REVIEW ARTICLE
Thyroid Adverse Effects of Psychotropic Drugs: A Review
Rami Bou Khalil, MD*Þþ and Sami Richa, MD, PhD*§
Objectives: Because many patients with mental illness take more than
one psychotropic drug, an understanding of the effects of every class of
these drugs is very important to manage any thyroid abnormalities that
can happen with these patients.
Methods: A systematic review of all the published literature was made
via Medline. Keywords used for the search were ‘‘thyroid side effects’’ in
association with one of the following: ‘‘antipsychotics,’’ ‘‘antidepressants,’’
‘‘lithium,’’ ‘‘anticonvulsants,’’ ‘‘benzodiazepines,’’ ‘‘anticholinergics,’’
‘‘antihistaminergics,’’ ‘‘cholinesterase inhibitors,’’ ‘‘stimulants,’’ ‘‘metha-
done,’’ and ‘‘naltrexone.’’
Results: Phenothiazines, which are antipsychotics, mainly alter
iodine capture, complex and deactivate it, as well as decrease thyroid-
stimulating hormone’s (TSH’s) response to thyroid-releasing hormone
(TRH). Nonphenothiazines, typical antipsychotics, can induce the for-
mation of thyroid autoantibodies and can elevate TSH levels. Atypical
antipsychotics may decrease TRH-stimulated TSH. Tricyclic antidepres-
sant drugs complex with iodine and thyroid peroxidase and deactivate
them, induce deiodinase activity and interfere with the hypothalamo-
pituitary-thyroid (HPT) axis by decreasing TSH response to TRH. The
main effect with other antidepressant drugs is a decrease in circulating
thyroid hormone levels. Lithium inhibits thyroid hormone release and
increases TRH-stimulated TSH, inducing goiter, clinical and subclinical
hypothyroidism, and hyperthyroidism. Carbamazepine mainly reversibly
decreases serum thyroid hormone levels. Other psychotropic drugs such
as valproic acid, benzodiazepines, opiates, anticholinergic and antihista-
minergic drugs, and stimulants have minor interferences with thyroid
functions.
Conclusion: Patients receiving lithium, phenothiazines, and tricyclic
antidepressants TCA should be closely monitored for the development
of thyroid function abnormalities. Only patients at risk for developing
thyroid function abnormalities should be monitored when they receive
typical and/or atypical antipsychotic drugs, nontricyclic antidepressant
drugs, and carbamazepine. No specific recommendations are proposed
as toward thyroid function monitoring for patients receiving any other
psychopharmacologic drug.
Key Words: thyroid function, side effects, antipsychotic drugs,
antidepressant drugs, mood stabilizers
(Clin Neuropharm 2011;34: 248Y255)
A ccording to many studies, patients with mental illness, espe-
cially those with mood disorders, frequently present thyroid
function abnormalities.1Y11 In 2 important reviews considering
the relationship between thyroid function and mental disorders, it
has been considered that most patients with mental illness are
euthyroid. However, most adults with thyroid dysfunction will
*Hotel Dieu de France Hospital, Beirut; †Saint Joseph University, Beirut;
‡Psychiatric Hospital of the Cross, Jalledib; and §Department of Psy-
chiatry, Saint Joseph University, Beirut, Lebanon.
Conflicts of Interest and Source of Funding: The authors have no conflicts
of interest to declare.
Address correspondence and reprint requests to Rami Bou Khalil, MD,
Psychiatric Hospital of the Cross, PO Box 60096, Jalledib, Lebanon;
E-mail: ramiboukhalil@hotmail.com
Copyright * 2011 by Lippincott Williams & Wilkins
DOI: 10.1097/WNF.0b013e31823429a7
248 www.clinicalneuropharm.com Clinical Neuropharmacology
Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
develop mental symptoms. In addition, hyperthyroidism-related
adrenergic hyperactivity is a major cause of psychiatric symp-
toms. Most patients with severe hypothyroidism will also dem-
onstrate psychiatric symptoms. Affective disorders seem to be, by
far, the most represented psychopathology related to thyroid ab-
normalities.12,13 Many psychotropic drugs also interfere with the
thyroid physiology as a result of their action on many levels of
the thyroid hormone synthesis.14Y16 Because many patients with
mental illness take more than one psychotropic drug, an under-
standing of the effects of every class of these drugs is very im-
portant to manage any thyroid abnormalities that can happen
with these patients. The purpose of this article was to review
published preclinical and clinical studies dealing with the adverse
effects on the thyroid of all classes of psychotropic drugs without
reviewing thyroid function abnormalities related to the psychiatric
illness itself.
MATERIALS AND METHODS
A systematic review of all the published literature was
made via Medline. All published articles in English or French
between January 1956 and May 2010 were considered.
Keywords used for the search were ‘‘thyroid side effects’’ in
association with one of the following: ‘‘antipsychotics,’’ ‘‘anti-
depressants,’’ ‘‘lithium,’’ ‘‘anticonvulsants,’’ ‘‘benzodiazepines,’’
‘‘anticholinergics,’’ ‘‘antihistaminergics,’’ ‘‘cholinesterase inhi-
bitors,’’ ‘‘stimulants,’’ and ‘‘opiate substitution drugs.’’
RESULTS
Our literature review findings are summarized in Table 1.
Effect of Antipsychotic Drugs on
Thyroid Function
Effects of Phenothiazines on Thyroid Function
At the thyroid gland and circulation level, phenothiazines
interfere with iodine capture by thyroid cells, increase protein-
bound iodine, and exert immunogenic effect on thyroid tissue.
Incubation of thyroid cells with chlorpromazine decreases iodine
uptake.14 In humans, an iodine uptake increase and a decrease
in renal clearance of iodide were observed after a 6-week treat-
ment with 300 to 1200 mg/d of chlorpromazine administered
in a double-blind study.17 Phenothiazines complex and de-
activate thyroid iodine. Drug-iodine complexes have formation
constants, Kc, that estimate the electron-donating potential of the
drug. Phenothiazines with high Kc (alimemazine and chlor-
promazine) may lead to iatrogenic hypothyroidism or thyroid-
itis.14 Phenothiazines without high Kc, such as perphenazine,
can also exert a peripheral effect by increasing T4 blood levels
and protein-bound iodine in 50 patients receiving the drug for
periods ranging from 8 to 50 months.18 Phenothiazine drugs
may exert immunogenic effects. Chlorpromazine is able to in-
duce systemic lupus erythematosus.12 Phenothiazines induce
experimentally the production of antithyroglobulin antibodies.
Phenothiazines can induce and perpetuate thyroid autoimmune
disorders through induction of class II major histocompatibility
complex antigen.15,16,19,20
& Volume 34, Number 6, November/December 2011
Clinical Neuropharmacology & Volume 34, Number 6, November/December 2011 Thyroid Adverse Effects of Psychotropic Drugs

TABLE 1. Effects of Different Psychotropic Drugs on the Thyroid Gland

Thyroid-Stimulating
T4 and fT4 T3 and f T3 Hormone (TSH) Hypothyroidism Hyperthyroidism Autoimmunity References
Phenothiazines ,*, j†, or ͇ ?§ , or Í ++|| +/j¶ ++ [4, 9, 15Y21]
Nonphenothiazines, , or Í , or Í j or Í +/Y ? +# [22, 23]
typical antipsychotics
Atypical antipsychotics , or Í , or Í jor Í + j** ? [24Y29]
Tricyclic antidepressants , or Í , or Í , or Í ++ j Y [9, 30Y37]
Nontricyclic j, ,, or Í j, ,, or Í ,, j, or Í +/j†† j Y [31,38Y45]
antidepressants
Lithium ,, j, or Í ,, j, or Í , or Í +++|| + +/Y [16, 46Y67]
Carbamazepine , or Í , or Í Í +/j†† j Y [68Y73]
Valproic acid j, ,, or Í j, ,, or Í Í +/j‡‡ j Y [69, 70, 73Y77]
Benzodiazepines j, ,, or Í j, ,, or Í Í j Y Y [78Y82]
Opiates substitution drugs j or Í j or Í Í Y Y Y [83Y87]
A-blockers j or Í , or Í Í Y Y Y [88Y91]
Orphenadrine Í j or Í Í ? ? ? [92]
Stimulants (methylphenidate j, ,, or Í j, ,, or Í Í§§ ? +/Y§§ ? [93, 94]
and atomoxetine)
*Decrease.
†Increase.
‡No effect.
§Evidence not clear.
||Strong evidence.
¶Weak or controversial evidence.
#Moderate level of evidence.
**No correlation.
††Hypothyroidism in predisposed patients.
‡‡Hypothyroidism in patients receiving a combination of VPA with an enzyme-inducing anticonvulsant.
§§Data originating from one case of elevated serum thyroid hormone level in one child on atomoxetine.

Phenothiazines have also an effect on the hypothalamo-
pituitary-thyroid (HPT) axis. Thioridazine and chlorpromazine
were shown to decrease thyroid-stimulating hormone (TSH)
response to thyroid-releasing hormone (TRH) stimulation by
inhibiting >-adrenergic receptors without altering basal TSH
levels in a sample of 75 subjects.21
In conclusion, phenothiazines can induce a hypothyroid
state through either their deiodination effect or their thyroid
autoimmune-inducing activity. Infrequently, they may induce a
hyperthyroid state if they induce a thyroiditis. Other central and
peripheral actions do not seem to have major clinical implications.
In all patients receiving phenothiazines, regular monitoring of
thyroid function parameters is recommended owing to the direct
interference of these drugs with thyroid functioning.
Effect of Typical Antipsychotic Drugs on
Thyroid Function
Typical antipsychotic drugs may exert an effect on thyroid
functioning through a central activity on tuberoinfundibular do-
paminergic pathway. The antagonism of dopamine receptors in
this pathway results in hyperprolactinemia. This pathway also
plays an important role in the regulation of various anterior pitu-
itary hormones. Changes of TSH levels after dopamine antago-
nism due to typical antipsychotic drug administration is rather
small or demonstrable only in female or hypothyroid patients.22
In a cross-sectional study, increased prolactinemia was associ-
ated with an increased prevalence of thyroid autoantibodies
(P = 0.039) in 74 schizophrenic outpatients.23 This effect is
similar to autoimmune thyroid abnormalities observed in patients
with prolactinomas.95
Accordingly, typical antipsychotic drugs, whether they
were phenothiazines or not, can induce autoimmune thyroid
abnormalities (anti-thyroid peroxidase [anti-TPO] and antithyro-
globulin increment) via their dopamine antagonism and subse-
quent induced hyperprolactinemia. Precautious monitoring of
thyroid function parameters is recommended in case these drugs
were accompanied with high blood prolactin level.
Effect of Atypical Antipsychotic Drugs on
Thyroid Function
Thyroid effects of atypical antipsychotic drugs can be
either central or peripheral. Amisulpride, quetiapine, and clo-
zapine are the most atypical antipsychotic drugs studied in this
domain. Dopamine 2 (D2) receptor blockade can increase TRH-
stimulated TSH levels. In a placebo-controlled study, 8 men
were administered intravenous amisulpride and had their TSH
levels significantly elevated compared to their TSH levels after
placebo administration (P G 0.01).24 In another randomized
comparative double-blind clinical trial, a sample of 32 patients
with schizophrenia were given amisulpride or flupenthixol and
showed a significant elevation in TRH-stimulated TSH secretion
in male patients receiving amisulpride.25 The non-D2 antagonist
atypical antipsychotic drug clozapine shows an inverse effect.
In a comparative clinical study, 13 patients treated with 150
to 250 mg/d of clozapine had their TRH-stimulated TSH sig-
nificantly decreased after 1 week of treatment compared with
13 patients treated with 20 to 40 mg/d of haloperidol (P G 0.01).26
Patients with compromised thyroid function who receive
treatment with atypical antipsychotic drugs may develop hypo-
thyroidism probably through a peripheral effect that involves a

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Bou Khalil and Richa Clinical Neuropharmacology
competition, with thyroid hormones, in the glucuronidation
process in the liver. Cyclic tertiary amines such as piperidine and
piperazines are most frequently incriminated in this process.
Many case reports describe cases of hypothyroidism in patients
receiving drugs such as quetiapine and aripiprazole.27,28 In a
prospective double-blind study, a group of 30 schizophrenic
patients taking quetiapine (n = 10), risperidone (n = 11), or
fluphenazine (n = 9) showed a significant decrease in T4 levels
after 6 weeks of treatment in the group receiving quetiapine,
whereas other patients receiving risperidone and fluphenazine
had no change in their thyroid hormones levels (P = 0.01).29
In conclusion, atypical antipsychotic drugs can, according
to their dopamine antagonism profile, moderately interfere with
TSH response to TRH without provoking major disturbances
to thyroid function. However, piperazine and piperidine com-
pounds are incriminated in clinical hypothyroidism in pre-
disposed patients receiving them. Precautions toward thyroid
function should be taken only in patients predisposed to develop
thyroid abnormalities and, as with typical antipsychotic drugs,
in those that present high blood prolactin levels.
Effect of Antidepressants on Thyroid Function
Effect of Tricyclic Antidepressants (TCA) on
Thyroid Function
Tricyclic antidepressants (TCA) may alter thyroid blood
parameters via peripheral and central effects. Tricyclic antide-
pressants deactivate iodine by complexation. Molecules with a
high Kc (desipramine, imipramine, or clomipramine) are incrim-
inated in this process.14 Tricyclic antidepressants also deactivate
TPO by binding covalently to its heme.14,30 In a double-blind
study desipramine (up to 300 mg/d) effect on thyroid hormones
was compared to fluoxetine in 39 patients with major depres-
sion and was found to induce a small and transient increase in total
T4 levels after 3 weeks of treatment with no changes occurring
to TSH level.31
Tricyclic antidepressants have also a central effect on HPT
axis. In two clinical trials, patients with major depressive dis-
order (n = 13 and n = 28, respectively), treatment with TCA
(eg, 2.5 mg/kg per day of desipramine) significantly decreased
free T4 (f T4; P G 0.01) and TSH levels.32,33 Finally, many
studies found no thyroid hormone alterations in patients taking
TCA.34Y37
As for phenothiazines, TCA may induce a hypothyroid state
via a deiodination process and deactivation of TPO. They may
also moderately interfere with T4 and TSH levels without
causing significant clinical adverse effects to thyroid function.
Regular monitoring of thyroid function parameters is recom-
mended owing to this possible direct interference of TCA in
thyroid functioning.
Effect of Other Antidepressants on
Thyroid Function
With antidepressant treatment, the most common change in
thyroid hormones is a decrease in T4 and fT4.37,38 Many studies
evaluated the effect of selective serotonin reuptake inhibitors
(SSRI) and showed that their effect is mainly a decrease in T3
and T4 levels without any change in TSH level. In a prospective
study where 17 patients were taking 200 mg/d of sertraline or
40 mg/d of fluoxetine over a 10-week period, T3 and T4 levels
were significantly decreased (P = 0.05 and P = 0.02, respec-
tively), whereas TSH levels did not change.40 In a previously
mentioned study, no significant changes were found in TSH
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& Volume 34, Number 6, November/December 2011
or total T4 with fluoxetine treatment, but a significant reduc-
tion in T3 levels was noted (after a six-week follow-up).31 In
25 depressed patients, treatment with 20 mg/d of paroxetine
significantly decreased T4 levels by 11.2%.41 In a prospective
controlled interventional study, 67 patients (28 with depression
and hypothyroidism, 29 with depression but without hypothy-
roidism, and 10 controls on levothyroxine) were administered
either fluoxetine or sertraline, and the group of euthyroid de-
pressed patients on fluoxetine showed a significant reduction
in T3 levels at 15 and 30 days of follow-up (P = 0.034 and
P = 0.011, respectively) and a decrease in T4 during the 90-day
follow-up period (P = 0.029).42
Other effects of non-SSRI antidepressant drugs on thyroid
function were evaluated and showed that T4 and TSH levels may
change in all direction. In a prospective study evaluating the
effect of mirtazapine on thyroid hormones in a small sample of
17 depressed outpatients, a significant increase in free T3 (f T3)
concentrations was found, whereas f T4 concentrations de-
creased (P = 0.015 and P = 0.046, respectively) after a 6-month
follow-up period. There were no significant changes in the TSH
levels. The deiodination process was potentially incriminated.43
In a prospective study, the differential effects of reboxetine
(25 patients on 8 mg/d), sertraline (11 patients on 50 mg/d), and
venlafaxine (26 on 150 mg/d) on thyroid hormones were eval-
uated in 62 depressed patients. After 10 weeks of follow-up,
TSH levels were significantly decreased (P = 0.033) and T4
levels increased (P = 0.009) in the reboxetine group, and TSH
levels were increased (P = 0.033) and T4 levels decreased
(P = 0.029) in the sertraline group.44 Finally, in a retrospective
case-control study, Saint John’s wort was administered to 6
of 37 patients with elevated TSH levels in the 6 months pre-
ceding the survey and to 2 of 37 controls with normal TSH
levels. The odds ratio for elevated TSH levels associated with
taking Saint John’s wort was 2.12 (95% confidence interval,
0.36Y12.36).45
In conclusion, SSRI and non-SSRI antidepressant drugs
may alter T4 and TSH levels without having major clinical
implications on thyroid function. Whereas SSRI seem to de-
crease T4 levels, non-SSRI antidepressant drugs seem to change
T4 and TSH levels in both directions. Precautions should be
taken only in patients at risk for thyroid function abnormalities.
Effect of Lithium on Thyroid Function
Effect of Lithium on Thyroid Physiology
and HPT Axis
Many studies evaluated the effect of lithium on thyroid
functioning and HPT axis. In a comparative case-control trial
where 5 euthyroid patients and 6 thyrotoxic patients were ad-
ministered lithium for 5 days, it was demonstrated that T4 re-
lease was inhibited in both groups (P G 0.01).46 Lithium was also
considered to be responsible for inhibiting type 1 5¶-deiodinase
activity in a prospective study where 18 schizophrenic inpatients
were administered lithium carbonate during a follow-up period
of 8 weeks.47 In one study, lithium therapy resulted in an increase
in TRH-stimulated TSH in 49% of 73 patients who had been
receiving lithium for at least 6 months.48 In a prospective study,
12 euthymic bipolar patients receiving lithium carbonate were
followed for over 12 months (some of them were followed fur-
ther); 10 (83%) of the 12 patients had their basal TSH levels
increased, and 11 of the 12 patients had their TRH-stimulated
TSH increased compared to baseline.49 In conclusion, lithium
competes for iodide transport. It inhibits T4 release to the blood
circulation. It is responsible for inhibiting type 1 5¶-deiodinase
* 2011 Lippincott Williams & Wilkins
Clinical Neuropharmacology & Volume 34, Number 6, November/December 2011
activity and inducing TSH secretion via the induction of a
hypothyroid state.
Lithium, Goiter, and Hypothyroidism
Lithium inhibits thyroid hormone secretion and results in an
increase in TSH and consequent thyroid enlargement. In a pro-
spective study where 8 women and 8 men received 600 mg/d
of lithium carbonate, thyroid volume increased in the women’s
group after 28 days of lithium initiation (P G 0.005).50 In a case
series reporting the occurrence of goiter in 330 bipolar patients,
12 patients were found to have goiter after a period of 5 months
to 2 years. The incidence of goiter of 4 per 100 patients per year
on continuous lithium therapy was calculated.51 A cross-sectional
study using ultrasonic measurement of thyroid volume showed
that goiter occurred in 40% of 100 bipolar patients treated for 1
to 5 years and in 50% of those treated for more than 10 years.52
In a cross-sectional controlled study including 96 patients with
bipolar, major depressive, or schizoaffective disorders who
had received lithium for at least 6 months, 55% of the subjects
had increased thyroid volume compared to 20% of controls
(P G 0.001).53 In conclusion, lithium is responsible of thyroid
gland enlargement and goiter, especially in female patients
shortly after the drug initiation.
Clinical and subclinical hypothyroidism may appear within
weeks of starting lithium therapy.54 Studies evaluating this ad-
verse effect of lithium therapy are mostly cross-sectional. In a
cross-sectional case-control study where 68 bipolar patients re-
ceiving lithium therapy were included, women had thyroid ab-
normalities 5.9 times more frequently than men (P G 0.05) and
clinical and subclinical hypothyroidism were present in 9% of
the patients included.55 In a cross-sectional study including
207 patients treated with lithium for a period ranging from 1 to
30 years, prevalence of hypothyroidism was found to be 6%.56
In a retrospective study including 201 lithium-treated patients
with mood disorders, 20 patients (0.099%), mainly females, de-
veloped hypothyroidism.57 In a cross-sectional case-control
study, 132 patients with mood disorders were evaluated; T4 levels
declined by 24% (P G 0.05) with lithium therapy and clinical
hypothyroidism was detected in 4 patients (0.03%).58 In a retro-
spective case-control review where 695 patients treated with
lithium were included, the prevalence of clinical hypothyroidism
was 10.4% with a prominent prevalence in women as compared
to men (P G 0.0001).59 In a cross-sectional and prospective study
(n = 57) where 115 men and 159 women on lithium were evalu-
ated, hypothyroidism rates calculated to range between 21.7 and
27.4 in 1000 survivor years.60 Data from a 15-year follow-up of
150 patients on long-term lithium therapy have shown that the
annual rate of development of subclinical hypothyroidism was
1.5%.61 After 2 and 10 years of follow-up in the cohort of
patients described previously, the incidence of subclinical
hypothyroidism was higher in women and in patients with
thyroid autoimmunity.62,63 A cross-sectional controlled study
where 100 patients with affective disorders received lithium for
at least 6 months did not support this finding.64 Accordingly,
although the etiology of lithium-induced hypothyroidism is re-
lated to various pathophysiologic mechanisms including the in-
hibition of thyroid hormone secretion (see ‘‘Effect of lithium on
thyroid physiology and HPT axis’’ subsection) some data support
that lithium accelerates the development of existing thyroiditis
and can increase circulating anti-TPO antibody titer in patients
who already had positive circulating antibodies at the beginning
of the treatment.
In conclusion, clinical and subclinical hypothyroidisms are
frequent adverse effects of lithium therapy occurring as shortly
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Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Thyroid Adverse Effects of Psychotropic Drugs
as few weeks after this drug initiation. Women seem to be more
vulnerable to the drug’s adverse effect than men. Patients receiv-
ing lithium should be screened for thyroid function abnormali-
ties before and regularly after this drug initiation. Thyroid function
monitoring is also important for a short period after lithium
withdrawal.
Lithium and Hyperthyroidism
Studies evaluating hyperthyroidism as a complication of
lithium therapy are mainly retrospective. Hyperthyroidism
occurs most probably after many years of lithium therapy.65 In a
retrospective study, a case series of 14 patients with lithium
thyrotoxicosis was described and the incidence rate was con-
sidered to be more than 3 times greater from lithium-unrelated
incidence rates (P G 0.05).66 Etiologies of hyperthyroidism in-
clude toxic nodular goiter and silent thyroiditis. A retrospective
epidemiological study showed that long-term lithium therapy
is associated with an increased risk of thyrotoxicosis. Lithium-
associated silent thyroiditis occurred with an incidence rate of
approximately 1 to 3 cases per 1000 person-years, and lithium-
associated thyrotoxicosis occurred with an incidence rate of
approximately 2 to 7 cases per 1000 person-years, higher than
the reported incidence rates of silent thyroiditis and of thyro-
toxicosis in the general population.67 Lithium directly damages
thyroid cells, with consequent release of thyroglobulin and
thyroid hormones into the circulation. Lithium treatment could
mask the underlying hyperthyroidism by reducing thyroid hor-
mones so that when lithium therapy is stopped, hyperthy-
roidism will appear. Lithium incrimination in Graves’ disease
is not clear.16 In conclusion, patients receiving lithium therapy
may develop hyperthyroidism many years after the initiation of
this drug. The yearly incidence of this complication seems to be
clearly lower than that of clinical and subclinical hypothyroid-
ism. Specific monitoring for this complication is not necessary
because it is the same as that for hypothyroidism in patients
receiving lithium.
Effect of Mood Stabilizer Anticonvulsants on
Thyroid Function
Effect of Carbamazepine (CBZ) on
Thyroid Function
Decreases in T4 and f T4 concentrations, without TSH level
changes during CBZ treatment, have been reported since 1978.68
In a cross-sectional controlled study evaluating thyroid function
in 45 patients on chronic CBZ therapy, T4 and f T4 were de-
creased in 53.3% and 28.9% of patients, respectively. Serum T4
(P G 0.001), f T4 (P G 0.001), and T3 (P G 0.05) levels were lower
than those of the control group.69 Carbamazepine interferes with
thyroid function without exerting an effect on the HPT axis.70
Decreases in serum thyroid hormone levels can be detected as
soon as 2 months after starting CBZ.69 This altered thyroid
function is attributed to the induction of the hepatic cyto-
chrome P450 enzyme system that increases the metabolism of
thyroid hormones.70 In a prospective study, 20 epileptic patients
on CBZ followed over a 5-year period, a decrease in fT4 was
noted as early as 2 months after treatment initiation and nor-
malized after switching to oxcarbazepine. Authors concluded
that induction of cytochrome P450 liver enzymes resulted in
the decrease in thyroxine levels.71 Although CBZ decreases
thyroid hormone concentrations, it rarely causes hypothyroid-
ism. In a prospective study, CBZ treatment was administered
to 29 patients with or without thyroid dysfunction at base-
line. After 7 weeks of follow-up, the patients without thyroid
www.clinicalneuropharm.com 251
Bou Khalil and Richa Clinical Neuropharmacology
abnormalities showed decreased thyroxine levels (P G 0.001)
with no TSH level changes, whereas the patients with thyroid
dysfunction had thyroxine level reduction and TSH level ele-
vation.72 However, data have demonstrated that the changes in-
duced by this drug are reversible after the drug discontinuation.
In a prospective, randomized, controlled double-blind study, a
sample of 130 adult patients receiving CBZ showed, especially
in the women group (P = 0.001), an increase in serum f T4
when withdrawn from the drug.73 In conclusion, CBZ seems to
be incriminated in thyroid hormones lowering without any
effect on HPT axis via a hepatic enzyme induction mechanism.
Clinical hypothyroidism may manifest only in patients pre-
disposed to thyroid function abnormalities. Precautious mea-
sures such as regular thyroid function monitoring should be
taken only in these at risk patients.
Effect of Valproic Acid (VPA) on Thyroid Function
Studies reporting altered thyroid function among valproic
acid (VPA)-treated epileptic patients are controversial, showing
elevated, diminished, or even normal thyroid hormone levels.74Y76
Most of the studies evaluating this adverse effect of VPA are cross-
sectional studies. In a cross-sectional comparative controlled
study, 21 epileptic men on VPA showed no abnormality in their
thyroid function.74 In a cross-sectional comparative controlled
study, 5 epileptic patients on VPA showed an increase in their
T3 and T4 levels compared to controls (P = 0.05).75 In a pro-
spective comparative study of adult patients on VPA (n = 8),
a decrease in T3 (P G 0.01), T4 (P G 0.025), and f T4 (P G 0.05)
levels were noted after 3 months of follow-up.76 Subclinical
hypothyroidism and increased TSH with normal f T4 and T4
were reported.70 In a controlled cross-sectional study described
earlier, TSH levels were higher in the group of patients on VPA
than in controls (P G 0.001).69 Other cross-sectional compara-
tive studies (n = 11, n = 20, and n = 21, respectively) showed
that thyroid hormones and TSH concentrations were normal and
VPA did not affect thyroid function.74,78 In a prospective, ran-
domized, controlled double-blind study, a group of adult female
patients (n = 8) withdrawn from VPA had a decrease in their
fT3 levels compared to women in the group who had not been
withdrawn from the drug (n = 7; P = 0.03).73 Coadministration
of VPA with enzyme-inducing anticonvulsant such as CBZ
was shown to decrease serum levels of T4 and fT4 and to in-
crease serum levels of TSH (P G 0.001).69 In conclusion, although
VPA may provoke some abnormalities in circulating thyroid
hormones levels, these abnormalities do not seem to have major
clinical implications. Precautious measures in thyroid function
monitoring should be restricted to patients who receive VPA with
another enzyme-inducing anticonvulsant drug such as CBZ.
Effect of Benzodiazepines on Thyroid Function
Since the report that diazepam may cause depression of
iodine 131 (131I) uptake, some studies tended to confirm this
belief.78,79 Diazepam was shown to have no effect on TSH re-
lease or thyroid gland activity in a double-blind placebo con-
trolled prospective study including 24 euthyroid adults followed
for 12 weeks (and 11 followed for 6 weeks further).80 In another
study, no effect on laboratory measurements was found in
3 patients with thyrotoxicosis.81 In a comparative prospective
study where 2 groups of 12 euthyroid patients and 6 patients
with thyrotoxicosis received 15 mg/d of diazepam, an increase
in the 131I uptake 1 hour after the diazepam ingestion in the
euthyroid patients’ group was noted (P G 0.05).82 In conclusion,
benzodiazepines may interfere with 131I uptake in both direc-
tions. This effect does not seem to interfere with thyroid func-
252 www.clinicalneuropharm.com
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& Volume 34, Number 6, November/December 2011
tion parameters. Accordingly, no monitoring precautions should
be taken in patients receiving benzodiazepines.
Effect of Opiates Substitution Drugs on
Thyroid Function
Methadone is frequently included as a cause of euthyroid
hyperthyroxinemia, although its initiation for heroine with-
drawal was reported to normalize the high serum T4 found in
opiate addicts.83Y85 Studies that were made in this domain are
cross-sectional. In a cross-sectional study evaluating thyroid
function in 285 male opiates addicts, 22% had their T4 above
the upper limits of normal, whereas 36 patients on methadone
had normal thyroid function tests.83 In a controlled retrospective
and cross-sectional study, 145 patients received methadone for
a mean period of 5.8 weeks. In comparison to a euthyroid con-
trol group, the principal difference was an increase in the con-
centration of thyroxin-binding globulin in the serum, which
augmented total T3 and T4 and diminished T3 uptake (P G 0.001
each).86 In a cross-sectional study, 24 euthyroid patients on
naltrexone (50 mg/d) were evaluated. The duration of their
naltrexone treatment was positively correlated with T3 level and
T3/T4  100 (a coefficient of peripheral conversion from T4
to T3; P G 0.001 each).87 In conclusion, patients receiving opiate
substitution drugs present higher T3 and T4 blood levels than
controls. This effect is due to an increase in thyroxin-binding
globulin in the serum and is devoid of any clinical repercussions
and any effect on TSH level. Accordingly, no thyroid function
monitoring is recommended in these patients.
Effects of A-Blockers on Thyroid Function
Abnormalities seen in patients taking high doses of pro-
pranolol are known to be due to drug-induced blockade of T4
deiodination resulting in euthyroid hyperthyroxinemia. Signs
and symptoms of hyperthyroidism were lacking in a sample of
6 patients, on high doses of propranolol (485 T 155 mg/d) de-
scribed in a cross-sectional study, although they manifested low
T3 and high T4 levels.88 In one cross-sectional study, the prev-
alence of hyperthyroxinemia in patients with hypertension
treated with high doses of propranolol (320 mg/d or more) was
determined. Four of 14 patients had elevated serum T4 levels.
As a group, the patients on propranolol therapy had higher
T4, f T4, and T3 levels than had healthy controls.89 In prospec-
tive controlled studies considering small samples of alcoholic
patients with liver cirrhosis (n = 10; n = 20), no major thyroid
function abnormalities were noticed after 2 weeks of propran-
olol administration, although in healthy controls, T3 levels were
lower (P G 0.001).90,91 In conclusion, patients receiving non-
selective A-blockers such as propranolol may present a state of
high T4 and/or low T3 levels, but these abnormalities do not
seem to have any clinical repercussion as well as any effect on
TSH level even at high doses of A-blockers. No monitoring is
recommended for these patients.
Effects of Anticholinergic and Antihistaminergic
Drugs on Thyroid Function
In one retrospective study, 13 psychiatric patients taking
orphenadrine or had recently stopped taking it showed an ele-
vation of their T3 levels. In the same study, thyroid function tests
were compared in 15 pairs of matched psychiatric patients
treated with orphenadrine or other anticholinergic drugs. Values
of T3 and free thyroxine index (FTI) were significantly higher
among patients treated with orphenadrine. Also in this study,
orphenadrine was instituted in four patients and withdrawn in
six patients. T3 values and free thyroxine indices increased
gradually after orphenadrine treatment had been initiated and
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Clinical Neuropharmacology & Volume 34, Number 6, November/December 2011
decreased gradually when it was withdrawn.92 No other ad-
verse effects to thyroid function are described with anticho-
linergic and antihistaminergic drugs. Although orphenadrine
seems to have an effect on thyroid hormones (increase in T3
levels), data emanating from one study are not sufficient to draw
conclusions toward clinical impact and monitoring recommen-
dations for patients receiving this drug.
Effects of Stimulants on Thyroid Function
Few studies have shown that stimulants such as methyl-
phenidate and atomoxetine exert an effect on thyroid function.
When methylphenidate was administered acutely to rats in a
controlled study, serum T3 and T4 levels diminished significantly
and TSH increased (P G 0.001). These changes were reversed
after the drug was been discontinued.93 In an open-label trial
evaluating the effects and adverse effects of atomoxetine in
20 children with attention-deficit/hyperactivity disorder, raised
serum levels of thyroid hormones were noted in one child, which
normalized after the drug was stopped.94 Because further studies
are needed in this domain, no specific recommendations for
thyroid function monitoring are proposed for patients receiving
stimulant drugs.
DISCUSSION
We have presented a unique review of all the studies that
evaluated the thyroid adverse effects of all the psychopharmaco-
logic agents. According to this review, major influence of psy-
chopharmacologic drugs is correlated to the administration of
lithium, phenothiazines, and TCA. Other psychotropic drugs
such as CBZ, non-TCA antidepressant, and typical and atypical
antipsychotic drugs can alter thyroid-function blood parameters
without causing major dysthyroidism except in patients pre-
disposed to thyroid abnormalities. Minor, clinically insignificant
thyroid-function blood parameters can be found with treatments
such as VPA, benzodiazepines, A-blockers, and opiate substi-
tution drugs. Further studies are needed to better understand
the effect of some antipsychotic drugs such as anticholinergic
and antihistaminergic agents and stimulants on thyroid gland
function.
Patients receiving lithium should be screened for thyroid
function abnormalities before and regularly after this drug ini-
tiation. This monitoring should be continued as long as the drug
is received and for a short period after its withdrawal. In addi-
tion, regular thyroid function parameter monitoring is recom-
mended owing to the direct interference of phenothiazines and
TCA with thyroid functioning.
Precautious monitoring measures of thyroid function are
recommended only in case typical or atypical antipsychotic drugs
were accompanied with high blood prolactin level or when the
concerned patient is at risk for development of thyroid function
abnormalities. In addition, these precautions should be taken in
patients receiving non-TCA antidepressant drugs and CBZ only
when they are at risk for developing thyroid function abnor-
malities. Precautious measures in thyroid function monitoring
should be restricted to patients that receive VPA with another
enzyme-inducing anticonvulsant drug such as CBZ. No speci-
fic recommendations are proposed as toward thyroid function
monitoring for patients receiving benzodiazepines, A-blockers,
opiates substitution drugs, anticholinergic, antihistaminergic, and
stimulant drugs.
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