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REVIEW ARTICLES
PSYCHOTROPIC MEDICATION AND THE
ENDOCRINE SYSTEM
Liana Dehelean1, Pompilia Dehelean2, Daniela Jitaru3, Elena ªtefan3, Claudia Vasilian3
Abstract:
Background: Both bipolar disorder and schizophrenia
are associated with imbalances affecting not only certain
neurotransmitter pathways, but also the endocrine system,
which is partly controlled by neurotransmitters. As a
result, the psychotropic treatment used to treat these
disorders can result in endocrine side effects.
Method: We reviewed recent searches to determine the
relevance of individual factors (genotype, sex, age,
duration of the illness, compliance to treatment) and
medication depending factors (specificity for binding on
certain receptors, the dissociation constant from D2
receptors, the degree of penetration of the blood – brain
barrier, the route of administration).
Results and conclusions: Medication induced
hyperprolactinemia has a negative impact on the
compliance to the treatment. The long-term consequences
of hyperprolactinemia can affect the cardio-vascular
system the bone metabolism, and possibly, the cognitive
status.
Because both schizophrenia and bipolar disorder need
continuous prophylactic treatment, some psychotropic
medication may produce long-term side effects such as
hypogonadodropic hypogonadism with its negative
consequences on cognition, cardio-vascular system and
bone metabolism. The authors discuss possible corrective
strategies to be followed, from both a psychiatric and an
endocrinologist point of view. There will be addressed
also, the consequences of medication induced
hypothyroidism with or without preexistent hormonal
disturbances, which could be linked or not with the
presence of the psychosis.
The clinical picture of schizophrenia and bipolar disorder
is heterogeneous, which makes their treatment to be
complex. Because of its side effects, psychotropic
medication should be individualized according to the
present status and to the potential side effects on endocrine
system, bone and energetic metabolism, cardio-vascular
and cognitive status. Baseline endocrine and metabolic
status should be assessed along with long-term side effects
monitoring.
Key words: hyperprolactinemia, hypothyroidism,
schizophrenia, bipolar disorder, medication
Rezumat:
Cadru: Atât tulburarea afectivã bipolarã, cât ºi
schizofrenia sunt asociate cu dezechilibre ce implicã nu
doar diverse sisteme de neuromediatori, ci ºi sistemul
endocrin aflat parþial sub controlul acestor
neuromediatori. Prin urmare tratamentul psihotrop
utilizat în aceste boli va avea la rândul sãu efecte
secundare asupra sistemului endocrin.
Metodã: Sunt trecute în revistã studii recente din
literaturã care evalueazã relevanþa factorilor favorizanþi
ce þin de individ (genotip, sex, vârstã, durata bolii,
complianþa la tratament) cât ºi factorii ce þin de tipul
tratamentului psihotrop administrat (specificitatea de
legare pe anumiþi receptori, constanta de disociere de
receptorii D2, gradul de penetrare a barierei hematoencefalice, forma de administrare).
Rezultate ºi concluzii:: Consecinþele pe termen scurt ale
hiperprolactinemiei influenþeazã complianþa la
tratament, iar cele pe termen lung ar putea afecta statusul
cardio-vascular, statusul cognitiv ºi metabolismul osos.
Datoritã faptului cã tratamentul de întreþinere atât în
schizofrenie, cât ºi în tulburarea afectivã bipolarã este de
lungã duratã, unele psihotrope pot produce efecte pe
termen lung de tipul hipogonadismului gonadotrop cu
consecinþe negative asupra statusului cognitiv, cardiovascular ºi asupra metabolismului osos. În articol sunt
discutate posibilele strategii terapeutice de urmat în
aceste cazuri. De asemenea sunt discutate consecinþele
hipotiroidismului indus iatrogen suprapus sau nu peste
tulburãri hormonale preexistente, care la rândul lor pot fi
legate sau nu de prezenþa psihozei.
Tabloul clinic al psihozelor este heterogen, fapt ce impune
adesea, un tratament complex. Acesta trebuie
individualizat atât în funcþie de simptomatologie cât ºi de
posibilele consecinþe ale medicaþiei psihotrope asupra
hormonilor sexuali ºi tiroidieni, precum ºi asupra
metabolismului osos ºi energetic, aparatului cardiovascular, respectiv funcþiilor cognitive. Din aceastã
cauzã monitorizarea clinicã ºi paraclinicã a
tratamentului este importantã.
Cuvinte cheie: hiperprolactinemie, hipotiroidism,
psihotrope, schizofrenie, tulburare bipolarã
BACKGROUND
for a particular patient is not an easy task. A
treatment requires efficacy, easy administration and good
tolerability to be accepted by the patient and used on a
long term. In clinical practice, beside the therapeutic
effect, adverse reaction can appear demanding treatment
reconsideration or corrective interventions. At the
beginning of the neuroleptic era, more attention was
focused on the extrapyramidal side effects. The use of
Schizophrenia and bipolar disorder have
heterogeneous clinical presentations. For this reason, their
treatment becomes complex, requiring association
between psychotropic medication from different classes
(antipsychotics, antidepressant, mood stabilizers,
anxiolytics and hypnotics). Matching the best treatment
Received July 7, 2010; revised July 30, 2010; accepted September 3, 2010
University Lecturer, University Department of Psychiatry, Victor Babeº University of Medicine and Pharmacy, Timiºoara, Romania. Contact - e-mail :
[email protected]
2
University Professor, Department of Psychiatry, Victor Babeº University of Medicine and Pharmacy, Timiºoara, Romania
3
Resident in Psychiatry at the Clinical Hospital of Psychiatry “Eduard Pamfil”, Timiºoara, Romania
1
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Liana Dehelean, Pompilia Dehelean, Daniela Jitaru, Elena ªtefan, Claudia Vasilian: Psychotropic Medication And The
Endocrine System
The use of tricyclic antidepressants was under the
precaution of cardio-vascular toxicity. Lithium therapy
has been always linked with a low therapeutic index and
hypothyroidism. New molecules such as atypical
antipsychotics, selective serotonin reuptake inhibitors,
valproate and lamotrigine, with fewer side effects were
introduced in the medical practice. Nevertheless, because
no medication lacks side effects, what matters is the risk benefice ratio. Nowadays more experience has been
accumulated with the use of novel medication, much safer
than first generation molecules, but side effects are still
linked with their use.
Already in the past, data concerning the
endocrine side effects of antipsychotics were reported
with the use of sedative antipsychotics such as
phenothiazines (thyroid effects linked with
autoimmunity). Other antipsychotics with more powerful
D2 receptor blockade produced hyperprolactinemia.
Atypical antipsychotics although much safer, did not
change much of the situation, because some of them are
the equivalent of high potency antipsychotics
(risperidone, ziprasidone), other are the equivalent of low
potency antipsychotics (clozapine, olanzapine,
quetiapine). amisulpride, a new variant of sulpiride
(bimodal neuroleptic) and aripiprazole are considered
dopamine stabilizers.
Both bipolar disorder and schizophrenia are associated
with imbalances affecting not only certain
neurotransmitter pathways, but also the endocrine system,
which is partly controlled by these neurotransmitters. As a
result, the psychotropic treatment used to treat these
disorders can result in endocrine side effects. Few data
exist in psychiatric and endocrinologic literature about
endocrine side effects of psychotropics. An exception is
the focus on the metabolic syndrome produced by
antipsychotics with multireceptoral binding profile. The
most important endocrine side effects of antipsychotics
are hyperprolactinemia and iatrogenic induced
hypothyroidism.
METHOD
The paper reviews the existing psychiatric and
endocrinologic literature regarding the mechanisms by
which psychotropic medication (antipsychotics,
antidepressants and mood stabilizers) are able to influence
the endocrine system, specifically the prolactin and
thyroid hormones levels.
Results
I. Antipsychotic induced hyperprolactinemia
Prolactin is a hormone with multiple actions
(some authors suggest to call it „omnipotin”). It intervenes
not only in milk secretion, but also in sexual function,
glucose metabolism and immunity. Prolactin secretion
from the anterior pituitary is under the hypothalamic
control and is stimulated probably by TRH (thyrotropin
releasing hormone) and inhibited by dopamine (also
known as PIF – prolactin inhibiting factor). Serotonin
mediates the nocturnal rise in prolactin levels. Its
stimulating effect on prolactin secretion is based on
GABA neuron inhibition (GABA neurons limit the
dopamine secretion). Tricyclic antidepressants and
selective serotonin reuptake inhibitors by blocking
serotonin can produce hyperprolactinemia.
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Figure 1: Antipsychotics, prolactin and thyroid
hormones
Legend: antipsychotics inhibit the prolactin inhibiting
factor (dopamine) stimulating by this way the prolactin
secretion. Prolactin inhibits GnRH – gonadotropin releasing
hormone which results in low FSH (follicle - stimulating
hormone) and low LH (luteinizing hormone) secretion. The
consequence of the gonadotropic hormones deficit, the gonadal
secretion of estrogens will decrease (gonadotropic
hypogonadism). Antipsychotics also reduce the levels of the
thyroid hormones with the appearance of hypothyroidism.
Hypogonadism and hypothyroidism increase the risk of cardiovascular accidents.
Antipsychotics may induce either a temporary or
a sustained increase in prolactin levels by blocking
dopamine secreted by the tubero-infundibular dopamine
neurons (TIDA) (figure1). Some antipsychotics such as
clozapine, olanzapine and quetiapine increase temporary
the prolactin levels at the onset of treatment. Others, like
risperidone, its active metabolite 9 – hydroxyrisperidone,
and amisulpride can produce sustained
hyperprolactinemia (1). Nevertheless, this effect depends
not only on the molecule type, but also on several
individual factors (2) such as:
- Genotype
- Sex
- Age
- Duration of the disorder
- Compliance to treatment
In some patients, the presence of A1 allele of the
gene responsible for the synthesis of D2 dopamine
receptor (DRD2) will result in a smaller number of D2
receptors (3). When these patients receive antipsychotic
medication, the competition for the dopamine receptors
leaves only a very small number of D2 receptors
unblocked for dopamine to bind on them. Consequently,
there will be little inhibition of prolactin by dopamine and
the patients will have increased risk of
hyperprolactinemia under the antipsychotic treatment.
The patients that do not have the A1 allele can benefit from
antipsychotic dose increase (in case of olanzapine,
quetiapine) in order to achieve a stronger antipsychotic
effect (4).
In women, drug induced hyperprolactinemia is
Romanian Journal of Psychiatry, vol. XII, No.4, 2010
five times the normal values, while in men only three
times. In addition, women have a better response to
antipsychotics. Men need higher doses of antipsychotics.
Older age and a longer duration of the disorder
are linked with lesser increases in prolactin levels. This
effect may suggest that the consequences of a long
evolution of the disorder may result in a lesser response to
antipsychotics, with little increase in prolactin levels.
Pituitary hyperplasia is present in treated patients at their
first episode of schizophrenia in comparison with normal
subjects. Patients with a longer history of schizophrenia
have a smaller volume of pituitary than healthy subjects
(5).
Compliance (adherence) to treatment is a critical
factor in the successful management of a psychotic
disorder. Low adherence appears when patients wish to
have an active sexual life or when planning to have
children. On the other hand, the presence of
hyperprolactinemia at laboratory tests indicates a good
adherence to treatment.
The factors that increase the risk for an
antipsychotic to induce hyperprolactinemia are:
- the receptor binding profile (specificity for D2 receptor
binding). Conventional high potency antipsychotics have
a higher risk to induce hyperprolactinemia than atypical
antipsychotics.
- dissociation constant (Ki) from D2 dopamine receptors
(the lower Ki, the higher the risk). Some antipsychotics
have a smaller Ki from the D2 receptors, which means a
stronger binding to these receptors (amisulpride 1.3 nM,
risperidone 4.9 nM). This results in lower dosages needed
to obtain a therapeutic effect. Other antipsychotics have a
higher Ki from the D2 receptors (olanzapine 72 nM,
clozapine 432 nM, quetiapine 567 nM), requiring higher
dosages to achieve the therapeutic effect (6). Apart from
these situations is the case of aripiprazole, which binds
strongly to the D2 receptors (aripiprazole Ki 0.95 nM), but
has also a partial agonist effect on these receptors. Some
authors find useful in clinical practice to add aripiprazole
when other antipsychotics induce hyperprolactinemia (7).
- the degree of blood-brain barrier penetrations. Anterior
pituitary is outside this barrier. A low lipophilicity of a
molecule means a lesser blood-brain barrier penetration
and therefore, a higher risk to induce hyperprolactinemia.
- the half-life of the drug (t ½). Molecules with a higher
half-life induce a more sustained hyperprolactinemia than
those with a lower half-life. For example, risperidone
induces sustained hyperprolactinemia through its active
metabolite 9 – hydroxyrisperidone that has a half-life of
20 hours, while risperidone has a half-life of 2-4 hours (8).
- the way the medication is administered. Depot and long
acting forms used to simplify the drug administration and
to increase the compliance to treatment are accompanied
by more sustained increases in prolactin levels)
The effects of hyperprolactinemia are important
at short term and at long term. In women appears
amenorrhea and galactorrhea, while in men gynecomasty
and sexual dysfunctions. In both cases, the patient are at
risk to stop taking the treatment, mainly young women
wanting to have children. Stopping treatment while being
pregnant increases the risk of the recurrence.
In the case of hyperprolactinemia,
endocrinologists recommend the correction of this
secondary effect by adding dopaminergic agonists such as
bromocriptine and cabergoline. Psychiatrists are
concerned that adding dopaminergic agonists
will stimulate psychotic symptoms and the switch to
another antipsychotic will be a better solution. There are
authors that recommend the use of aripiprazole, because
of its partial dopaminergic agonism.
On a long term, inhibiting the secretion of the
sexual hormones (secondary to the prolactin inhibition on
gonadotropic hormones FSH and LH), can lead to
osteoporosis, cardio-vascular events, and possibly,
cognitive impairment. Regarding the bone metabolism,
estrogen hormones inhibit bone resorption. A deficit in
estrogen hormones will increase the risk of osteoporosis
(9), especially in the case of a diet poor in proteins and
calcium, while lack of sun exposure, reduces D3 vitamin
synthesis. Estrogen hormones lower the risk of cardiovascular events in women. Consequently, inhibition of
these hormones in the presence of other cardio-vascular
risk factors such as hyperlipidemia with dyslipidemia,
high LDL cholesterol with low HDL cholesterol,
smoking, obesity, hyperglycemia and lack of physical
exercise, will increase the risk of ischemic heart disease in
women.
An interesting question is whether low estrogen
hormones could increase the risk of developing cognitive
deterioration in the future. A hypothesis regarding the risk
of developing Alzheimer's dementia includes low levels
of estrogen hormones in normal or surgical induced
menopausal women. This hypothesis is based on some
facts:
- Alzheimer dementia is more frequent in women than in
men.
- Estrogen hormones stimulate acetylcholine synthesis
acting on cholin acetyltransferase.
- Estrogen hormones also stimulate alpha secretase, an
enzyme located in the neuronal membrane that cuts the
amyloid precursor protein in a position favoring the
production of a nonpathogenic amyloid (10).
Prolactin influences glucose and lipid
metabolism stimulating insulin synthesis in the
Langerhans beta cells and inhibiting the synthesis of
lipoproteinlipase in the adipose cells (figure2).
Prolactin stimulates the proliferation of an
important number of cells: astrocytes, immune cells,
smooth muscle cells and pancreatic cells (11). In addition,
it stimulates the development of hypothalamic tuberoinfundibular cells secreting dopamine / TIDA (12). At the
level of pancreatic Langerhans beta cells, prolactin
stimulates insulin synthesis through glucose dependent
and glucose independent mechanisms using the JAK
(Janus kinase) – STAT (signal transducers and activators
of transcription) pathway (13). In return, insulin acts at the
pituitary level stimulating the synthesis of prolactin (14).
Prolactin and insulin effects on the target cells
are mediated by IRS (insulin receptor substrate) 1,2,3
phosphorylation. These cytoplasmic proteins act like
metabolic switches implicated in glycogen synthesis, in
protein synthesis and in lipolysis. The IRS proteins are
associated with the phosphatidyl inositole kinase, which
mediates the glucose receptors translocation from the
cytoplasmatic vesicles to the cell membrane (15).
At the adipocyte level, insulin stimulates the
synthesis of lipoproteinlipase and its translocation in the
vascular endothelial cell. Acting at the level of the
vascular endothelium, lipoproteinlipase liberates fatty
acids from the circulating lipoproteins. Insulin stimulates
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Liana Dehelean, Pompilia Dehelean, Daniela Jitaru, Elena ªtefan, Claudia Vasilian: Psychotropic Medication And The
Endocrine System
the capture of glucose the adipocyte. Inside the adipose
cell, glycerol synthesized from glucose will bind free fatty
acids forming the triglycerides stored in these cells.
Prolactin inhibits the synthesis of lipoprotein lipase in the
adipocyte.
Figure 2: Prolactin and metabolism.
Legend: Prolactin stimulates the beta cell proliferation in the
pancreatic Langerhans islands. It also stimulates the synthesis
of insulin. At the level of the adipocyte insulin stimulates the
lipoprotein lipase while prolactin inhibits it.
II. Hypothyroidism induced by psychotropic
medication
A study measuring thyroid function (T3, T4, rT3,
TSH) in schizophrenic patients showed that the level of
the T4 fraction in acutely ill patients is high comparing to
the T4 level in remitted and residual form patients (being
under treatment or without treatment). The increased T4
level correlates with the severity of the disorder and with
the degree of the response to antipsychotics. The blood
levels of T3, rT3 and TSH were normal. After four weeks
of treatment, the T4 level decreased significantly
correlating with the response to medication. Patients in
remission and those with the residual form of
schizophrenia did not show any disturbance of the thyroid
hormones (16).
The mechanisms through which psychotropic
medication inhibits thyroid function are not yet known.
Either the drugs interfere with the synthesis of thyroid
hormones, or act through an autoimmune mechanism.
(17). Psychotropic medication may impair thyroid
function in several ways:
– Affecting iodine capture by thyroid cells
–Making iodine unavailable for thyroid hormone
synthesis (complex iodine)
– Inhibiting thyroid peroxidase (affecting the synthesis
of T3 andT4)
– Enhancing deiodination of T4 to T3
– Inhibiting noradrenergic and serotonergic reuptake
(tricyclic antidepressants)
– Favoring autoimmune mechanism (phenothiazines)
Clinical manifested hypothyroidism disturbs lipid
metabolism and increases the risk of cardio-vascular
136
complications through obesity, high LDL cholesterol and
diastolic type hypertension. Hypothyroidism does not
produce increased resistance to insulin. A risk factor for
developing metabolic complication when using
antipsychotics is subclinical hypothyroidism, which is
rather frequent (7.5% of women and 3% of men) but rarely
put into evidence (18). The manifestations of subclinical
hypothyroidism are a mild increase in global lipidemia
and LDL cholesterol associated with TSH blood levels of
10 mU/L (19).
Iatrogenic induced hypothyroidism is linked too
with the use of antidepressants such as amitriptiline,
doxepin and paroxetin, which have high binding affinity
on muscarinic M3 receptor. By blocking these receptors,
antidepressants can inhibit the secretion of insulin into the
blood.
The consequences of hypothyroidism such as
obesity and dyslipidemia amplify the glucose and lipid
metabolism disturbances produced by some
antipsychotics. Psychotropic medication (mainly
antipsychotics and antidepressants) stimulate weight
increase acting:
-centrally at the hypothalamic level by blocking histamine
H1 receptors and serotonin 5HT2C receptors
-in the periphery on the Langerhans beta cell inhibiting
insulin secretion by blocking muscarinic M3 (20).
Antipsychotics associating antihistaminic H1,
antimuscarinic M3 and antiserotoninic 5HT2C effects
have the highest risk of inducing weight gain (clozapine
and olanzapine).
At the hypothalamic level, in the arcuate and
paraventricular nuclei, histamine binding on H1 receptors
inhibits AMPK (AMP activated protein kinase).
Orexigenic substances stimulate hypothalamic AMPK,
while anorexigenic substances inhibit it (21). AMPK is an
enzyme activated by AMP accumulation in an energydepleted cell. Thus, AMPK acts like an energy sensor
responding to an altered AMP/ATP ratio, which favors
AMP. To correct the energetic disequilibrium, AMPK
stimulates energy producing metabolic pathways while
inhibiting the energy consuming ones. Particularly,
AMPK will stimulate lipid beta oxidation and glucose
capture and glucose use by the cell (22).
DISCUSSIONS
Knowing that there are forms of depression
associated with hypothyroidism where TRH stimulation
cannot correct the deficit, the choice of the antidepressant
treatment becomes a critical issue. In these cases, the
antidepressant medication should lack secondary
metabolic effects.
In bipolar disorder, the acute phase and the
maintenance treatment require the association between
psychotropic drugs. For example, in the depressive
episode, mood stabilizers added to antidepressants
prevent the risk of a manic switch. In the manic phase,
mood stabilizers can be used in association with
antipsychotics to potentiate the antimanic effect. Mood
stabilizers have their own side effects such as weight gain
(mainly valproate), or hypothyroidism associated with
weight gain in the case of lithium. Rapid cycling bipolar
disorder is triggered by hypothyroidism (23). Therefore,
the selection of psychotropic medication in bipolar
Romanian Journal of Psychiatry, vol. XII, No.4, 2010
disorder must be done according to:
- patient's comorbidity (sublinical hypothyroidism or
clinically manifest hypothyroidism)
- the potential effects of the medication on the endocrine
system (prolactin and thyroid hormones) and on energetic
metabolism (glucose and lipids)
- the type of the disorder (bipolar disorder with rapid
cycling)
Because psychotic disorders have a
heterogeneous clinical presentation, their treatment is
complex, requiring association of an antipsychotic or of
an antidepressant with a mood stabilizer. The association
of psychotropic drugs can increase the risk of drug
interactions and of cumulative side effects. Therefore, the
treatment should be individualized according to the
clinical presentation and the potential effects of
psychotropic medication on the endocrine system and
energetic metabolism. Even if the degree of
hyperprolactinemia does not always correlate with
experiencing clinical side effects (24), blood tests are
recommended. Laboratory test should be repeated to
verify the presence and the dynamic of possible side
effects produced by the psychotropic medication.
CONCLUSION
The success of a psychotropic treatment is based
on the efficacy of the medication, on its tolerability and
easy to use. This requires an active collaboration from the
patient who must understand and accept the necessity of
initial and dynamic monitoring of the endocrine and
metabolic side effects of psychotropic medication. Before
starting a psychotropic medication, it is recommended to
do biochemical lab tests and, where it is possible, to make
hormonal test intended to discriminate between
medication side effects and the baseline hormonal and
biochemical status of the patient.
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