REVIEW ARTICLES

PSYCHOTROPIC MEDICATION AND THE ENDOCRINE SYSTEM

Liana Dehelean1, Pompilia Dehelean2, Daniela Jitaru3, Elena tefan3, 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 BACKGROUND 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
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Rezumat: Cadru: Att tulburarea afectiv bipolar, ct i schizofrenia sunt asociate cu dezechilibre ce implic nu doar diverse sisteme de neuromediatori, ci i sistemul endocrin aflat parial sub controlul acestor neuromediatori. Prin urmare tratamentul psihotrop utilizat n aceste boli va avea la rndul su efecte secundare asupra sistemului endocrin. Metod: Sunt trecute n revist studii recente din literatur care evalueaz relevana factorilor favorizani ce in de individ (genotip, sex, vrst, durata bolii, compliana la tratament) ct i factorii ce in de tipul tratamentului psihotrop administrat (specificitatea de legare pe anumii receptori, constanta de disociere de receptorii D2, gradul de penetrare a barierei hematoencefalice, forma de administrare). Rezultate i concluzii:: Consecinele pe termen scurt ale hiperprolactinemiei influeneaz compliana la tratament, iar cele pe termen lung ar putea afecta statusul cardio-vascular, statusul cognitiv i metabolismul osos. Datorit faptului c tratamentul de ntreinere att n schizofrenie, ct i n tulburarea afectiv bipolar este de lung durat, unele psihotrope pot produce efecte pe termen lung de tipul hipogonadismului gonadotrop cu consecine negative asupra statusului cognitiv, cardiovascular i asupra metabolismului osos. n articol sunt discutate posibilele strategii terapeutice de urmat n aceste cazuri. De asemenea sunt discutate consecinele hipotiroidismului indus iatrogen suprapus sau nu peste tulburri hormonale preexistente, care la rndul lor pot fi legate sau nu de prezena psihozei. Tabloul clinic al psihozelor este heterogen, fapt ce impune adesea, un tratament complex. Acesta trebuie individualizat att n funcie de simptomatologie ct i de posibilele consecine ale medicaiei psihotrope asupra hormonilor sexuali i tiroidieni, precum i asupra metabolismului osos i energetic, aparatului cardiovascular, respectiv funciilor cognitive. Din aceast cauz monitorizarea clinic i paraclinic a tratamentului este important. Cuvinte cheie: hiperprolactinemie, hipotiroidism, psihotrope, schizofrenie, tulburare bipolar 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

Received July 7, 2010; revised July 30, 2010; accepted September 3, 2010 University Lecturer, University Department of Psychiatry, Victor Babe University of Medicine and Pharmacy, Timioara, Romania. Contact - e-mail : lianadeh@upcmail.ro 2 University Professor, Department of Psychiatry, Victor Babe University of Medicine and Pharmacy, Timioara, Romania 3 Resident in Psychiatry at the Clinical Hospital of Psychiatry Eduard Pamfil, Timioara, Romania

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Liana Dehelean, Pompilia Dehelean, Daniela Jitaru, Elena tefan, 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. 134 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 ). 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 135

Liana Dehelean, Pompilia Dehelean, Daniela Jitaru, Elena tefan, 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. 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

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

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. REFERENCES
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