CNS Drugs 2009; 23 (12): 1003-1021

REVIEW ARTICLE 1172-7047/09/0012-1003/$49.95/0

ª 2009 Adis Data Information BV. All rights reserved.

Adverse Endocrine and Metabolic Effects

of Psychotropic Drugs
Selective Clinical Review
Chaya G. Bhuvaneswar,1 Ross J. Baldessarini,2,3 Veronica L. Harsh4 and Jonathan E. Alpert2
1 Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA
2 Departments of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston,
Massachusetts, USA
3 McLean Hospital, Belmont, Massachusetts, USA
4 Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, Maryland, USA

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
1. Hyperprolactinaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
2. Water Homeostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
2.1 Hyponatraemia and Syndrome of Inappropriate Antidiuretic Hormone . . . . . . . . . . . . . . . . . . . 1007
2.2 Diabetes Insipidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
3. Thyroid and Parathyroid Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
3.1 Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
3.2 Hyperparathyroidism and Hypocalcaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
4. Reproductive Dysfunctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
4.1 Sexual Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
4.2 Virilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
5. Bodyweight and Metabolic Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
5.1 Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
5.2 Obesity and Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
5.3 Clinical Management of Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013

Abstract The article critically reviews selected, clinically significant, adverse endo-
crine and metabolic effects associated with psychotropic drug treatments,
including hyperprolactinaemia, hyponatraemia, diabetes insipidus, hypo-
thyroidism, hyperparathyroidism, sexual dysfunction and virilization, weight
loss, weight gain and metabolic syndrome (type 2 diabetes mellitus, dyslipi-
daemia and hypertension). Such effects are prevalent and complex, but can be
managed clinically when recognized. They encourage continued criti-
cal assessment of benefits versus risks of psychotropic drugs and underscore
the importance of close coordination of psychiatric and general medical care
to improve long-term health of psychiatric patients. Options for management
of hyperprolactinaemia include lowering doses, switching to agents such as
aripiprazole, clozapine or quetiapine, managing associated osteoporosis,
1004 Bhuvaneswar et al.

carefully considering the use of dopamine receptor agonists and ruling out stress,
oral contraceptive use and hypothyroidism as contributing factors. Disorders of
water homeostasis may include syndrome of inappropriate antidiuretic hormone
(SIADH), managed by water restriction or slow replacement by hypertonic
saline along with drug discontinuation. Safe management of diabetes insipidus,
commonly associated with lithium, involves switching mood stabilizer and con-
sideration of potassium-sparing diuretics. Clinical hypothyroidism may be a
more useful marker than absolute cut-offs of hormone values, and may be asso-
ciated with quetiapine, antidepressant and lithium use, and managed by thyr-
oxine replacement. Hyper-parathyroidism requires comprehensive medical
evaluation for occult tumours. Hypocalcaemia, along with multiple other psy-
chiatric and medical causes, may result in decreased bone density and require
evaluation and management. Strategies for reducing sexual dysfunction with
psychotropics remain largely unsatisfactory. Finally, management strategies for
obesity and metabolic syndrome are reviewed in light of the recent expert
guidelines, including risk assessment and treatments, such as monoamine
transport inhibitors, anticonvulsants and cannabinoid receptor antagonists, as
well as lifestyle changes.

A wide range of adverse metabolic effects are
associated with psychotropic drugs, including anti-
psychotics, mood stabilizers and antidepressants.
As many questions remain regarding the epide-
miology, pathophysiology, medical implications
and clinical management of such effects, we re-
viewed recent clinical and research literature on
the topic, based on computerized searching through
the MEDLINE database (1980 to mid-2008). We
used the following search terms: ‘diabetes type I’,
‘diabetes type II’, ‘dyslipidemia’, ‘endocrine’, ‘hyper-
calcemia’, ‘hyperglycemia’, ‘hyperprolactinemia’,
‘hyperosmolar’, ‘hyponatremia’, ‘ketoacidosis’,
‘lipid metabolism’, ‘weight-gain’, as well as speci-
fic pituitary, gonadal, thyroid and adrenal hormone
names, each in combination with: ‘anxiolytic’,
‘antidepressant’, ‘antipsychotic’, ‘hypnotic’, ‘mood
stabilizer’, ‘psychotropic’, ‘psychostimulant’, ‘stim-
ulant’, ‘sedative’, as well as with names of com-
monly used generic and brand-name medicines
(see the list of the drug names used for compu-
terized literature searching, Supplemental Digital
Content 1, http://links.adisonline.com/CNZ/A4).
We also considered possible sex and age differ-
ences in adverse effects, and proposed recom-
mendations for clinical management based on
both published guidelines and clinical experience.
Major adverse effects, suspect agents and poten-
tial remedies are summarized in table I.
1. Hyperprolactinaemia
Major hormones of the anterior pituitary
(adenohypophysis) are normally controlled by
hypothalamic regulatory molecules. Important ex-
amples include adrenocortocotropic hormone
(ACTH), follicle-stimulating hormone (FSH),
growth hormone (GH), luteinizing hormone (LH),
prolactin, and thyroid-stimulating hormone (TSH).
These large peptides and the cells that produce
them are influenced by various psychotropic
agents. Increased output of prolactin, a 199-amino
acid peptide regulated by genes on human chro-
mosome 6, is of particular concern regarding
antipsychotic and other psychotropic drugs.[1]
Serum prolactin levels are considered normal at
5–20 ng/mL (170–700 mIU/mL) in men, 10–25 ng/mL
(300–800 mIU/mL) in nonpregnant women and
200–300 ng/mL in pregnant women, with 2- to 3-fold
circadian variations and highest output several hours
after sleep onset.[1]
Hyperprolactinaemia was first encountered
with use of chlorpromazine in the 1950s,[2] has been

ª 2009 Adis Data Information BV. All rights reserved. CNS Drugs 2009; 23 (12)
Endocrine and Metabolic Effects of Psychotropic Drugs 1005

Table I. Representative adverse endocrine and metabolic effects of psychotropic medicinesa

Effect Implicated drugs Treatment options
Hyperprolactinaemia Antipsychotics, risperidone, paliperidone Change to aripiprazole, clozapine, ziprasidone; cautious
use of dopamine receptor agonist; supplemental
estrogen/progesterone; bisphosphonates, calcium
supplements
Hyponatraemia/SIADH Carbamazepine, oxcarbazepine, desmopressin, Use alternative treatments, restrict water intake, ‘slow’
SRIs, NSAIDs, diuretics, opioids, NMDA receptor intravenous infusion of saline if severe
antagonists, nicotine
Nephrogenic diabetes Lithium, clozapine Reduce dose, use alternative treatments, amiloride
insipidus (cautiously)
Hypothyroidism Lithium; rarely anticonvulsants, antidepressants or Use alternative treatments, consider replacement therapy
antipsychotics
Hyperparathyroidism Lithium; rarely carbamazepine or valproate Use alternative treatments, consider cinacalcet
Sexual dysfunction SRIs (anorgasmia), valproate (PCOS) Use alternative treatments, bupropion, sildenafil, herbals
(?); avoid valproate in young women
Weight loss Psychostimulants, topiramate, SRIs Use alternative treatments
Obesity and metabolic Antipsychotics, mood stabilizers, antidepressants, Reduce dose, use alternatives; consider amantadine,
syndrome sedatives bupropion, metformin, modafinil, memantine, orlistat,
rimonabant, sibutramine, topiramate, zonisamide
a Suggested active treatments presume that conservative steps, including removal or reduced dosing of offending agents or changing to
similar, but less risky alternatives are considered first. Clinical manifestations and diagnostic considerations are summarized in the text.
NSAIDs = non-steroidal anti-inflammatory drugs; PCOS = polycystic ovary syndrome; SIADH = syndrome of inappropriate antidiuretic
hormone; SRIs = serotonin reuptake inhibitors.

associated with most antipsychotics introduced over
the past half-century and may be more common
among women than men.[3,4] High-potency anti-
psychotics that strongly block dopamine D2 re-
ceptors on anterior pituitary mammotrophic cells
are most likely to disinhibit prolactin release, and
in turn, dopamine from the hypothalamus is
a prolactin inhibitory factor transported from
the median eminance through the hypophyseo-
portal vasculature.[5] Other pituitary hormones
that influence prolactin secretion, including
TSH-releasing hormone and vasoactive inhibitory
peptide, can also be influenced by dopamine and
by some antipsychotic and other drugs.[5] Drugs
that increase prolactin output include some anti-
depressants (clomipramine, fluoxetine), opioids
and cocaine (mild elevations), antihypertensives
(particularly verapamil, also used in the treatment
of anxiety disorders, and a-methyldopa), and
antiretroviral drugs.[4,6-11] Psychotropic drugs
unlikely to induce hyperprolactinaemia include
benzodiazepines, buspirone, lithium and anti-
manic anticonvulsants including carbamazepine
and divalproex sodium.[4,12-16] Renal failure
may also increase elevations of circulating prolactin
induced by drugs.[8] In addition, variable sponta-
neous increases in prolactin output have been
reported among unmedicated patients with psy-
chotic disorders, independent of adverse drug
effects.[17]
Strongly prolactin-elevating antipsychotics
include haloperidol, fluphenazine, trifluperazine and
most other older, potent antipsychotics, as well as
risperidone, its active metabolite paliperidone
and the antidopaminergic gastrointestinal agents
domperidone and metoclopramide. The US
FDA-nonapproved, substituted benzamide com-
pound sulpiride and its congener amisulpride, have
mesolimbic regional selectivity in the brain with
little antiserotonergic effect, and can elevate serum
prolactin levels dose dependently, but reversibly,
when the drugs are stopped.[18,19] Injected, long-
acting antipsychotics (fluphenazine and haloper-
idol decanoate, paliperidone palmitate and
risperidone microspheres) all increase serum pro-
lactin levels.[20-22] Among modern antipsychotics,
aripiprazole, clozapine, quetiapine and ziprasidone
have little effect on prolactin. Although olanzapine
has substantial antidopaminergic effects and can
elevate tissue prolactin levels to some extent,[23-26]

ª 2009 Adis Data Information BV. All rights reserved. CNS Drugs 2009; 23 (12)
1006
the effects are less significant than those of other
antipsychotics, such as risperidone, particularly in
women.[27] The D2 receptor partial-agonist ari-
piprazole, when used adjunctively, may help to
reverse hyperprolactinaemia induced by other
antipsychotics.[28-30]
Typically, antipsychotic-associated hyperpro-
lactinaemia begins within days, persists through-
out treatment, and gradually disappears after
discontinuing treatment over times that probably
reflect the rate of elimination of tissue-bound
pools of the relatively lipophilic agents implicated
in hyperprolactinaemia.[31,32] Occasionally, serum
prolactin levels increase transiently and return to
normal even with continued treatment.[33,34] Among
older antipsychotics, prolactin elevation (typically
to 20–200 ng/mL)[32] correlates approximately with
antipsychotic potency (and other pharmacodyna-
mic effects) and with typical daily doses or affi-
nity at dopamine receptors. Prolactin elevation was
formerly proposed as an index of effective anti-
psychotic dosing,[3] as were emerging symptoms
of extrapyramidal syndromes (EPS) with older
antipsychotics.[35,36] However, use of such effects
to guide dosing can be misleading, owing to dis-
parities between D2 receptor antagonist potency
and clinical efficacy, particularly among newer,
second-generation or ‘atypical’ antipsychotics,
and adverse effects including hyperprolactinae-
mia and EPS are best minimized or avoided.[37-39]
Manifestations of hyperprolactinaemia should
be inquired about routinely among patients taking
any agent with D2 receptor antagonist activity, and
serum prolactin assays can confirm suspected
cases. In both men and women, typical clinical
manifestations of hyperprolactinaemia include
breast enlargement and tenderness, galactorrhoea,
decreased libido and variable osteoporosis. Some
of these effects may reflect inhibition by prolactin
of the release of hypothalamic gonadotropin-
releasing hormone (GRH), with decreases in cir-
culating estrogen in women and in testosterone in
men, both resulting in increased osteoclast activ-
ity.[40,41] Women with hyperprolactinaemia may
also experience virilization and menstrual irregu-
larities.[3,42-44] Men also may experience erectile
or ejaculatory dysfunction or decreased sperma-
togenesis.[45-47] Sometimes it may be unclear whether
ª 2009 Adis Data Information BV. All rights reserved.
Bhuvaneswar et al.
altered sexual functioning reflects major mental
illnesses themselves, or effects of their treat-
ment.[48] It is also uncertain whether prolonged
hyperprolactinaemia increases long-term risk of
pituitary or breast cancer, particularly since the
hyperprolactinaemia associated with most anti-
psychotics is typically moderate.[49,50] Major in-
creases in serum levels of prolactin (>250 ng/mL)
or increases that do not abate with a change in
treatment may call for more extensive evaluation
for pituitary tumour.[51] Options for clinical man-
agement of hyperprolactinaemia include lowering
doses of suspect agents when possible, or switch-
ing to one less likely to elevate prolactin, such as
aripiprazole, clozapine, quetiapine or moderate
doses of olanzapine.[52,53]
Dopamine agonists (including apomorphine,
bromocriptine, cabergoline, pergolide, prami-
pexole, quinagolide, ropinirole and rotigotine)
suppress prolactin secretion, and should be used
with caution for this effect, as they increased
agitation, psychosis or mania, particularly if ade-
quate treatment with an antipsychotic or mood
stabilizer is not continued.[54-56] Antiestrogenic
effects of hyperprolactinaemia also require man-
agement. Associated risk of antiestrogenic effects
including osteoporosis may resolve with weight-
bearing exercises and calcium supplementa-
tion or use of bisphosphonates, and supplemental
estrogen/progesterone treatment may mitigate
hypogonadism in women.[57]
Stress, oral contraceptives and hypothyroid-
ism may complicate development and presenta-
tion of hyperprolactinaemia, particularly among
women. Normal physiological causes of hyper-
prolactinaemia in women include pregnancy and
lactation, which must be excluded among wo-
men with severe mental illness, whose sexual
activity may be covert, non-consensual and not
accompanied by basic general medical and
gynaecological healthcare.[58] Sleep deprivation
can represent a reversible cause of hyperpro-
lactinaemia along with other physical stresses,
including starvation and intensive athletic train-
ing.[59] Finally, hypothyroidism can cause hyper-
prolactinaemia, mediated by increased release of
thyroid-releasing hormone, which directly stimu-
lates pituitary lactotrophs.[60]
CNS Drugs 2009; 23 (12)
Endocrine and Metabolic Effects of Psychotropic Drugs
2. Water Homeostasis
2.1 Hyponatraemia and Syndrome of
Inappropriate Antidiuretic Hormone
The posterior pituitary (neurohypophysis) pro-
duces oxytocin and antidiuretic hormone (ADH;
arginine-vasopressin). AHD is a nonapeptide
(9 amino acids), produced from a 164-amino acid
precursor protein synthesized in the hypothalamic
suprachiasmatic nucleus, under genetic control of
chromosome 20, and transported to the posterior
pituitary for processing and distribution to act
peripherally and on the brain.[1] A syndrome of in-
appropriate ADH (SIADH) is characterized by
hyponatraemia arising from retention of water
(by inhibited secretion of water) through vasopressin
V2 receptors in renal tubules and conducting
ducts.[61] SIADH occurs with malignancies and in
neurological, hepatic and pulmonary diseases.[62]
Hyponatraeemia can also arise with excessive
water intake, as in psychogenic polydipsia asso-
ciated with psychotic disorders.[63] SIADH has
been associated with several psychotropic drugs,
notably serotonin reuptake inhibitors (SRIs), the
anticonvulsants carbamazepine and oxcarbaze-
pine and, less often, tricyclic antidepressants (TCAs)
or other types of antidepressants, opioids and
perhaps nicotine and the psychoactive agent 3,4-
methylenedioxy-N-methylamphetamine (MDMA;
‘ecstasy’).[64-72] Although antipsychotics rarely
cause SIADH, coadministration of multiple anti-
psychotics can lead to hyponatraemia.[73-75]
SIADH can also complicate the use of synthetic
ADH-like agents including desmopressin (espe-
cially with rapidly absorbed nasal sprays), some-
times used to treat enuresis, including polyuria
associated with psychotropics such as lithium
and clozapine.[76,77] Risks of clinically dangerous
hyponatraemia can increase when multiple agents
with SIADH-promoting effects are combined,
including common analgesic non-steroidal anti-
inflammatory drugs (NSAIDs) (e.g. indometacin,
diclofenac, ibuprofen, mefenamic acid, mizoribine,
paracetamol [acetaminophen]) and salt-losing
thiazide diuretics.[78,79] Severe hyponatraemia
with SIADH can present with confusion or de-
lirium, seizures and coma associated with cerebral
ª 2009 Adis Data Information BV. All rights reserved.
1007
oedema.[80] Elderly patients and women appear
to be at particularly high risk.[80,81] SIADH
should be considered among psychiatric patients
medicated with at-risk drugs and showing changes
in mental status, especially new lethargy, confu-
sion, epileptic seizures or coma. Treatment of
SIADH induced by psychotropics includes iden-
tification and removal of suspected drugs. Severe,
symptomatic hyponatraemia calls for the use of
fluid restriction or cautious infusion of hyper-
tonic saline, given slowly to avoid risk of hyper-
natraemic pontine myelinolysis.[81,82]
2.2 Diabetes Insipidus
Lithium can interfere with the actions of ADH
at its renal tubular receptors, leading to increased
circulating levels of the hormone, hypernatraemia,
increased thirst and output of dilute urine, with
risk of nephrogenic diabetes insipidus, which oc-
curs in at least 10% of patients treated long term
with lithium.[69,83-85] Usually diabetes insipidus
reverses soon after stopping lithium, and is in-
consistently associated with risk of late, chronic
granulomatous inflammatory changes found in
renal biopsies of patients treated for years with
lithium.[85-87] Such risks with lithium mainte-
nance treatment encourage routine monitoring of
serum levels of creatinine, electrolytes and lithium,
ideally at baseline and 6 months, and subsequently
at not less than annual intervals. Consultation
with a renal expert and evaluations including
creatinine clearance and 24-hour urine volume and
osmolality are warranted with a persistently high
output of urine (>4 L/day) – all of which help to
distinguish diabetes insipidus from more com-
mon, benign polyuria.[88,89]
Diabetes insipidus is typically associated with
24-hour urine volumes of >3 L (or >2 L/m2 in
children), which are unlikely in association with
the common complaints of frequency, urgency or
nocturia, especially early in lithium treatment,
with excessive fluid intake associated with ‘dry
mouth’ (xerostomia) associated with many
psychotropic agents, or with psychogenic poly-
dipsia.[89] In addition to long-term lithium treat-
ment, diabetes insipidus has been associated with
clozapine treatment.[83] Paradoxically, clozapine
CNS Drugs 2009; 23 (12)
1008
has also been used with promising results to treat
psychotic patients at risk for polydipsia with
diabetes insipidus-like symptoms.[90-92] Diabetes
insipidus requires consideration of a broad range
of differential diagnoses, including germinomas
and other tumours, polycystic kidney, sickle-cell
anaemia, syphilis, tuberculosis, tissue trauma,
and uncommon causes such as histiocytosis, sar-
coidosis, or hypothalamic dysfunction (central
diabetes insipidus), or hypothalamic damage
secondary to excessive fluid intake, as well as
disordered metabolism of calcium or potassium.
In addition, pregnancy, owing to increased pla-
cental ADH-metabolizing activity, may increase
the risk of diabetes insipidus.[93]
Diagnostic assessment of possible diabetes
insipidus usually includes initial water restric-
tion to test ability to concentrate urine, followed
by an oral dose of desmopressin. If desmopressin
decreases urine output and increases urine osmo-
lality, then central diabetes insipidus is likely,
whereas lack of effect suggests nephrogenic dia-
betes insipidus, especially with nonresponse of
ADH receptors to the synthetic ADH-like agent.
Treatment can be conservative, based on stop-
ping the suspected agent (most often lithium),
if possible, or lowering doses if symptoms are
mild. Most diuretics, paradoxically, can reverse
diabetes insipidus at the renal-tubule level. Thia-
zides are effective against diabetes insipidus, but
promote retention of lithium as sodium is wasted.
They induce potentially dangerous loss of potas-
sium and are usually avoided; if not, the dose of
lithium typically is reduced by half before a
thiazide is added, with weekly initial monitoring
of daily trough serum lithium concentrations
(usually between 8:00am and 10:00pm, before a
first dose) to assure stable, therapeutic concen-
trations. Similarly, some NSAIDs, including in-
dometacin, reverse diabetes insipidus, but such
agents, as a class, also promote lithium retention,
calling for close monitoring of serum lithium
concentrations and reducing the dose of lithium,
as required. Potassium-sparing diuretics, includ-
ing amiloride and perhaps triamterene, appear to
be safer options if lithium is continued, although
they, too, promote natriuresis and can lead to
retention of lithium.[94] Instead of such poten-
ª 2009 Adis Data Information BV. All rights reserved.
Bhuvaneswar et al.
tially risky treatments, current practice favours
changing to an alternative mood stabilizer, such
as an anticonvulsant.
3. Thyroid and Parathyroid Function
3.1 Hypothyroidism
Several psychotropic drugs can alter thyroid
function, usually by decreasing circulating thy-
roid hormones, often anticipated by early increases
in circulating TSH.[95] Lithium has most often been
implicated. In about 10% of patients maintained
on lithium, output of triiodothyronine (T3) and
thyroxine (T4) is impaired, owing in part to de-
creased end-organ sensitivity to TSH, possibly
decreased thyroid uptake of iodine, less efficient
release of synthesized T3 and T4 and their de-
creased coupling with thyroglobulin.[95,96] Some
antidepressants, anticonvulsants and antipsycho-
tics may also decrease thyroid function.[96-101] Other
agents employed for mood-stabilizing effects, in-
cluding carbamazepine, divalproex sodium and
lamotrigine, are far less likely to affect thyroid
functioning than lithium.[99] However, carbamaze-
pine and phenytoin can reduce binding to thyroid-
binding globulin to increase circulating levels of
free thyroid hormone, as well as increasing meta-
bolic clearance of T4. In patients given T4 sup-
plements, hormone metabolism is increased by
barbiturates, carbamazepine or phenytoin. Among
antipsychotics, quetiapine is most associated with
hypothyroidism (about 0.4% incidence), especially in
patients previously treated with radioiodine.[102]
Clinically significant hypothyroidism or myxoedema
can be confused with major depression, and both are
more likely among mature women, especially fol-
lowing unrecognized thyroid inflammatory disease
with compromised reserves.[103-105]
Antidepressant treatment or recovery from
major depression is sometimes associated with
minor decreases in thyroid hormone produc-
tion,[103] and estrogen replacement therapy may
require increased T4 to sustain suppression of
serum TSH levels.[104] During long-term treat-
ment with lithium, quarterly, and then twice-
yearly monitoring of thyroid status, especially
with serum TSH assays, is recommended.[105]
CNS Drugs 2009; 23 (12)
Endocrine and Metabolic Effects of Psychotropic Drugs
Treatment of hypothyroidism associated with
lithium or other psychotropic drug treatments is
often managed conservatively by reducing the
dose, or using alternative agents with similar
psychotropic actions. If clinical indications for
continuing treatment with lithium are compel-
ling, thyroid hormone supplementation may be
appropriate.
Recent guidelines for detection and manage-
ment of lithium-induced, late thyroid dysfunction
emphasize laboratory testing and clinical ex-
amination prior to starting lithium, and then
regular follow-up during treatment. Rather than
simply relying on specific values for TSH or free
T4 index to guide treatment, monitoring of clin-
ical symptoms more often provides useful guide-
lines.[105] In addition, bipolar disorder patients
with initial thyroid abnormalities may be less re-
sponsive to lithium treatment.[106] More assertive
treatment of even subclinical hypothyroidism
may improve outcomes among bipolar disorder
patients.[105-107] T4 is longer acting, though less
potent than T3; it is generally preferred as a more
physiological option, although addition of T3
has, inconsistently but specifically, been asso-
ciated with subjective improvements in mood and
energy levels.[108,109]
3.2 Hyperparathyroidism and
Hypocalcaemia
Parathyroid hormone (PTH; parathormone)
is an 84-amino acid peptide produced by para-
thyroid tissue, under genetic control by chromo-
some 11. It increases intestinal absorption and
renal retention of calcium and increases osteo-
clast formation and activity in bone.[1] Hyper-
parathyroidism, with variable hypercalcaemia,
has been associated with long-term treatment
with lithium, sometimes in association with
diabetes insipidus.[110,111] Lithium appears to stim-
ulate PTH release, as well as inhibit renal excre-
tion of calcium. Such effects occasionally persist
after lithium treatment is discontinued, and may
require medical intervention, such as with the
calcium mimetic agent cinacalcet.[112] Hyper-
parathyroidism with hypercalcaemia may be
asymptomatic, but can present with psychiatric
ª 2009 Adis Data Information BV. All rights reserved.
1009
disorders including anxiety, depression, obsessive
compulsion or paranoia, as well as with cognitive
impairment.[113] Hypercalcaemia is readily as-
sessed with assays of serum calcium and PTH
levels. As hyperparathyroidism is often associated
with benign or malignant parathyroid tumours, it
requires comprehensive medical evaluation.
Treatment with carbamazepine and valproic
acid salts (valproate) has been associated with
hypocalcaemia, particularly in children and pa-
tients with a deficient intake of vitamin D.[114,115]
SRIs can directly increase osteoclast functioning
and reduce bone density with long-term use,
whereas TCAs are much less likely to do so.[116]
Such loss of bone density, with risk of fractures, is
likely to be worsened by lack of weight-bearing
exercise and malnutrition.[117,118] Another poten-
tial cause of decreased bone density is hyperpro-
lactinaemia. As noted in section 1, antipsychotics,
especially those with prominent increases in
prolactin and associated decreases in estrogen
production, can produce indirect changes in bone
mineralization to promote osteoporosis. Poly-
therapy with combinations of psychotropic drugs
(e.g. antidepressants plus antipsychotics) may
carry a greater risk than monotherapies.[119] Ab-
normal bone density associated with a sedentary
lifestyle and abnormalities of prolactin and estro-
gen output can add further complexity, especially
among women with psychiatric illnesses, includ-
ing eating disorders.[120,121]
Current recommendations for patients at risk
for osteoporosis and taking a medicine that can
increase this risk include initial and follow-up
assays of serum calcium level, with PTH assays
added if hypocalcaemia or radiological evidence
of osteoporosis is found. Clinical management
requires weight-bearing exercise, calcium and
vitamin D supplementation and consideration of
bisphosphonates in men and postmenopausal
women.[122]
4. Reproductive Dysfunctions
4.1 Sexual Dysfunction
Some psychotropic agents regularly induce ad-
verse sexual effects, including those associated with
CNS Drugs 2009; 23 (12)
1010
hyperprolactinaemia, as considered in section 1.
Alterations in libido, arousal, erectile function and
orgasm have been associated with other psycho-
tropic agents, especially SRIs, which carry high
risks of delayed orgasm in men and women.[123]
Such problems surely are much more common
than is widely appreciated, owing mainly to lack of
clinical inquiry and confusion about dysfunctions
associated with many psychiatric disorders them-
selves versus their treatment.
4.2 Virilization
Virilization is a condition associated specifi-
cally with use of valproate in young women.[124-126]
This disorder is often associated with polycystic
ovaries as detected by transvaginal ultrasonogra-
phy. Polycystic ovary syndrome (PCOS) presents
clinically with oligomenorrhoea, anovulation,
infertility, hirsutism, acne vulgaris and variable
obesity, sometimes with elevated circulating le-
vels of testosterone and altered ratios of LH and
FSH. PCOS has been identified in as many as
10% of young women given divalproex sodium for
bipolar disorder longer than a year, as well as
among young women treated for epilepsy, in
whom it appears to be a drug-specific effect and
not a manifestation of seizure disorders.[124-126]
New virilization emerging during treatment
with psychotropic agents calls for referral to a
specialist in reproductive endocrinology. Treat-
ments for adverse sexual effects associated with
psychiatric disorders and their treatment are still
emerging. The antidepressants bupropion, bus-
pirone, mirtazapine, nefazodone and trazodone
lack adverse sexual effects, but yield variable
benefits when added to antidepressant, anti-
psychotic or other agents associated with sexual
dysfunctions.[127,128]
Treatment of sexual dysfunction associated
with psychotropic agents such as SRIs is often
difficult, and includes reducing doses or changing
to better tolerated options. Agents used for the
treatment of erectile dysfunction, such as silde-
nafil or tidalafil, may be of some benefit for
women as well as men with drug-induced dys-
functions.[127,129] There are also claims that var-
ious complementary or ‘alternative’ medications,
ª 2009 Adis Data Information BV. All rights reserved.
Bhuvaneswar et al.
including the natural products gingko biloba,
yohimbine and maca root, might be beneficial,
but none is an established treatment.[130-132]
5. Bodyweight and Metabolic
Dysfunction
5.1 Weight Loss
Although weight gain is by far a more prevalent
and clinically significant effect of many psycho-
tropic agents, some drugs, including bupropion,
nefazodone, SRIs, sibutramine (a centrally acting
monoamine reuptake inhibitor), psychostimulants
and topiramate, can induce weight loss. Appetite
and caloric intake can be reduced by bupropion,
sibutramine and psychostimulants.[133,134] In addi-
tion, nausea is common early in treatment with
SRIs and occasionally other antidepressants, and
can occur later as a manifestation of initial with-
drawal from short-acting SRIs including parox-
etine and venlafaxine, and so may be associated
with weight loss.[135,136] Weight loss may also be
more likely with nefazodone than some other
antidepressants, but nefazodone is rarely used
owing to hepatic toxicity.[137] The similar sedative
antidepressant trazodone can also produce minor
weight loss through an unknown mechanism.[138]
Management of weight loss associated with psy-
chotropic drugs includes monitoring diet, weight
and body mass index (BMI), considering sub-
stance abuse and other medical disorders, remov-
ing nonessential drugs, lowering drug doses or
changing to alternative treatments less likely to
induce weight loss.
5.2 Obesity and Metabolic Syndrome
Weight gain and associated metabolic compli-
cations, including type 2 diabetes mellitus, hyper-
tension and dyslipidaemia, are common adverse
effects of antipsychotics, mood stabilizers, anti-
depressants and sedatives, and frequently lead
to non-adherence or discontinuation of treat-
ment.[139,140] Metabolic risk and treatment non-
adherence may be even greater with the growing
use of complex combinations of psychotropic
agents (‘polytherapy’). Particular concern has been
directed at modern antipsychotics associated with
CNS Drugs 2009; 23 (12)
Endocrine and Metabolic Effects of Psychotropic Drugs
obesity and the metabolic syndrome. Since 2004,
the FDA has required warning labels for all second-
generation antipsychotic drugs regarding their
risks of hyperglycaemia and weight gain.[141] Among
such drugs, clozapine, olanzapine and quetiapine
are particularly strongly associated with weight
gain and diabetes, but risperidone is also impli-
cated, especially in children and adolescents,[142]
and aripiprazole has been associated with dia-
betes in children, even without substantial weight
gain.[143]
Other psychotropics associated with weight
gain include older antipsychotics, most mood
stabilizers and many antidepressants; sedative
anxiolytics have variable and inconsistent effects.
Among older antipsychotics, agents of low po-
tency such as chlorpromazine and thioridazine
are more likely to induce weight gain than high-
potency drugs such as fluphenazine or haloperi-
dol; molindone and loxapine have even lower
risk.[144-154] Lithium and some mood-stabilizing
anticonvulsants (especially valproate) are routine-
ly associated with weight gain.[151] Evidence
for carbamazepine is mixed. In one study, it
appeared to cause greater weight gain in combi-
nation with olanzapine than olanzapine alone,
despite its ability to increase clearance of many
drugs.[155] As monotherapy, carbamazepine was
associated with much less weight gain than with
olanzapine, but had similar, moderate effects
as aripiprazole, lamotrigine and ziprasidone in
another study.[156] Others rank carbamazepine
as causing more weight gain than lamotrigine or
ziprasidone, though less than valproate or olan-
zapine.[157,158] Antidepressants most frequently
associated with weight gain include older TCAs,
mirtazapine, paroxetine and phenelzine.[159]
Weight gain is commonly associated with ele-
ments of the metabolic syndrome, which includes
abdominal obesity (waist circumference and waist/
hip circumference ratio: men: >40 inches [100 cm]
and ratio >0.90; women: >35 inches [88.9 cm] and
ratio >0.85), elevated serum triglyceride level
(>150 mg/dL), low levels of high-density lipopro-
tein (HDL) cholesterol (men: <40 mg/dL; women:
<50 mg/dL), blood pressure ‡140/90 mm and
fasting serum glucose levels ‡110 mg/dL. Such
metabolic factors greatly increase risk of athero-
ª 2009 Adis Data Information BV. All rights reserved.
1011
sclerotic disease, including myocardial infarction
and stroke.[160] The American Heart Association
and the US National Heart, Lung, and Blood
Institute suggest the following guidelines for
supporting the diagnosis of metabolic syndrome:
(a) impaired fasting glucose if serum glucose le-
vels >100 mg/dL; (b) HDL cholesterol may be low
even if its measurements appear to be normal if
cholesterol-lowering agents such as inhibitors
(statins) of the reductase of 3-hydroxy-3-methyl-
glutaryl-coenzyme-A (HMG-CoA) that is required
for the synthesis of cholesterol are used; (c) hyper-
tension is considered even if systolic blood pres-
sure is only ‡130 mm or diastolic blood pressure is
‡85 mm.[161] In addition, insulin resistance is a
common, though infrequently assessed, feature
of metabolic changes associated with antipsy-
chotic or other psychotropic treatment.[162,163]
Apart from routine measurement of waist-
circumference and bodyweight or BMI, the role
of the psychiatrist in monitoring for adverse
metabolic effects should include following the
medical status of patients and collecting data to
complement measures followed by primary care
physicians who are contacted regularly, as well
as providing ongoing patient education about
risks and benefits of medication and the need
for regular medical follow-up. Moreover, per-
sons with major mental illness appear to be at
increased risk of weight gain, diabetes and
cardiovascular disease, independent of effects of
treatment with antipsychotic or mood-altering
drugs, possibly due to dietary choices, activity
levels and other lifestyle factors, as well as genetic
contributions.[164-168]
Modern antipsychotic drugs contribute speci-
fically to risk of dyslipidaemia, as reflected in
increased serum levels of total cholesterol, low-
density lipoprotein and triglycerides, with sub-
normal HDL.[169-175] Increased triglyceride levels
are particularly common during treatment with
clozapine, olanzapine or quetiapine, especially
among women.[176-179] Such changes in lipid me-
tabolism may arise semi-independently of weight
gain and other components of the metabolic syn-
drome.[176-179] Children and adolescents may be
particularly vulnerable to weight gain and metabo-
lic effects of antipsychotic and mood-stabilizing
CNS Drugs 2009; 23 (12)
1012
drugs and their combinations.[180,181] In addition,
the elderly are especially prone to the motility-
inhibiting effects of many sedative and psychotro-
pic drugs, with increased risk of weight gain.[182,183]
The relationship between drug dose and oral
versus injected administration and risks of weight
gain and metabolic changes is unclear, though
specific biological mechanisms have been impli-
cated. These include inhibitory effects of psycho-
tropic drugs on central histamine (H1) and
serotonin (5HT2C or 5HT3) receptors, and anti-
muscarinic (M3) actions on pancreatic b cells, as
well as dysregulation of appetite hormones, in-
cluding increases in leptin, adiponectin and tumour
necrosis factor (TNF).[184] Valproic acid can also
impair leptin release and shift balances among an-
drogen, estrogen and cortisol production, to alter
insulin response.[185] The role of leptin, adiponectin
and TNF a in obesity and responses to psycho-
tropic drugs is under investigation.[186-189]
Special consideration should be given to
weight gain induced by substance abuse, such as
of alcohol (ethanol) or cannabis, which can occur
among psychotic disorder patients, and at any
age. Young patients are at especially high risk for
substance abuse that is co-morbid with major
mental illnesses. Review of metabolic effects of
abused substances is beyond the scope of this
paper, but is considered elsewhere.[190-195]
5.3 Clinical Management of Metabolic
Syndrome
Weight gain and associated hyperglycaemia
and dyslipidaemia are sometimes improved by
switching to agents with lower risk, for example,
from clozapine or olanzapine to aripiprazole
or ziprasidone, or by augmenting lowered doses
of clozapine or olanzapine treatment with either
of these.[196-199] Adverse metabolic effects that
cannot be managed conservatively may require
pharmacological interventions for obesity, hyper-
lipidaemia or diabetes.[200-202]
In addition, specific psychotropic and other
treatments for drug-induced weight gain, hyper-
glycaemia or hyperlipidaemia includes considera-
tion of: (i) selective monoamine transport inhibi-
tors (bupropion, sibutramine, psychostimulants);
ª 2009 Adis Data Information BV. All rights reserved.
Bhuvaneswar et al.
(ii) insulin-promoting agents including metformin;
(iii) specific anticonvulsants with anti-obesity ef-
fects (topiramate, zonisamide); and (iv) other
agents with effects on appetite and bodyweight
(the pancreatic lipase inhibitor orlistat, the can-
nabinoid CB1 receptor antagonist rimonabant)
and possibly amantadine, modafinil or memantine).
The mild stimulant-antidepressant bupropion
has only minor benefits in limiting weight gain
associated with other psychotropics, but may
reduce serum cholesterol levels.[203,204] The sym-
pathomimetics benzphetamine, diethylpropion,
phendimetrazine and phentermine are approved
by the FDA for the short-term treatment of
obesity, but are contraindicated with monoamine
oxidase inhibitors (MAOIs), for agitated pa-
tients, and have some potential for abuse.[205] The
nonselective monoamine reuptake inhibitor (for
dopamine as well as noradrenaline [norepineph-
rine] and serotonin) sibutramine is effective in
facilitating weight loss, with some risk of in-
creasing pulse rate and blood pressure and indu-
cing cardiac arrhythmias,[206-211] as well as mania
or psychosis.[212-214] Fatal cases of delirious cer-
ebral intoxication (‘serotonin syndrome’) have
been associated with combinations of sibutra-
mine with SRIs, antimigraine triptans and agents
with MAO-inhibiting activity.[215] Metformin can
be combined with antipsychotics to manage
hyperglycaemia by increasing insulin sensitivity
and decreasing leptin levels, ideally in combina-
tion with weight control or perhaps with topir-
amate.[201,216,217] Lifestyle modification combined
with metformin appears to be more effective for
weight loss than either treatment alone, and
metformin alone is more effective than placebo in
improving insulin sensitivity.[216]
Another trial of olanzapine for schizophrenia or
bipolar disorder patients found metformin supe-
rior to placebo for weight loss, with somewhat
greater decreases in serum leptin levels.[218] The
sedating anticonvulsant topiramate, a sulfamate
derivative of fructose, appears to lack antimanic or
acute mood-stabilizing activity, but can promote
weight loss, and is sometimes combined empiri-
cally with weight gain-promoting psychotropic
agents.[219-222] Adverse effects of topiramate include
perceptual and cognitive abnormalities, metabolic
CNS Drugs 2009; 23 (12)
Endocrine and Metabolic Effects of Psychotropic Drugs
acidosis, renal stones and glaucoma.[223,224] The
sulfonamide anticonvulsant zonisamide shares
with topiramate a lack of weight gain and some
ability to reduce weight, but its effects on mania
and mood stabilization appear to be weak.[225]
Orlistat, a pancreatic lipase antagonist that inhibits
absorption of dietary fats, may also be effective in
treating psychotropic-induced weight gain.[226-228]
The CB1 receptor antagonist rimonabant can
facilitate weight control but may increase risk of
depression and suicidality.[229-231] The antiparkin-
sonism, monoamine-enhancing drug amantadine
may also limit weight gain with antipsychotics
including olanzapine.[232,233] The mild stimulant,
anti-narcolepsy agent modafinil may produce
weight loss with antipsychotics, possibly with less
risk of inducing mania or worsening psychosis
than standard psychostimulants such as ampheta-
mines or methylphenidate.[234,235] The uncom-
petitive glutamic acid NMDA receptor antagonist
memantine may also contribute to weight control,
in addition to its cognition-enhancing effects.[236,237]
Management of psychotropic drug-induced weight
gain includes efforts to prevent or limit risk of
obesity and components of the metabolic syn-
drome. Ideally, initial as well as follow-up assess-
ments should include monitoring of weight, BMI,
waist circumference, blood pressure and fasting
serum glucose. Repeated assays of glycosylated
haemoglobin (HbA1C) in established diabetes, and
of serum lipid levels and ratios can be useful – all
following available expert guidelines.[238]
Dyslipidaemia can be limited by using anti-
psychotics with relatively low risk of adverse
metabolic effects, including aripiprazole and
ziprasidone.[197,239-241] Aripiprazole, and possibly
quetiapine or risperidone, may be of benefit in
increased bodyweight and dyslipidaemia, as well
as new-onset type 2 diabetes, but clinical test-
ing and comparison of such options remain
inadequate.[197,239-241]
Statins can reduce serum levels of triglycerides
as well as cholesterol following increases in asso-
ciation with treatment with various antipsychotic
drugs.[242] In general, prevention of obesity (BMI
‡30 kg/m2) and the metabolic syndrome among
psychiatric patients includes repeated encourage-
ment of lifestyle changes, including increased
ª 2009 Adis Data Information BV. All rights reserved.
1013
regular exercise, dietary modifications and smok-
ing cessation – all supported and enhanced by
collaborations with primary care physicians and
other health professionals to increase access to
interventions and programmes aimed at improving
general health.[243-245] Support for such interven-
tions, as well as descriptions of model interven-
tions that can be encouraged by psychiatrists in
concert with primary care physicians, can be
found elsewhere.[246-248]
6. Conclusions
The preceding brief overview underscores
selected, common adverse metabolic effects as-
sociated with use of many psychotropic drugs.
These include adverse effects on prolactin, thy-
roid, calcium distribution and bone density, wa-
ter homeostasis, and risk for sexual dysfunction,
obesity and the metabolic syndrome. Such prevalent
adverse effects can both exacerbate underlying
psychiatric conditions as well as cause additional
morbidity and disability. Long-term metabolic
complications of the many psychotropic agents
that promote obesity include type 2 diabetes,
dyslipidaemia and hypertension. Psychopharma-
cological drug treatments for psychiatric disorders,
although very useful, appear to have become
overvalued and often uncritically applied, some-
times in untested combinations and at high doses.
Their rational and safe use requires objective
risk/benefit assessment when starting or adding
medications. In addition, clinicians prescribing
psychiatric drugs should both anticipate and take
steps to reduce risks of endocrine and metabolic
effects, including adequate counseling of pa-
tients, and arrangements for regular monitoring
of laboratory assays, bodyweight and other
health-related measures. Recognition, monitor-
ing and treatment of adverse metabolic effects of
psychotropic agents encourage close collabora-
tive relationships between mental health profes-
sionals and colleagues in general medicine.
Greater coordination of psychiatric and general
medical aspects of overall clinical care should
substantially improve the outcomes and well-being
of patients receiving treatment with psychotropic
medications.
CNS Drugs 2009; 23 (12)
1014
Acknowledgements
Supported, in part, by an American Psychiatric Institute
for Research and Education (APIRE)-Janssen Research
Scholarship and NIMH Diversity Supplement grant (to CGB)
and by a grant from the Bruce J. Anderson Foundation and
McLean Private Donors Fund for Psychopharmacology Re-
search (to RJB). Drs John D. Matthews, Theodore A. Stern
and Muhamet Yildiz, PhD provided helpful advice.
Dr Bhuvaneswar has received training awards from:
Merck, Janssen, Johnson and Johnson, Novartis, Sepracor,
Cypress Bio and Infiniti Pharmaceuticals. Dr Baldessarini has
recently been a consultant or investigator-initiated research col-
laborator with: Auritec, Biotrofix, IFA SpA, Janssen, JDS,
Lilly, NeuroHealing, Novartis, Solvay and SK-BioPharma-
ceuticals Corporations. Dr Harsh has no relevant disclosures.
Dr Alpert is a consultant or has received research sup-
port from: Aspect Medical Systems, Lilly, Forest, Organon,
Pamlab, Pfizer and Pharmavite, and honoraria from Organon
and Janssen Corportions. No author is a member of phar-
maceutical speakers’ bureaus nor do they or family mem-
bers hold equity positions in biomedical or pharmaceutical
corporations.
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Correspondence: Dr Chaya G. Bhuvaneswar, Department of
Psychiatry, University of Pennsylvania, 3535 Market Street,
2nd Floor, Outpatient Clinic of Hospital of University of
Pennsylvania, Philadelphia, PA 19104, USA.
E-mail: cbhospitalpsychiatry@live.com
CNS Drugs 2009; 23 (12)