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CLINICAL FEATURES
© Postgraduate Medicine, Volume 125, Issue 5, September 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 117
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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-decit/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
signicant 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, efcacy, side effect prole,
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-decit/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 signicant 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 signicant 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-
specic 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 reected 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 signicant
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 signicant 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 signicant 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 benecial 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 signicantly 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 signicantly after 6 months of ziprasidone
treatment. Switching to aripiprazole may also be benecial.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-decit/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 efcacy 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 benecial for morbidly
obese patients.32 For best results, make the switch as soon as a
trajectory of rapid and/or signicant 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-decit/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 specically 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 ≈2≈18
Aripiprazole Low ≈1≈10
Asenapine Low ≈1≈15
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 ≈1≈10
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 reected 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 signicant 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 signicant 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 signicant 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 efcacy 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 signicant ($ 7% from baseline) weight; and 1.3%
in the nefazodone group compared with 3.5% in the SSRI
group lost signicant weight. At the end of long-term phase
(16–46 weeks), the number for signicant weight gainers
had increased to 6.9% compared with 13.8%, respectively,
and the number for signicant 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.
Mehrul Hasnain and W. Victor R. Vieweg
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Patients gaining (or losing) signicant 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 difcult-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 specically 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 signicant 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 efcacy 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. Signicant individual variations in weight change can occur.
Abbreviation: ADHD, attention-decit/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 signicant weight
effect.7 Non-benzodiazepine hypnotics are also not known
to alter weight.
Melatonin does not seem to have signicant 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 specic 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 signicant 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 efcacy 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 identied as a signicant 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 signicant 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 signicantly 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, efcacy, frequency of administration, side effect
prole (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 specically 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 briey
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 specic populations, such as chil-
dren, older individuals and child-bearing women. The review
also did not specically 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.
Conict of Interest Statement
Mehrul Hasnain, MD, and W. Victor R. Vieweg, MD, declare
no conicts of interest.
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