching such medications in situations whereby weight gain becomes troublesome, taking into consideration both the patient's condition and possible side effects. Notably, a recent systematic review suggests that metabolic disorders are often exacerbated in people taking antidepressant or antipsychotic medications, with most of the reviewed studies showing a 5% weight gain in individuals under antidepressant therapy [101]. ...
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Zusammenfassung Ziel Gewichtsänderungen als ungewollte Folge der Arzneimitteltherapie sind nicht ungewöhnlich, werden aber oft übersehen oder ignoriert oder – mangels therapeutischer Alternativen – in Kauf genommen. Methodik Selektive Literatursuche. Ergebnisse Zu den wichtigsten Arzneimitteln, die zu ungewolltem Gewichtsverlust führen, gehören Bupropion, Fluoxetin, Topiramat, Zonisamid und die Antidementiva Donepezil, Rivastigmin und Galantamin. Zu den wichtigsten Arzneimitteln, die zu ungewollter Gewichtszunahme führen, gehören verschiedene Neuroleptika und Antidepressiva, außerdem Insuline, Sulfonylharnstoffe und manche Immunsuppressiva. Schlussfolgerungen Die Beurteilung ungewollter Gewichtsänderungen durch Arzneimittel hängt von einer Vielzahl von Faktoren ab, die in Studien oft nicht berichtet und erst recht nicht kontrolliert werden. Dies bedingt eine insgesamt schlechte Evidenzlage. Der Umgang mit unerwünschten Gewichtsänderungen durch Arzneimittel erfordert umfassende klinische und therapeutische Kenntnisse, um prophylaktisch agieren oder eine sinnvolle Therapieumstellung vornehmen zu können.
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Purpose: Attention deficit hyperactivity disorder (ADHD) affects children and adults and is treated with both pharmacologic and nonpharmacologic interventions. Multiple drugs are used to treat ADHD. This review evaluates the evidence on how these drugs compare to each other in benefits and harms. Data Sources: To identify published studies, we searched MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and reference lists of included studies. We also searched the US Food and Drug Administration Center for Drug Evaluation and Research website for additional unpublished data and requested information from pharmaceutical manufacturers. Review Methods: Study selection, data abstraction, validity assessment, grading the strength of the evidence, and data synthesis were all carried out according to our standard review methods. Results and Conclusions: Evidence on the comparative effectiveness of drugs to treat ADHD was insufficient. Evidence on the comparative efficacy in children and adolescents was moderate to low strength and indicated very few differences among the drugs in improving symptoms or in adverse event rates. Sustained-release formulations of stimulants showed benefit over comparators at specific times of day depending on the pharmacokinetics of the specific formulation, but overall differences were not found. Atomoxetine (a nonstimulant) was not found superior to some extended-release stimulant products. Atomoxetine resulted in higher rates of vomiting and somnolence, similar rates of nausea and anorexia, and lower rates of insomnia than stimulants. Extended-release formulations of other nonstimulant drugs (clonidine, guanfacine) have no comparative evidence to date. Immediate-release clonidine was similar to immediate-release methylphenidate. Comparative evidence in adults provided low-strength evidence of no significant differences in efficacy between switching to methylphenidate OROS compared with continuing with immediate-release methylphenidate or between immediate-release guanfacine or modafinil compared with immediate-release dextroamphetamine. Low-strength evidence found no significant differences between immediate-release guanfacine or modafinil compared with immediate-release dextroamphetamine. Evidence on the risk of serious harms was primarily indirect, and indicated atomoxetine has increased risk of suicidal behavior compared with placebo. Differences in risk for sudden death was unclear, cardiac adverse events were not different between stimulants, and cerebrovascular adverse events in adults did not differ between stimulants and atomoxetine. Dextroamphetamine immediate-release caused more inhibition of growth than other stimulants, but the difference was influenced by dose and resolved after 2 years of treatment. Atomoxetine caused similar inhibition of weight gain that lasted up to 5 years. Evidence on abuse, misuse, and diversion was limited, but indicated that stimulant use during childhood is not associated with increased risk of substance use later. Misuse and diversion rates varied by age and were highest among college students, and rates of diversion were highest with amphetamine-based products but similar among methylphenidate products. Evidence of effects in important subgroups of patients with ADHD (e.g. comorbid anxiety) was not comparative. Available at http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0034136.
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Increasingly, it is recognized that first-episode schizophrenia represents a critical stage of illness during which the effectiveness of therapeutic interventions can affect long-term outcome. In this regard, the advent of clozapine and subsequent atypical antipsychotic drugs held promise for improved outcomes in patients with first-episode schizophrenia, given the expectation of improved therapeutic efficacy and a more benign side effect burden compared with typical antipsychotic drugs. A growing number of large clinical trials have evaluated the merits of atypical antipsychotic drugs in the early stages of psychosis. A number of conclusions can be drawn from studies completed to date, with the caveat that data are either limited or unavailable for the antipsychotic drugs most recently approved by the US FDA. Studies of atypical antipsychotic drugs support data obtained with typical agents indicating that positive symptoms of psychosis are very treatment responsive and generally at lower doses than in chronic illness. It also appears that first-episode patients tend to stay on atypical antipsychotic drugs longer than on typical agents when all-cause discontinuation criteria are considered as the primary outcome measure. However, there are few differential advantages of clinical efficacy among the individual atypical antipsychotic drugs and there is little evidence to support distinct therapeutic advantages for negative symptoms or cognitive symptoms for atypical agents. Furthermore, while new-onset psychosis patients are particularly susceptible to extrapyramidal symptoms, they are also prone to gain weight and related metabolic adverse effects associated with many, but not all, atypical antipsychotic drugs. Recent data indicating that certain atypical antipsychotic drugs may have a sparing effect on cortical grey matter loss in first-episode schizophrenia is intriguing, given the potential long-term benefits. In summary, atypical antipsychotic drugs represent an incremental advance for patients in first-episode schizophrenia, especially in the area of neurological tolerability. However, metabolic concerns associated with many atypical agents along with limited benefits in cognition and negative symptom domains highlight the persistent therapeutic needs of these patients.
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To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood pressure augmented significantly under both treatments whereas excessive body weight was seen in rats receiving the 10% fructose only. Rats drinking 5% fructose showed a greater tolerance to a glucose load while rats having access to a 10% fructose drinking solution exhibited the expected impaired glucose tolerance found in the metabolic syndrome. Circulating triglyceride and low density lipoproteins-cholesterol (LDL-c) concentration augmented significantly in rats showing a fully developed metabolic syndrome only, while high blood cholesterol levels were found at both stages examined. Melatonin (25 μg/mL drinking solution) counteracted the changes in body weight and systolic blood pressure found in rats administered with fructose. Melatonin decreased the abnormal hyperglycemia seen after a glucose load in 10% fructose-treated rats but it did not modify the greater tolerance to glucose observed in animals drinking 5% fructose. Melatonin also counteracted the changes in plasma LDL-c, triglyceride and cholesterol levels and decreased plasma uric acid levels. The results underline a possible therapeutical role of melatonin in the metabolic syndrome, both at initial and established phases.
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Objective: To investigate the associations of anxiety and depression symptoms with weight change and incident obesity in men and women. Design: We conducted a prospective cohort study using the Norwegian Nord-Trøndelag Health Study (HUNT). Subjects: The study cohort included 25 180 men and women, 19-55 years of age from the second survey of the HUNT (1995-1997). Measurements: Anxiety and depression symptoms were measured using the Hospital Anxiety and Depression Scale. Weight change was determined for the study period of an average 11 years. Incident obesity was new-onset obesity classified as having a body mass index of 30.0 kg m(2) at follow-up. The associations of anxiety or depression with weight change in kilograms (kg) was estimated using linear regression models. Risk ratios (RRs) for incident obesity associated with anxiety or depression were estimated using log-binomial regression. Results: In men, any anxiety or depression was associated with an average 0.81 kg (95% confidence interval (CI) 0.27-1.34) larger weight change after 11 years compared with those without such symptoms (mean weight change: 5.04 versus 4.24 kg). Women with any anxiety or depression had an average 0.98 kg (95% confidence interval (CI) 0.49-1.47) larger weight change compared with those without such symptoms (mean weight change: 5.02 versus 4.04 kg). Participants with any anxiety or depression had a significantly elevated cumulative incidence of obesity (men: RR 1.37, 95% CI 1.13-1.65; women: RR 1.18, 95% CI 1.00-1.40). Conclusion: We found that symptoms of anxiety and depression were associated with larger weight change and an increased cumulative incidence of obesity in both men and women.
Article
Background: The introduction of second-generation antipsychotics (SGAs) over the past 2 decades generated considerable optimism that better antipsychotic treatments for schizophrenia and bipolar disorder were possible. SGAs offer several tolerability benefits over first-generation antipsychotics (FGAs), particularly with respect to extrapyramidal symptoms. However, SGAs can induce serious metabolic dysregulations, especially in drug-naive, first-episode, and child and adolescent populations, with olanzapine and clozapine having the highest propensity to cause these abnormalities. In this context, newer SGAs were developed to further improve the adverse effect burden of available agents. However, until now, the metabolic risk profile of the newly approved SGAs - asenapine, iloperidone, lurasidone and paliperidone (paliperidone extended release and paliperidone palmitate) - has not been compared. Objective: The objective of this systematic review and exploratory meta-analysis was to assess the effects of asenapine, iloperidone, lurasidone and paliperidone on body weight and other metabolic parameters (cholesterol, triglycerides and glucose), as this information is relevant to guide clinical decision making. Method: A systematic literature search (1966-March 2012), using the Cochrane Central Register of Controlled Trials and MEDLINE, CINAHL and EMBASE databases, was conducted for randomized, placebo-controlled and head-to-head clinical trials of asenapine, iloperidone, lurasidone and paliperidone. Published and unpublished data on changes in body weight and glucose and lipid metabolism parameters were extracted. For placebo-controlled, short-term (<= 2 weeks) and longer-term (>12 weeks) trials with available data on >= 7% weight increase compared with pre-treatment weight, or mean weight change with standard deviation, a formal meta-analysis was performed, estimating the pooled effect size (represented as relative risk [RR], numbers-needed-to-harm [NNH] and weighted mean difference [WMD]). An exploratory meta-analysis was also performed for the other metabolic variables (cholesterol, triglycerides and glucose). Data from active- and placebo-controlled studies were used for a pooled comparison of simple mean changes in weight, cholesterol, triglyceride and glucose levels. Results: Fifty-six trials (n = 21 691) in schizophrenia (N = 49, n = 19 299) or bipolar disorder (N = 7, n = 2392) were identified (asenapine: N = 9, iloperidone: N = 11, lurasidone: N = 8, paliperidone: N = 28). Most of the trials (64.3%) were of <= 12 weeks' duration. In the short-term trials, compared with placebo, a >= 7% weight increase was statistically significantly (p < 0.05) most prevalent for asenapine (5 trials, n = 1360, RR = 4.09, 95% confidence interval [CI] 2.25, 7.43, NNH = 17), followed by iloperidone (4 trials, n = 1931, RR = 3.13, 95% CI 2.08, 4.70, NNH = 11) and paliperidone (12 trials, n = 4087, RR = 2.17, 95% CI 1.64, 2.86, NNH = 20). The effect of lurasidone on body weight (6 trials, n = 1793, RR = 1.42, 95% CI 0.87, 2.29) was not statistically significant. Short-term weight gain was statistically significantly (p < 0.001) greater than placebo with iloperidone (I trial, n = 300, +2.50 kg, 95% CI 1.92, 3.08), paliperidone (15 trials, n = 3552, +1.24 kg, 95% CI 0.91, 1.57), asenapine (3 trials, n = 751, +1.16 kg, 95% CI 0.83, 1.49), as well as with lurasidone (5 trials, n = 999, +0.49 kg, 95% CI 0.17, 0.81, p < 0.01). Sufficient meta-analysable, longer-term, weight change data were only available for asenapine and paliperidone, showing statistically significantly (p < 0.001) greater weight gain versus placebo for both drugs (asenapine, 3 trials, n = 311, +1.30 kg, 95% CI 0.62, 1.98; paliperidone, 6 trials, n = 1174, +0.50 kg, 95% CI 0.22, 0.78). Although statistically significant, in general, no clinically meaningful differences were observed between the four newly approved SGAs and placebo regarding the mean change from baseline to endpoint in cholesterol levels in short-term trials, with the exception of iloperidone for total cholesterol (1 trial, n = 300, +11.60 mg/dL, 95% CI 4.98, 18.22, p 0.001), high-density cholesterol (1 trial, n = 300, +3.6 mg/dL, 95% CI 1.58, 5.62, p < 0.001) and low-density cholesterol (1 trial, n = 300, +10.30 mg/dL, 95% CI 4.94, 15.66, p < 0.001) and with the exception of lurasidone for high-density cholesterol (5 trials, n = 1004, +1.50 mg/dL, 95% CI 0.56, 2.44, p < 0.01). Asenapine increased total cholesterol statistically significantly (p < 0.05) during longer-term treatment (1 trial, n = 194, +6.53 mg/dL, 95% CI 1.17, 11.89). Regarding triglycerides, only short-term (3 trials, n = 1152, +1.78 mg/dL, 95% CI 0.40, 3.17, p < 0.01) and longer-term treatment with paliperidone (4 trials, n = 791, -0.20 mg/dL, 95% CI 0.40, -0.01, p < 0.05) had a statistically, but not clinically, significant effect. Statistically significant changes in glucose levels were noticed during short-term treatment with asenapine (2 trials, n = 379, -3.95 mg/dL, 95% CI -7.37, -0.53, p < 0.05) and iloperidone (1 trial, n = 300, +6.90 mg/dL, 95% CI 2.48, 11.32, p < 0.01), and during long-term treatment with paliperidone (6 trials, n = 1022, +3.39 mg/dL, 95% CI 0.42, 6.36, p < 0.05). Conclusion: While preliminary data suggest the lowest weight gain potential with lurasidone and potentially relevant short-term metabolic effects for asenapine and iloperidone, data are still too sparse to comprehensively evaluate the metabolic safety of the newly approved SGAs. Therefore, there is a clear need for further controlled studies to evaluate whether these agents are less problematic regarding treatment-emergent weight gain and metabolic disturbances than other currently available antipsychotics.
Article
Bupropion is presumed to be a dopamine-norepinephrine reuptake inhibitor and is n effective antidepressant. It is available as three oral formulations: (i) bupropion immediate release (IR) [Wellbutrin®] administered three times daily; (ii) bupropion sustained release (SR) [Wellbutrin SR®] administered twice daily; and (iii) bupropion extended/modified release (XR) [Wellbutrin XL®/Wellbutrin XR®] administered once daily. All three formulations are bioequivalent in terms of systemic exposure to bupropion. Oral three-times-daily bupropion IR was effective and generally well tolerated in the treatment of major depressive disorder (MDD). It was as efficacious and as well tolerated as some tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Moreover, it was associated with less somnolence and weight gain than some TCAs. Twice-daily bupropion SR was also efficacious and generally well tolerated in the treatment of MDD. It was as effective as and had a generally similar tolerability profile to some SSRIs, but had the advantage of less somnolence and sexual dysfunction. The efficacy of bupropion XR in terms of primary efficacy measures was established in two of six well designed placebo-controlled studies. Bupropion XR also demonstrated efficacy in terms of some secondary outcomes in five of these studies. Additionally, bupropion XR was similar, in terms of the primary efficacy outcomes, to the SSRI escitalopram in two placebo-controlled trials and to the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine extended release (XR) in two trials (one of which was placebo-controlled), but not in a third placebo-controlled trial where venlafaxine XR was better than bupropion XR. It was generally as well tolerated as escitalopram and venlafaxine XR, but was associated with less sexual dysfunction than escitalopram. Available clinical data suggest that bupropion is an effective and generally well tolerated option in the treatment of MDD, with the newer formulations having the advantage of reduced frequency of daily administration. Pharmacological Properties As with all antidepressants, the precise mechanism of action of bupropion in MDD is unknown, although bupropion selectively inhibits dopamine and norepinephrine reuptake. The reuptake inhibition potential of bupropion is greater for dopamine than for norepinephrine. Importantly, bupropion does not affect serotonergic pathways and does not act on postsynaptic histamine, α- or β-adrenergic, dopamine or acetylcholine receptors. Time to reach maximum plasma concentration (Cmax) varied between bupropion formulations (IR ≈2 h, SR ≈3 h and XR ≈5 h). A decreased number of peak plasma levels were associated with bupropion SR and XR, compared with bupropion IR. However, bioequivalent systemic exposure (as assessed by Cmax and area under the plasma concentration-time curve) was established between all formulations of bupropion and its three pharmacologically active metabolites. Steady state is reached within 8 days. Bupropion is extensively metabolized, mainly by cytochrome P450 (CYP) isoenzymes or via carbonyl reduction. As the active metabolites of bupropion reach higher steady-state concentrations than those of bupropion, these metabolites may be of clinical importance. Bupropion has an elimination half-life (t½) of 20–21 hours and is predominantly (87%) excreted in the urine as metabolites. The t½ of the active metabolites of bupropion are ≈20, ≈33 and ≈37 hours. There is potential for drug-drug interactions between bupropion and drugs that affect CYP2B6 and 2D6 metabolism, drugs that are substrates of these isoenzymes and drugs that affect metabolism in general. Therapeutic Efficacy Three-times-daily bupropion IR was effective in the treatment of MDD in a 6-week randomized, double-blind clinical trial in adults with moderate to severe disease, demonstrating greater improvement from baseline in several efficacy measures relative to placebo. Moreover, bupropion IR was as effective as the SSRI fluoxetine, the TCAs nortriptyline, amitriptyline and doxepin, and the atypical antidepressant trazodone in reducing symptoms of depression and anxiety assessed by several efficacy measures in 6- to 13-week trials in adults with MDD. Similarly, twice-daily bupropion SR was effective in the treatment of MDD in 8-week, randomized, double-blind clinical trials in adults with moderate to severe disease, demonstrating greater improvements from baseline in several efficacy measures relative to placebo. In addition, bupropion SR was effective in preventing relapse in one 52-week relapse-prevention study in a similar patient population. In comparative trials, there were no significant differences between bupropion SR and the SSRIs sertraline or fluoxetine in adults and the SSRI paroxetine in elderly patients with moderate to severe disease in randomized studies of 6- to 16-weeks' duration. Furthermore, bupropion SR was as effective as the SSRI sertraline and the SNRI venlafaxine XR with respect to remission rates (primary efficacy measure) in patients who were switched from citalopram therapy because of a lack of remission of symptoms or because they could not tolerate citalopram in the large, randomized, multicentre STAR*D trial. In the same study, bupropion SR was shown to be as effective as the serotonin receptor agonist buspirone, in terms of remission rates, when used to augment citalopram therapy in a similar patient population. There were some benefits with bupropion SR relative to buspirone therapy as demonstrated by a greater reduction from baseline in self-rated 16-item Quick Inventory of Depressive Symptomology (QIDS-SR-16) score and a lower QIDS-SR-16 score with bupropion compared with buspirone therapy at study end. Two of six placebo-controlled trials in adult and elderly patients with moderate to severe MDD demonstrated greater improvements from baseline in the 30-item self-rated Inventory of Depressive Symptomology scale or Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary efficacy measures) with once-daily bupropion XR relative to placebo. However, in the trial involving elderly patients, although significant reduction from baseline in MADRS total scores in bupropion XR relative to placebo recipients in the last-observation-carried-forward analysis (primary efficacy measure) was not observed, significant improvements from baseline were observed in the protocol-defined observed-case or per-protocol analyses and according to the rank analysis of covariance and robust regression analysis. Benefit with respect to some secondary measures was observed with bupropion XR relative to placebo in five of six placebo-controlled efficacy studies in adults and the elderly. There were no significant differences between bupropion XR and the SSRI escitalopram in terms of the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score (primary efficacy measure) in patients with moderate to severe disease in placebo-controlled studies of 8 weeks' duration. Similarly, in two 8- and 12-week studies, one of which was placebo-controlled, in patients with similar disease, there were no significant differences between bupropion XR and the SNRI venlafaxine in terms of primary (MADRS total score) or secondary (HAM-D-17 total score) efficacy measures. Additionally, in the 12-week study, more patients achieved remission with bupropion XR than venlafaxine XR therapy. However, in one 8-week placebo-controlled study, venlafaxine XR was better than bupropion XR in terms of MADRS total scores (primary efficacy measure). Tolerability All three formulations of bupropion (IR, SR or XR) were generally well tolerated in patients with moderate to severe MDD. Adverse event-related withdrawal rates in pooled analyses were 5–11 % in bupropion IR, SR or XR recipients. Overall, the most common treatment-emergent adverse events reported in bupropion IR, SR or XR versus placebo recipients were headache (20–26% vs 20–23%), dry mouth (16–28% vs 7–18%) and nausea (13–23% vs 8–19%); agitation was another common treatment-emergent adverse event reported in 32% of bupropion IR compared with 22% of placebo recipients. Bupropion SR and XR were also well tolerated in terms of their effects on sexual functioning in patients with MDD. Most adverse events associated with bupropion SR or XR relative to placebo were mild to moderate in severity. However, there is a dose-dependent risk of seizures (0.4% with bupropion IR 300–450 mg/day; 0.1% with bupropion SR 100–300 mg/day, increasing to 0.4% with bupropion SR 400 mg/day; and 0.1% with bupropion XR ≤450 mg/day) associated with the use of bupropion. Although the effect of bupropion (IR, SR or XR) on suicidality is not clear, it is recommended that patients should be monitored closely. In general, the effects of bupropion (IR, SR or XR) on vital signs (systolic and diastolic blood pressure and heart rate) were small, although some changes (largely an increase in ≤12% of patients) in these parameters with bupropion XR were of potential concern or were sustained (in 3–11% of patients) during therapy. Although the tolerability profile of bupropion (IR, SR or XR) was generally similar to that of TCAs (nortriptyline, amitriptyline and doxepin), an atypical antidepressant (trazodone), SSRIs (including sertraline, fluoxetine and escitalopram) and an SNRI (venlafaxine XR) in patients with moderate to severe MDD, some adverse events were reported in fewer bupropion than comparator recipients. Bupropion SR and XR were associated with less sexual dysfunction than SSRIs, such as sertraline and escitalopram. Bupropion XR had a more favourable effect on sexual function than venlafaxine XR in one study, which assessed the parameter as the primary outcome measure, but not in two others where sexual function was assessed as a secondary outcome measure. Bupropion IR and SR were associated with less somnolence relative to some TCAs and SSRIs. On the other hand, the incidence of dry mouth was higher with bupropion IR and SR than with some SSRIs, but lower than that observed with some TCAs. In patients receiving citalopram therapy augmented with bupropion SR or buspirone in the STAR*D trial, discontinuation rates due to intolerance were lower with bupropion SR plus citalopram than with buspirone plus citalopram. Although bupropion IR, SR and XR were associated with a weight gain of >2.3 kg (>5 lb), the incidence of weight gain was ≈4-fold lower with bupropion IR than with TCAs. Bupropion (IR, SR or XR) was also associated with a weight loss of >2.3 kg (>5 lb). However, the incidence of weight loss with bupropion IR was approximately twice that observed with TCAs. No clinically significant changes in weight were observed in bupropion SR or placebo recipients after 52 weeks of therapy.
Article
Antipsychotic-induced weight gain is an important issue in the treatment of psychotic illnesses, and affects 80% of individuals being treated with antipsychotic drugs. However, the true dimension of weight gain and many accepted ‘facts’ in this area remain unclear as most research has been conducted in short-term trials and has included individuals receiving prolonged antipsychotic treatment. This review aims to systematically and critically review the evidence on weight gain induced by the two leading second-generation antipsychotics (olanzapine and risperidone) and the most widely researched first-generation antipsychotic (haloperidol) in patients with chronic and first-episode psychotic disorders. Weight gain was 3- to 4-fold greater in studies that included young patients with limited previous exposure to antipsychotic agents in both short-term studies (7.1–9.2 kg for olanzapine, 4.0–5.6 kg for risperidone and 2.6–3.8 kg for haloperidol vs 1.8–5.4 kg, 1.0–2.3 kg and 0.01–1.4 kg, respectively, in studies that included patients with chronic psychotic disorders) and long-term trials (10.2–15.4 kg for olanzapine, 6.6–8.9 kg for risperidone and 4.0–9.7 kg for haloperidol vs 2.0–6.2 kg, 0.4–3.9 kg and −0.7 to 0.4 kg, respectively). The same disparity was observed regarding the proportion of patients increasing their baseline weight by ≥7% (the cut-off for clinically significant weight gain). Recent studies carried out in young patients with first-episode psychosis (FEP), along with methodological artefacts in studies of chronic populations, suggest that the magnitude of weight gain reported by much of the literature could in fact be an underestimation of the true magnitude of this adverse effect. Although antipsychotics present idiosyncratic patterns of weight gain, they may also generate similar absolute gains.