Treatment of clozapine-associated weight gain: a systematic review.

PURPOSE: Clozapine is an antipsychotic drug with superior efficacy in treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side-effects but a high propensity to induce weight gain and general metabolic dysregulation. Various pharmacological and behavioral treatment approaches for reducing clozapine-associated weight gain exist in the literature; however, there are currently no clear clinical guidelines as to which method is preferred. The aim of the current review is to systematically summarize studies that have studied both pharmacological and non-pharmacological interventions to attenuate or reverse clozapine-associated weight gain. METHODS: A systematic review of EMBASE and MEDLINE databases of all articles published prior to January 2014 was conducted. Seventeen studies were identified as meeting inclusion criteria and included in the review. RESULTS: Aripiprazole, fluvoxamine, metformin, and topiramate appear to be beneficial; however, available data are limited to between one and three randomized controlled trials per intervention. Orlistat shows beneficial effects, but in males only. Behavioral and nutritional interventions also show modest effects on decreasing clozapine-associated weight gain, although only a small number of such studies exist. CONCLUSIONS: While a number of pharmacological interventions can produce modest weight loss, each may be associated with negative side effects, which should be considered before beginning treatment. Given the pressing need to improve cardiometabolic health in most clozapine-treated patients, substantially more research is needed to develop sound clinical practice guidelines for the treatment of clozapine-associated weight gain.

Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats.

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

A comparison of the effects of clozapine and its metabolite norclozapine on metabolic dysregulation in rodent models.

RATIONALE: The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine. METHODS: Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance. RESULTS: In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance. ABSTRACT: While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise.

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals.

Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine.

Interleukin-18 null mice show diminished microglial activation and reduced dopaminergic neuron loss following acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment.

Recent reports have revealed an involvement of microglial cells in dopaminergic neurodegeneration. In the present study, we tested the hypothesis that interleukin-18 (IL-18) plays a role in the microglial activation. The present study investigated microglial activation and dopaminergic neurodegeneration in substantia nigra pars compacta (SNpc) following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in wild type (WT) and IL-18 knockout (KO) mice. The number of dopaminergic neuron loss in WT mice was significantly decreased 7 days after MPTP treatment compared with IL-18 KO mice. In WT mice microglial activation occurred in the SN at 1 day after MPTP treatment, progressively increased within the SNpc until 7 days post MPTP, and subsided by 14 days. In contrast, in IL-18 KO mice microglial activation occurred in the SN at 1 day post-MPTP, and decreased by 7 days, earlier than in WT mice. The lesser microglial activation and dopaminergic neurodegeneration in the SNpc following MPTP treatment in WT indicates the possibility that IL-18 may participate in microglial activation and dopaminergic neurodegeneration.

Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement.

Numerous studies have shown that withdrawal from sustained high doses of psychostimulant drugs such as cocaine or d-amphetamine produces depressive-like symptoms in both rats and humans. The majority of experiments with rodents have assessed the effects of amphetamine withdrawal on reinforcing electrical self-stimulation in different brain regions, but relatively few have examined effects on responding for natural reinforcers. In the present study, two groups of mildly food and water deprived male rats were trained to respond on a lever for a 4% sucrose solution under a progressive ratio schedule of reinforcement. One group was subsequently administered a 4-day regimen of injections of increasing doses of d-amphetamine based on a schedule shown previously to reduce self-stimulation behaviour. Break points were significantly reduced for up to 4 days after the termination of drug administration, suggesting a decreased motivation to obtain the natural reward. A further experiment demonstrated that the identical drug regimen produced no effect upon consumption of the 4% sucrose solution when it was freely available. These results demonstrate that the progressive ratio procedure may be a useful technique for evaluating changes in motivation for natural reinforcing stimuli following withdrawal from psychostimulant drugs.

Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression.

The effect of hormone withdrawal following hormone-simulated "pregnancy" on "depressive-like behavior" in the Forced Swim Test (FST) was investigated in female Long-Evans rats. Females were randomly assigned to "pregnant", "pregnant"+estradiol benzoate (EB), and control groups. Both the "pregnant" and "pregnant"+EB groups received daily injections of the hormones estradiol and progesterone to simulate the 23-day gestational period in the rat. However, the "pregnant"+EB group continued to receive daily estradiol injections after "pregnancy". All groups were tested 48 h after the last injection of the pregnancy period in the FST and subsequently in the Open Field Test (OFT). Results revealed that the "pregnant" rats exhibited significantly increased immobility and decreased struggling and swimming behaviors as compared to the "pregnant"+EB and control groups. These findings could not be explained by an overall depression in general locomotor activity among "pregnant" rats, as the "pregnant" rats made more area crossings in the OFT. Thus "pregnant" rats exhibited behaviors consistent with "depressive-like" symptoms "post-partum" (after their hormone regime was discontinued). Continual treatment with high levels of estradiol in the "pregnant"+EB group, however, reversed the exhibition of these behaviors. These results imply that withdrawal from chronic high levels of pregnancy-associated hormones (estradiol and progesterone) can produce depressed symptomology in rodents, which can be prevented by prolonging exposure to high levels of estradiol through the post-partum period. These findings are the first demonstration of "depressive-like" symptoms in a rodent model of post-partum pregnancy and the ability of high levels of estradiol to attenuate these "depressive-like" symptoms.

Chronic corticosterone enhances the rewarding effect of hypothalamic self-stimulation in rats.

Excessive levels of glucocorticoids have been implicated in the etiology of affective disorders in humans, and in a range of behavioral deficits in animals. In the present study, we used an established regimen of corticosterone administration (40 mg/kg, for 21 days) to determine its effects upon responding for rewarding brain stimulation in rats. After chronic treatment, subjects exhibited an unexpected but significantly increased sensitivity to the rewarding effects of brain stimulation. These results suggest that chronic, high levels of corticosterone are unlikely to cause anhedonia in rodents.

Paradoxical effects of chronic corticosterone on forced swim behaviours in aged male and female rats.

The effects of chronically administered corticosterone on forced swim test and open field test behaviours were explored in aged male and female rats. Though corticosterone has typically been associated with depressive behaviours, recent data have suggested a putative antidepressive effect of corticosterone. The current study used the forced swim test as a model of antidepressant efficacy in order to explore this. Aged male and female rats received either corticosterone (20 mg/kg) or the vehicle for 10 days before testing in the forced swim test, then for an additional 3 days before testing in the open field test. On day 11, each animal was individually tested on the duration of swimming, immobile, and struggling behaviours, and on day 14, for the display of rearing and line crossing behaviours. Results revealed that corticosterone significantly increased swimming and decreased immobility behaviour in females, but failed to do so in males. Additionally, there was a main effect of corticosterone on struggling behaviour such that it decreased it in males. There were no effects of corticosterone or sex on open field test behaviours, suggesting that the present findings are not accounted for by a general effect of corticosterone on motor behaviour. Overall, the data suggest that chronically administered corticosterone possesses effects that are sex-specific, and that it may exert mildly antidepressive effects in females, but the opposite effects in males. These data are consistent with emerging evidence that corticosterone may play a paradoxical antidepressive effect.

Sex differences in forced-swim and open-field test behaviours after chronic administration of melatonin.

The effects of melatonin administered chronically on forced-swim test and open-field test behaviours were examined in male and female rats. The forced-swim test has been shown to be sensitive to all major classes of antidepressants and evidence indicates that melatonin possesses putative antidepressive properties. Male and female Long-Evans rats received either a regimen of chronic administration of melatonin or the control condition for 14 days via the drinking water. On day 15, each animal was individually introduced into a swim chamber, and was scored for 15 min on the duration of swimming, struggling, and immobility. After 24 h, each animal was again tested in the forced-swim test for 10 min. On day 18, all animals were tested in the open-field test apparatus for 5 min. Results revealed that females consistently showed higher activity levels than males in the forced-swim and open-field tests. Melatonin significantly increased struggling in males on day 15, but failed to do so in females. Also, whereas melatonin-treated females showed higher levels of behavioural immobility during their first exposure to the forced-swim test, this effect was prevented upon a second exposure. In both males and females, melatonin decreased swimming in the forced-swim test while increasing open-field ambulatory behaviour. Therefore, it is unlikely that melatonin's mechanism of action is a general inhibitory effect on motor activity. Taken together, the results suggest that the effects of melatonin treatment on forced-swim test behaviours are sex- and test-dependent.

Chronic mild stress has no effect on responding by rats for sucrose under a progressive ratio schedule.

Exposure of rats to chronic unpredictable mild stress (CMS) has been shown to produce a syndrome in which a wide range of consummatory behaviors are attenuated, resembling a state of anhedonia, which may be reversed by treatment with antidepressant drugs. The aim of the present study was to determine whether CMS would also affect a rat's motivation to respond for a sucrose solution, as assessed by its performance under a progressive ratio (PR) schedule of reinforcement. Control studies demonstrated that break points in nonstressed rats were sensitive to both the concentration of sucrose solution used, as well as the period of food and water deprivation used prior to testing. Exposure of rats to CMS had no effect upon break points when responding under a progressive ratio schedule for either a 1% or 7% sucrose solution, although subjects did display the typical reduction in consumption of a freely consumed 1% sucrose solution. These results are not readily understood within the theoretical framework of the CMS model of anhedonia and imply instead that both the neural and psychological correlates of motivation may be less susceptible to modulation by the effects of CMS than the free consumption of sweet solutions.

Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat.

The present study sought to determine the effect of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in male rats. Tests were conducted every 5 days until stable levels of sexual behavior were obtained. With repeated testing, male rats displayed an increase in their exploration of the testing chambers prior to the introduction of an estrous female. Half of the male rats were then subjected to a 4-day escalating dose schedule of d-amphetamine administration (1-12 mg/kg), while half received vehicle. Twelve hours after the final drug injection, subjects were tested for sexual behavior. Withdrawal from the drug was associated with decrements in several motivational components of sexual behavior, including decreased anticipatory locomotor and increased postejaculatory intervals, while consummatory measures remained largely unaffected. This pattern of sexual deficits resembles those seen in human depressive disorders, and therefore, provides additional support for the use of psychostimulant withdrawal as a rodent model of depression.

Peripheral adrenoceptors: the impetus behind glucose dysregulation and insulin resistance.

It is now accepted that several pharmacological drug treatments trigger clinical manifestations of glucose dysregulation, such as hyperglycaemia, glucose intolerance and insulin resistance, in part through poorly understood mechanisms. Persistent sympathoadrenal activation is linked to glucose dysregulation and insulin resistance, both of which significantly increase the risk of emergent endocrinological disorders, including metabolic syndrome and type 2 diabetes mellitus. Through the use of targeted mutagenesis and pharmacological methods, preclinical and clinical research has confirmed physiological glucoregulatory roles for several peripheral α- and ß-adrenoceptor subtypes. Adrenoceptor isoforms in the pancreas (α(2A) and ß(2) ), skeletal muscle (α(1A) and ß(2) ), liver (α(1A & B) and ß(2) ) and adipose tissue (α(1A) and ß(1 & 3) ) are convincing aetiological targets that account for both immediate and long-lasting alterations in blood glucose homeostasis. Because significant overlap exists between the therapeutic applications of numerous classes of drugs and their associated adverse side-effects, a better understanding of peripheral adrenoceptor-mediated glucose metabolism is thus warranted. Therefore, at the same time as providing a brief review of glucose homeostasis in the periphery, the present review addresses both functional and pathophysiological roles of the mammalian α(1) , α(2) , and ß-adrenoceptor isoforms in whole-body glucose turnover. We highlight evidence relating to the clinical use of common adrenergic drugs and their impacts on glucose metabolism.

Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats.

Numerous studies have reported that the hippocampus in schizophrenia patients is reduced in volume compared to the normal population. Antipsychotic medications have had mixed benefits in maintaining hippocampal volume or reversing volume loss. Recent evidence indicates that routine aerobic exercise represents a promising intervention for reversing hippocampal loss and cognitive deficits. In the present study, we measured the effects of chronic treatment with olanzapine and daily exercise on the hippocampal volumes of rats. Adult female rats were treated during the week with either olanzapine (10mg/kg) or vehicle for 9 consecutive weeks. Subgroups of animals were provided access to exercise running wheels for 1 or 3h per day during the same period, or were sedentary. Metabolic indices, including glucose tolerance, were measured on a weekly basis. At the conclusion of the study, brains were perfused and hippocampal sections were Nissl stained. Total hippocampal volume was measured using the Cavalieri estimator. Treatment with olanzapine caused a significant decrease in hippocampal volume in sedentary rats. However, exercise was able to reverse most of this volume loss. The hippocampal sub-regions of the dentate gyrus and CA1 were most strongly affected by olanzapine and exercise. Of interest, there was a strong and highly significant negative correlation between glucose intolerance and hippocampal volume, whereby greater glucose intolerance was associated with a smaller hippocampal volume. These findings indicate that exercise may have beneficial effects on the hippocampus when antipsychotic medication can contribute to changes in volume.

Intermittent treatment with olanzapine causes sensitization of the metabolic side-effects in rats.

The second generation antipsychotic drugs are effective treatments for psychotic disorders. Many of these compounds, including the drug olanzapine, have been associated with metabolic side-effects, including weight gain, impaired glucose tolerance and insulin resistance, which increase the risk of developing cardiometabolic disorders. Rodent models of olanzapine-induced metabolic side-effects have been used to study the physiology of these effects, but only at a single time point after drug treatment. The purpose of the present study was to examine longitudinal changes with chronic antipsychotic drug treatment. Adult female rats were treated with either olanzapine (15 mg/kg) or vehicle for five consecutive days each week, followed by a 48 h washout period. Animals were then challenged with either olanzapine (15 mg/kg) or vehicle, and fasting glucose and insulin values were recorded, as well as glucose clearance in the glucose tolerance test. Treatment with olanzapine was continued for 10 weeks, with weekly tests of metabolic indices. Rats treated acutely with olanzapine showed both glucose dysregulation and insulin resistance; for the group treated during the week with olanzapine, these effects did not change by the end of ten weeks of treatment. However, in the group of animals challenged only once per week with olanzapine, the metabolic side-effects markedly intensified with the passage of time, whereby glucose intolerance and insulin resistance increased significantly compared to both baseline values and all other treatment groups. This previously unreported sensitization phenomenon represents a novel finding that may have clinical implications for patients receiving intermittent antipsychotic drug dosing or with variable adherence to treatment.

Cognitive reserve, presynaptic proteins and dementia in the elderly.

Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N = 97 (38.3%), a pathologic diagnosis of AD in N = 142 (56.1%) and cerebral infarcts in N = 77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio = 0.36-0.68, P < 0.001 to P = 0.03) and better cognitive function (P < 0.001 to P = 0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P = 0.01) and lower SNAP-25/syntaxin interaction (P < 0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein-protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.

Anterior internal capsule volumes increase in patients with schizophrenia switched from typical antipsychotics to olanzapine.

Abnormalities in connectivity are thought to contribute to the symptoms of schizophrenia. Accumulating evidence suggests that antipsychotic medication affects both subcortical and cortical grey and white matter volumes. The goal of this study was to investigate the effects of antipsychotic medication on two white matter tracts: a subcortical-cortical tract, the anterior and posterior limbs of the internal capsule; and a cortical-cortical tract, the corpus callosum. Magnetic resonance imaging was conducted on 10 chronic schizophrenia patients treated with typical antipsychotics and 20 healthy controls at baseline. Patients were switched to olanzapine and both groups were rescanned after 1 year. At baseline, the volume of the anterior limb of the internal capsule was 24% smaller in typical-treated patients than controls (p = 0.009). Patients treated with greater amounts of chlorpromazine-equivalent daily dosage had smaller anterior internal capsule volumes at baseline (r = -0.65, p = 0.04). At follow-up, after being switched to olanzapine, there were no significant differences between patients and controls. Patients with schizophrenia had a significant 25% increase in anterior internal capsule volume from baseline to follow-up compared with controls (p = 0.04). These effects were most prominent in the anterior limb of the internal capsule, which consists of fronto-thalamic pathways, and were not statistically significant in the posterior limb of the internal capsule or corpus callosum. Olanzapine may be effective in normalizing fronto-thalamic structural connectivity in schizophrenia.

Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine.

The significant proportion of depressed patients that are resistant to monoaminergic drug therapy and the slow onset of therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs)/serotonin/noradrenaline reuptake inhibitors (SNRIs) are two major reasons for the sustained search for new antidepressants. In an attempt to identify common underlying mechanisms for fast- and slow-acting antidepressant modalities, we have examined the transcriptional changes in seven different brain regions of the rat brain induced by three clinically effective antidepressant treatments: electro convulsive therapy (ECT), sleep deprivation (SD), and fluoxetine (FLX), the most commonly used slow-onset antidepressant. Each of these antidepressant treatments was applied with the same regimen known to have clinical efficacy: 2 days of ECT (four sessions per day), 24 h of SD, and 14 days of daily treatment of FLX, respectively. Transcriptional changes were evaluated on RNA extracted from seven different brain regions using the Affymetrix rat genome microarray 230 2.0. The gene chip data were validated using in situ hybridization or autoradiography for selected genes. The major findings of the study are: 1. The transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment. 2. The fast-onset, short-lived antidepressant treatments ECT and SD evoked transcriptional changes primarily in the catecholaminergic system, whereas the slow-onset antidepressant FLX treatment evoked transcriptional changes in the serotonergic system. 3. ECT and SD affect in a similar manner the same brain regions, primarily the locus coeruleus, whereas the effects of FLX were primarily in the dorsal raphe and hypothalamus, suggesting that both different regions and pathways account for fast onset but short lasting effects as compared to slow-onset but long-lasting effects. However, the similarity between effects of ECT and SD is somewhat confounded by the fact that the two treatments appear to regulate a number of transcripts in an opposite manner. 4. Multiple transcripts (e.g. brain-derived neurotrophic factor (BDNF), serum/glucocorticoid-regulated kinase (Sgk1)), whose level was reported to be affected by antidepressants or behavioral manipulations, were also found to be regulated by the treatments used in the present study. Several novel findings of transcriptional regulation upon one, two or all three treatments were made, for the latter we highlight homer, erg2, HSP27, the proto oncogene ret, sulfotransferase family 1A (Sult1a1), glycerol 3-phosphate dehydrogenase (GPD3), the orphan receptor G protein-coupled receptor 88 (GPR88) and a large number of expressed sequence tags (ESTs). 5. Transcripts encoding proteins involved in synaptic plasticity in the hippocampus were strongly affected by ECT and SD, but not by FLX. The novel transcripts, concomitantly regulated by several antidepressant treatments, may represent novel targets for fast onset, long-duration antidepressants.