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The investigation of leptin and hypothalamic neuropeptides role in first attack psychotic male patients: olanzapine monotherapy.
Ak, M, Sezlev, D, Sutcigil, L, Akarsu, S, Ozgen, F, Yanik, T
Psychoneuroendocrinology. 2013;(3):341-7
Abstract
The mechanism underlying the weight gain due to treatment with olanzapine and other second generation antipsychotics has not been fully understood. To examine olanzapine's weight gain effects, we accepted first attack psychotic patients with no medication (pre-treatment) (n=22) and the healthy control group (n=26) in this study. After patientś diagnosis, they were hospitalized and then treated for four weeks with olanzapine (post-treatment). We used case-control association design to test body mass index (BMI) and biochemical changes in each group. We also investigated peripheral leptin and neuropeptides/hormones namely, pro-opiomelanocortin (POMC), cocaine and amphetaime regulated transcript (CART), and neuropeptide Y (NPY) levels. These neuropeptides which are synthesized/secreted from arcuate nucleus of hypothalamus affect food intake and therefore, body weight. After 4 weeks of olanzapine treatment; BMI (body mass index), waist circumference, blood triglyceride, total cholesterol, and very low density lipoprotein (VLDL) levels were increased significantly in patients compared to their pre-treatment baseline. In pre-treatment, patients' NPY levels were significantly lower while α-MSH, the anorexigenic product of POMC levels were significantly higher vs. control. Both leptin and NPY levels were significantly increased in patients after the treatment but the NPY levels were also significantly lower in post-treatment vs. the control group. The CART levels did not change after the treatment. We may presume that the antagonist effect of olanzapine on the serotonin (5HT2CR and 5HT1BR) receptors of the arcuate hypothalamic neurons may be a basis for a deregulation of the neurohormones secretion.
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Proton magnetic resonance spectroscopy study of brain metabolite changes after antipsychotic treatment.
Szulc, A, Galinska, B, Tarasow, E, Waszkiewicz, N, Konarzewska, B, Poplawska, R, Bibulowicz, D, Simonienko, K, Walecki, J
Pharmacopsychiatry. 2011;(4):148-57
Abstract
INTRODUCTION Proton magnetic resonance spectroscopy (¹H MRS) enables the observation of brain function in vivo. The aim of our study was to evaluate the effects of antipsychotic medication on metabolite levels in the brain of schizophrenic patients based on a ¹H MRS examination. METHODS We examined 42 patients previously diagnosed with chronic schizophrenia twice: firstly, after the neuroleptic wash-out (baseline) and secondly, under stable medication (follow-up, after treatment). The study had a naturalistic design and several different neuroleptic medications were used during the treatment phase. The clinical evaluation, MRI and MRS procedures were performed. The group of 26 healthy controls were also examined to compare MRS results. RESULTS We found a significantly lower NAA/Cr (N-acetylaspartate/creatine) ratio in the frontal lobe and thalamus in patients (after the wash-out) as compared to controls. After treatment a significant decrease of the Glx/Cr ratio in the temporal lobe and a trend for an increase of the NAA/Cr ratio in the thalamus were observed. CONCLUSION Our results confirm that antipsychotic medication modifies brain metabolism measured by means of ¹H MRS. The pattern of the changes suggests a neuroprotective action of antipsychotic medication in schizophrenia.
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Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications.
Weickert, TW, Goldberg, TE, Mishara, A, Apud, JA, Kolachana, BS, Egan, MF, Weinberger, DR
Biological psychiatry. 2004;(9):677-82
Abstract
BACKGROUND The gene encoding catechol-O-methyltransferase (COMT), an enzyme that regulates prefrontal cortex dopamine, contains a common functional polymorphism (val(108/158)met) that influences prefrontal cortex function in an allelic dose-dependent manner. A recent study reported that the COMT val(108/158)met polymorphism influences cognitive- and physiologic-related prefrontal cortex responses to antipsychotic treatment. The present study tested the effects of several COMT polymorphisms on the cognitive response to antipsychotic medication in patients with schizophrenia. METHODS Twenty inpatients with schizophrenia or schizoaffective disorder (5 with the val-val genotype, 11 with val-met, and 4 with met-met) were administered cognitive tests at two time points: once after 4 weeks of treatment with antipsychotic medication and once after 4 weeks of placebo administration, according to a counterbalanced, double-blind, within-subject study design. RESULTS Patients homozygous for the COMT met allele displayed significant improvement on the working memory task after treatment. Patients homozygous for the COMT val allele did not show working memory improvement with treatment. Other COMT polymorphisms were not associated with significant differences between treatment and placebo conditions. CONCLUSIONS These results support other data suggesting that the COMT val(108/158)met polymorphism might be an important factor in the cognitive response to antipsychotic medication.
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Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia.
Tsai, G, Lane, HY, Yang, P, Chong, MY, Lange, N
Biological psychiatry. 2004;(5):452-6
Abstract
BACKGROUND Hypofunction of N-methyl-D-aspartate glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine or glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate receptor, or D-cycloserine, a partial agonist, improve the symptoms of schizophrenia. N-methylglycine (sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on N-methyl-D-aspartate glycine site and can have beneficial effects on schizophrenia. METHODS Thirty-eight schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/d), which was added to their stable antipsychotic regimens. Twenty of them received risperidone. Measures of clinical efficacy and side effects were determined every other week. RESULTS Patient who received sarcosine treatment revealed significant improvements in their positive, negative, cognitive, and general psychiatric symptoms. Similar therapeutic effects were observed when only risperidone-treated patients were analyzed. Sarcosine was well-tolerated, and no significant side effect was noted. CONCLUSIONS Sarcosine treatment can benefit schizophrenic patients treated by antipsychotics including risperidone. The significant improvement with the sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Glycine transporter-1 is a novel target for the pharmacotherapy to enhance N-methyl-D-aspartate function.
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Effects of ketanserin and haloperidol on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man.
Graham, SJ, Langley, RW, Balboa, VA, Bradshaw, CM, Szabadi, E
Journal of psychopharmacology (Oxford, England). 2002;(1):15-22
Abstract
Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effects of the serotonin (5-HT)2 receptor antagonist ketanserin and the D2 dopamine receptor blocking antipsychotic drug haloperidol on these responses. Fifteen males (aged 18-35 years) participated in four sessions at 7-day intervals, in which they received ketanserin 20 mg, ketanserin 40 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 3 h after ingestion of haloperidol or 1 h after ingestion of ketanserin. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials), and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Ketanserin 40 mg significantly reduced the amplitude of the EMG response and both doses of ketanserin significantly suppressed prepulse inhibition of the response; haloperidol had no effect on EMG response amplitude or prepulse inhibition. Neither drug affected N1/P2 amplitude or prepulse inhibition of this response. Ketanserin, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not ketanserin, elevated serum prolactin level. These results confirm that prepulse inhibition of the startle response and of the N1/P2 complex have different pharmacological sensitivities. The ability of ketanserin to attenuate the startle response may reflect its sedative action, as other drugs with sedative properties have also been found to attenuate the startle response in man. The ability of ketanserin to suppress prepulse inhibition of the startle response is consistent with previous evidence for the involvement of 5-HTergic mechanisms in the regulation of prepulse inhibition in man.