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Rationale: Antipsychotic-induced parkinsonism (AIP) is a severe adverse affect of antipsychotic drug treatment. Recently, our group performed a genome-wide association study (GWAS) for AIP severity, and identified several potential AIP risk variants., Objectives: The aim of this study was to validate our original AIP-GWAS susceptibility variants and to understand their possible function., Methods: We conducted a validation study of 15 single-nucleotide polymorphisms (SNPs) in an independent sample of 178 US schizophrenia patients treated for at least a month with typical or atypical antipsychotics. Then, a sample of 49 Jewish Israeli Parkinson's disease (PD) patients with available neuroimaging ([(123)I]-FP-CIT-SPECT) data was analyzed, to study association of confirmed AIP SNPs with level of dopaminergic deficits in the putamen., Results: Using logistic regression and controlling for possible confounders, we found nominal association of the intronic SNP, rs12678719, in the Zinc Finger Protein Multitype 2 (ZFPM2) gene with AIP (62 affected/116 unaffected), in the whole sample (p = 0.009; P = 5.97 × 10(-5) in the GWAS), and in the African American sub-sample (N = 111; p = 0.002). The same rs12678719-G AIP susceptibility allele was associated with lower levels of dopaminergic neuron related ligand binding in the contralateral putamen of PD patients (p = 0.026)., Conclusions: Our preliminary findings support association of the ZFPM2 SNP, rs12678719, with AIP. At the functional level, this variant is associated with deficits in the nigrostriatal pathway in PD patients that may be related to latent subclinical deficits among AIP-prone individuals with schizophrenia. Further validation studies in additional populations are required.

Rationale: Antipsychotic-induced parkinsonism (AIP) is a severe adverse affect of neuroleptic treatment. Interindividual heterogeneity in AIP development and severity is associated with risk factors such as antipsychotic drug type, old age, and female gender. There is evidence for genetic predisposition to develop AIP but the variants that confer susceptibility or protection are mostly unknown., Objective: To identify genes related to AIP susceptibility, we performed a pharmacogenomic genome-wide association study (GWAS) for AIP severity., Methods: Three hundred ninety-seven American schizophrenia patients who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-GWAS project were included in our analysis. Patients had been randomized to treatment with antipsychotic monotherapy for periods ranging from 2 weeks to 18 months during phase 1 of the CATIE trial. They were regularly assessed for AIP severity using the modified Simpson-Angus Scale (SAS). For statistical analysis, patients were dichotomized as cases (average SAS mean global score > 0.3 during CATIE phase 1, N = 199) or controls (average SAS mean global score 0, N = 198)., Results: Using logistic regression and controlling for population stratification, age, gender, SAS score at baseline, and concomitant use of anticholinergic drugs, we identified several single-nucleotide polymorphisms associated with AIP severity. Although none reached the GWAS significance level of P < 4.2 x 10(-7), some promising candidate genes for further research on genetic predisposition to AIP were identified including EPF1, NOVA1, and FIGN., Conclusions: Our finding may contribute to understanding of the pathophysiology of AIP as well as to a priori identification of patients vulnerable for development of AIP.

Rationale: Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychotic drugs., Objectives: To examine the association of a functional polymorphism in the 5-HT2C receptor gene (HT2CR) with TD and the joint contribution of HT2CR and DRD3 to susceptibility., Methods: Case control association analysis of allele and genotype frequencies among schizophrenia patients with (n=55) and without TD (n=60), matched for antipsychotic drug exposure and other relevant variables, and normal control subjects (n=97). Parametric analyses of the contribution of 5-HT2Cser and DRD3gly alleles to dyskinesia scores., Results: We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02). Analysis of covariance (ANCOVA), controlling for age at first antipsychotic treatment, revealed a significant effect of 5-HT2C genotype on orofacial dyskinesia (OFD) scores (F=3.47, df 2, P=.03). In a stepwise multiple regression analysis, 5-HT2C and DRD3 genotype (5-HT2Cser and DRD3gly allele carriage) respectively contributed 4.2% and 4.7% to the variance in OFD scores., Conclusions: These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.

Objective: The present study investigated whether administration of a 5-HT1A receptor agonist would increase growth hormone (GH) and oxytocin levels in normal human subjects, and whether the responses would be modified according to the age and gender of the subjects., Methods: Ipsapirone (0.3 mg/kg body weight), or placebo was administered to 30 normal subjects (14 males, 19-74 years and 16 females, 22-69 years) using a randomized, double blind design., Results: Stimulation of GH secretion by ipsapirone was significantly greater in male compared to female subjects, with no apparent effect of age. Oxytocin secretion was not stimulated by ipsapirone compared to placebo in any of the groups., Conclusions: The effects of gender and age on the degree of stimulation of GH secretion by 5-HT1A agonists in human subjects differ from their effects on secretion of the hormones ACTH and cortisol. A higher dose of ipsapirone is required to stimulate oxytocin secretion in normal human subjects.

Rationale: Of the specific serotonin reuptake inhibitors (SSRIs), fluoxetine is perhaps the most widely used. Anecdotal reports, mostly in the non-medical press, have suggested that it may positively affect psychological functioning and enhance quality of life in the absence of overt psychiatric disorder. Such wide-spread use in not supported by scientific data., Objective: This prospective single blind study examined the effects of long term administration of clinical doses of fluoxetine on cerebral blood flow (CBF) in healthy volunteers., Methods: Fifteen healthy subjects were examined by Tc99m HMPAO SPECT after 2 weeks of placebo administration and then after 6 weeks of fluoxetine, administered at 20 mg per day. Blood for fluoxetine and norfluoxetine plasma levels was drawn to ensure compliance. Tc99m HMPAO uptake was analyzed by the region of interest approach, normalized to the cerebellum, and by statistical parametric mapping (SPM)., Results: No statistically significant differences between the two conditions were detected by both techniques. Correlation analysis between fluoxetine and norfluoxetine plasma levels and rCBF yielded no statistically significant values., Conclusion: Our findings suggest a differential effect of fluoxetine on CBF under the following conditions: (i) mental health versus psychiatric illness; (ii) acute versus long term administration. Our findings further emphasize the importance of longitudinal studies in elucidating the physiology of the normal brain as well as the pathophysiology of psychiatric disorders.

The effects of a challenge dose of the 5-HT1A agonist, ipsapirone (0.3 mg per kg body weight), or placebo on body temperature and on adrenocorticotrophic hormone (ACTH) and cortisol release, were examined in 30 normal subjects (14 males, 19-74 years and 16 females, 22-69 years) using a randomized, double blind design. Irrespective of age or gender, ipsapirone induced a significant reduction in body temperature relative to placebo and a significant increase in ACTH and cortisol release. Maximal temperature reduction by ipsapirone was significantly blunted in older subjects and was inversely related to age. There was no gender difference in the hypothermic response to ipsapirone. ACTH and cortisol responses showed an opposite impact of aging in males and females. Whereas both responses diminished with age in male subjects, they increased with age in females. The cortisol response of older females was significantly larger than that of all the other subjects. Adverse effects of ipsapirone were also more marked in elderly females and were correlated with ACTH and cortisol responses. These findings should be taken into consideration in the use of ipsapirone and other 5-HT1A agonists as challenge procedures for studying central serotonergic function in depression and other disorders. Careful matching of control and experimental subjects is indicated so as to avoid spurious results which reflect the effects of age and gender rather than the pathophysiology of the disorders being investigated.

Onset and time course of antidepressant effect were examined in 47 patients with major depressive disorder who had been randomly assigned to twice weekly bilateral, brief pulse electroconvulsive therapy plus one simulated treatment per week (ECTx2) or to a three times weekly schedule of administration (ECTx3). Rapid improvement was observed in the ECTx3 group in whom the number of real ECTs to 30% reduction on the Hamilton Depression Scale (HAM-D) was 3.2 +/- 1.90, administered over 7.3 +/- 4.43 days and to 60% reduction, 5.9 +/- 3.09 real ECTs over 13.7 +/- 7.21 days. Among the responders in both groups combined, 24.3 +/- 29.58% of the overall improvement in HAM-D was contributed by the first real ECT, 60.9 +/- 28.13% by the first four real ECTs and 91.6 +/- 25.82% by the first eight. Although 85.3% of the responders had reached 60% HAM-D improvement after eight ECTs, a clinically significant minority (14.7%) responded later in the course (ECT 9-12). However, response was predictable on the basis of symptomatic improvement (30% on the HAM-D) by the sixth real ECT. Thirty-three out of 34 responders would have been correctly identified by this criterion and only 2 out of 13 non-responders mis-identified (P < 0.000001). Once achieved, the antidepressant effect was stable, without continuation pharmacotherapy, until 1 week after the last treatment and on lithium carbonate (Li) or Li plus clomipramine for a further 3 weeks. These findings confirm the clinical impression that ECT is a rapidly effective treatment for major depression with a shorter latency than generally reported for antidepressant drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet adenylate cyclase activity was measured in 16 control subjects and 16 patients who developed post-traumatic stress disorder (PTSD) as a result of damage inflicted on their homes during the Iraqi Scud missile attacks on Israel which occurred during the 1991 Gulf War. There were no differences in basal, NaF-stimulated, PGE1-stimulated or forskolin-stimulated activity between controls and PTSD subjects. Epinephrine inhibition of forskolin-stimulated activity, an effect mediated by alpha 2 adrenergic receptors, was slightly but not significantly increased in the PTSD patients compared to the controls, while 5-HT induced inhibition, an effect mediated by putative 5-HT1a-like receptors, was unchanged. The relationship of these activities to measures of anxiety and depression in these patients is discussed.

Adenylate cyclase activity was measured in platelet membranes from 10 healthy controls, 12 depressed patients, and the same patients after treatment with clomipramine (CMI) followed by lithium carbonate (Li) supplementation, in an attempt to determine whether any evidence for an effect on the serotonergic system could be obtained in peripheral cells. There were no differences in basal, NaF-, PGE1-, or forskolin-stimulated activity either between the control subjects and depressed patients or between activities in the patients measured before treatment, after CMI, and after CMI+Li. The degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT, an effect putatively mediated by a 5-HT1A-like receptor, was not different in the depressed patients compared to controls or affected by CMI treatment, but was significantly reduced after Li supplementation.

Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct beta-adrenergic receptor agonist have only recently been tested in the treatement of depression. Moreover, newer theories of antidepressant action suggest that a reduction in beta-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. Eleven depressed patients were treated with salbutamol, a beta-2-adrenergic agonist, and beta-2-adrenergic receptor sensitivity was evaluated before, during, and after treatment. beta-Adrenergic receptor sensitivity was evaluated by measuring the plasma cyclic AMP increase after an IV dose of salbutamol. The beta-adrenergic agonist exhibited antidepressant efficacy and induced subsensitivity of the beta-adrenergic adenylate cyclase with a time course paralleling the antidepressant effects. The results support the concept that receptor sensitivity changes occur during antidepressant therapy.

Electroconvulsive shock (ECS) reduces the number of rat cortical beta-adrenergic receptors. Lithium has been reported in several systems to prevent receptor changes induced by other agents. However, the present experiment reports that chronic lithium does not prevent the reduction in dihydroalprenolol binding induced by ten daily ECS treatments.

Previous studies have indicated that the endogenous peptide, melanotropin release inhibiting factor (MIF) and its analog cyclo(Leu-Gly) ( CLG ) facilitate dopamine (DA) receptor agonist binding and inhibit DA receptor supersensitivity induced by neuroleptics and opiates. The effect of CLG was tested on beta-adrenergic hypersensitivity induced by reserpine to ascertain whether CLG has effects on other neuronal systems besides DA. Administration of reserpine to rats induced hypomotility and enhanced binding of [3H]dihydroalprenolol (DHA) to cortical membranes. Concurrent administration of CLG blocked both the hypomotility and the enhanced [3H]DHA binding to cortical membranes. Lithium has also been shown to prevent reserpine induced hypomotility and increased cortical [3H]DHA binding. These studies suggest that CLG may be producing its effect either like lithium or by an amphetamine like action. If CLG can be shown to have lithium like activity, it could prove to be useful in the treatment of mania.

Chronic treatment with dopamine (DA) agonists has been reported in various paradigms to cause supersensitivity of DA receptors or, contradictorily, subsensitivity of DA receptors. The present study administered 15 mg/kg bromocriptine for 7 days and measured both striatal spiperone binding and apomorphine (AP)-induced stereotypy. A significant decrease in AP-induced stereotypies was observed after chronic bromocriptine treatment, but without a significant parallel decrease in striatal spiperone binding. These results probably do not represent a true agonist-induced subsensitivity, but possibly show that residual bromocriptine in vivo may antagonize AP-induced stereotypy. Since some reports have suggested that L-Dopa may specifically reverse the increases in DA receptor number induced by chronic haloperidol, we also studied the effect of 7 days of L-Dopa treatment after 6-week chronic haloperidol treatment of mice. While chronic haloperidol significantly increased striatal spiperone binding, subsequent L-Dopa treatment did not reverse this biochemical supersensitivity. It is concluded that agonist induction of subsensitivity in the DA system is difficult to reproduce and may depend on highly specific dosage conditions and treatment schedules.