Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics

Several lines of evidence suggest that central brain-derived neurotrophic factor (BDNF) modulates food intake, metabolism, and increases in body weight. Reports have also shown that serum BDNF is altered in schizophrenic patients treated with antipsychotics. This study aimed to determine if there was a relationship between BDNF and antipsychotic-induced weight gain in patients with chronic schizophrenia. Serum BDNF was measured in 124 schizophrenia patients chronically treated with clozapine (n = 57), risperidone (n = 23) or typical antipsychotics (n = 44) and 50 healthy control subjects. To further assess group differences in serum BDNF, additional analyses were performed in a subset of patients and controls individually matched for body mass index (BMI). BDNF levels were lower in patients with schizophrenia than normal controls. However, this difference was not present when controlling for current BMI. In the individually BMI-matched sample, no differences in serum BDNF levels were observed in schizophrenic patients compared to BMI-matched healthy controls. BDNF levels negatively correlated with BMI gain in female but not in male patients when gender was considered. Antipsychotic class exerted differential effects over BDNF levels and BMI gain. Our findings suggest that decreased BDNF levels may be associated with weight gain in female schizophrenic patients on long-term antipsychotic treatment.     

Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain

Schizophrenic patients commonly suffer weight gain, which is often associated with widely prescribed antipsychotic medicines. It is distressing to most patients who experience it and may affect their response to treatment of schizophrenia. Weight gain is also associated with treatment noncompliance and several medical conditions. This study explored the efficacy and tolerability of topiramate as an adjuvant treatment of patients with schizophrenia who were carrying excess weight. In this 12-week, randomized, placebo-controlled prospective study, 66 hospitalized patients with schizophrenia who were carrying excess weight were given topiramate at doses of 100 mg/day or 200 mg/day, or a placebo. The primary measures made were body weight, body mass index, waist measurement, hip measurement, and waist-to-hip ratio. Safety measures included physical examinations and the monitoring of adverse effects, clinical laboratory data, and vital signs. The Clinical Global Impression-Severity of Illness scale (CGI-S) and the Brief Psychiatric Rating Scale (BPRS) were used to quantify changes in schizophrenic symptoms and signs. In the 200-mg/day topiramate group, body weight, body mass index, waist measurement, and hip measurement decreased significantly compared with the 100-mg/day topiramate and placebo groups over 12 weeks. However, the waist-to-hip ratio did not change in any group. Scores on the CGI-S and BPRS decreased significantly over the 12-week period in both topiramate groups, but the decrease was not clinically meaningful. These results suggest that a higher dose of topiramate is efficacious as an adjuvant treatment of patients with schizophrenia experiencing excess weight gain. Further clinical research is required to establish guidelines for the use of topiramate as an antiobesity agent in schizophrenic patients.     

Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics

Neurotrophic factors regulate neuronal development and synaptic plasticity, possibly playing a role in the pathophysiology of schizophrenia and other psychiatric disorders. Decreased brain-derived neurotrophic factor (BDNF) levels have been found in brains and in the serum of schizophrenic patients, but results are inconsistent. Also, clozapine may upregulate brain BDNF expression. In the present study, we assessed serum BDNF immunoreactivity in 44 schizophrenic patients (20 on clozapine and 24 on typical antipsychotics) and in 25 healthy volunteers. Serum BDNF levels were measured using an enzyme immunoassay. Healthy controls showed significantly higher levels of BDNF compared to the whole group of schizophrenic patients (p<0.001) as well as to the subgroups on typical antipsychotics and clozapine (p<0.001). Serum BDNF values for controls were 168.8+/-26.3pg/ml, for the clozapine group were 125.4+/-44.5pg/ml and for the group on typicals were 101.3+/-51.6pg/ml. BDNF values from patients on clozapine were non-significantly higher than values from patients on typical antipsychotics (p=0.09). Serum BDNF was strongly and positively correlated with clozapine dose (r=0.643; p=0.002) but not with other demographic characteristics. These results reinforce previous findings of reduced serum BDNF levels in schizophrenic patients and suggest a differential effect of clozapine compared to typical antipsychotics on such levels.     

Abnormal diurnal weight gain among long-term patients with schizophrenic disorders

We found diurnal weight gain to be abnormal among 65 long-term patients with schizophrenic disorders. Patients were weighed at 7 a.m. and 4 p.m. serially and diurnal weight gain was normalized (NDWG) as a percentage by subtracting the 7 a.m. weight from the 4 p.m. weight, multiplying the difference by 100, and then dividing the result by the 7 a.m. weight. NDWG was 2.2 +/- 1.5% for 47 male patients compared (P = 0.001) with 0.6 +/- 0.4% for 11 male controls. NDWG was 1.7 +/- 0.7% for 18 female patients compared (P less than 0.0001) with 0.5 +/- 0.3% for 14 female controls. We hypothesize that NDWG may be an index of both the severity and duration of the schizophrenic disorder.     

Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Decreased BDNF levels have been found in the serum of schizophrenic patients with mixed results. In the present study, we assessed serum BDNF levels in a large group of 364 schizophrenic patients (157 on clozapine, 89 on risperidone and 118 on typical antipsychotics), compared to 323 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were significantly lower in chronic patients with schizophrenia than in healthy control subjects (9.9 ± 2.0 ng/ml vs.11.9 ± 2.3 ng/ml, p < 0.0001). Lower BDNF levels were observed in patients treated with risperidone (9.3 ± 2.3 ng/ml) compared to those with clozapine (10.2 ± 2.0 ng/ml, p < 0.001) and typical antipsychotics (10.0 ± 2.1 ng/ml, p < 0.01). Furthermore, a stepwise multiple regression analysis identified types of antipsychotic drugs (beta = − 0.37, t = − 3.15, p = 0.001) and BDNF levels (beta = − 0.26, t = − 2.51, p = 0.014) as the influencing factor for the positive symptom subscore of PANSS. In addition, there was a sex difference in BDNF levels in patients with schizophrenia (9.7 ± 1.9 ng/ml for males vs.10.4 ± 2.1 ng/ml for female, p < 0.005), but not in normal controls. Our findings indicated decreased BDNF serum levels in chronic patients with schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment and the severity of psychotic symptoms.     

Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics

BACKGROUND: Weight gain is a common adverse effect associated with the use of most antipsychotic drugs. Leptin has been reported to be associated with antipsychotic-induced weight gain. Previous studies have demonstrated a relationship between the atypical antipsychotics clozapine and olanzapine and serum leptin levels. We planned to comparatively investigate the effects of the atypical antipsychotics quetiapine, olanzapine, risperidone, and clozapine on leptin and triglyceride levels and weight gain. METHOD: The study population comprised 56 patients with DSM-IV schizophrenia, who were divided into 4 treatment groups: quetiapine (N = 14), olanzapine (N = 14), risperidone (N = 14), or clozapine (N = 14) monotherapy, and a control group of 11 patients receiving no psychopharmacologic treatment. The patients were evaluated at baseline and at the sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, and fasting serum leptin and triglyceride levels. Data were gathered in 2001 and 2002. RESULTS: Olanzapine and clozapine caused a marked increase in weight and serum triglyceride and leptin levels, though increases in these variables were modest in the patients receiving quetiapine and minimal in those receiving risperidone. There were positive correlations between serum leptin levels and BMI and triglyceride levels. Clinical efficacy, as indicated by decrease in total PANSS scores, was associated with leptin levels in all atypical antipsychotic groups. CONCLUSION: Our results suggest that leptin may be associated with olanzapine- and clozapine-induced weight gain and that quetiapine appears to have modest influence and risperidone appears to have minimal influence on leptin and triglyceride levels and weight gain compared with olanzapine and clozapine.     

Serum leptin and gonadotropin levels in patients with anorexia nervosa during weight gain

Leptin plays an important role in reproductive function. In patients with acute anorexia nervosa, serum leptin levels have repeatedly been shown to be lower than in age-matched controls. We have previously hypothesized that the amenorrhea characteristic of anorexia nervosa is related to this low leptin secretion. In an attempt to address this hypothesis, serum levels of leptin and follicle stimulating hormone (FSH) and luteinizing hormone (LH) of 16 female inpatients with anorexia nervosa or an eating disorder not otherwise specified (atypical anorexia nervosa) were measured on a biweekly basis during weight gain. We hypothesized that a serum leptin level of 1.85 microg L(-1) would be associated with gonadotropin levels at or above the minimal level observed during the menstrual cycle in healthy adult fertile females. Our results revealed that increments of LH levels generally tracked increments of leptin levels during the first weeks of treatment. Similarly, in those patients with low referral leptin levels, FSH initially also tracked leptin levels. In contrast, a relationship between gonadotropin levels and leptin secretion was no longer discernible after LH and FSH levels had peaked. Those patients with exceedingly low leptin levels upon admission revealed a slow increase of gonadotropin levels. Our hypothesis of a threshold leptin level of 1.85 microg L(-1) was supported for LH only.     

Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus

The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover.     

Managing weight gain and metabolic issues in patients treated with atypical antipsychotics

The proven efficacy of second-generation antipsychotics (SGA) has led many clinicians to switch patients from a conventional antipsychotic to an SGA. However, SGAs may be associated with weight gain, dyslipidemia, high blood pressure, and ultimately with cardiovascular disease, diabetes, and metabolic syndrome. Clinicians should be aware of patients' individual risk factors for developing these illnesses and should carefully screen for changes in weight, body mass index, waist size, or lipid levels that could be potentially harmful and increase the risk for a more serious illness.     

Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse,who were treated with typical or atypical antipsychotics

Brain-derived neurotrophic factor signals and dopaminergic function in the brain are strongly associated, and research on BDNF in schizophrenia may enhance our insights on the pathophysiological mechanisms of this disease. In the present study we aimed to investigate the possible association between serum BDNF levels and schizophrenic relapses and the possible differential effects of treatment with typical and atypical antipsychotics on serum BDNF levels in the same group of patients. We measured serum BDNF levels in 47 patients with schizophrenia during a relapse and again 6 weeks after administration of antipsychotic treatment (14 on risperidone, 18 on haloperidol, 10 on olanzapine and five on amisulpride) and in 44 healthy volunteers. Patients with schizophrenia showed reduced serum BDNF levels in relation to healthy volunteers at study entry. No significant differences were revealed in BDNF serum levels after 6 weeks of antipsychotic treatment in the patients compared to their own levels at study entry. However, serum BDNF was significantly increased in the subgroup receiving olanzapine compared to the other antipsychotics. Our findings may indicate a differential effect of olanzapine on BDNF levels compared to haloperidol, risperidone, and amisulpride.     

Therapeutic options for weight management in schizophrenic patients treated with atypical antipsychotics

Extensive, selective literature review of 2500 articles from the last years (up to December 2007) predominantly from Medline and Cochrane, using as search terms "antipsychotic or schizophrenia or individual drug names (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone)" and the terms "BMI, weight gain, metabolic syndrome, diabetes, lipid(s), cholesterol, triglycerides" was conducted. Regardless of the advantages ascribed to atypical antipsychotics and the special effectiveness of clozapine in patients resistant to therapy and at risk for suicide, the probability of weight gain is considerably increased for some of these substances. Patients with schizophrenia have a considerably reduced life expectancy associated with an increased prevalence of cardiovascular risk factors. There is a lack of practical guidelines integrated into clinical psychiatric care for the management of cardiovascular risk factors. The monitoring of patients treated with atypics, which has been recommended in the APA/ADA Consensus Paper in light of these facts, is insufficiently established in clinical practice. A regular monitoring can convey self control and motivation to the patient. In the case of corresponding risk constellations further decisions regarding indication and therapy have to be considered. Especially patients with a high cardiovascular risk profile are highly recommended to participate in a weight-management program for prevention purposes. Such a special program should include elements of dietetic treatment and behaviour and exercise therapy. First controlled studies suggest an effective prevention of weight gain and metabolic changes when applying such a structured program. The practice oriented step by step concept presented here is meant to provide points of reference for the implementation of required medical and psychoeducative measures facilitating the management of weight and further cardiovascular risk factors in the context of psychiatric care in patients with schizophrenia.     

Management of atypical antipsychotic-induced weight gain in schizophrenic patients with topiramate

Patients treated with atypical antipsychotic drugs commonly gain excess weight. Because obesity is associated with considerable morbidity and decreased life expectancy, treatment of weight gain in these patients is critical. Topiramate, a fairly new anticonvulsant, promotes bodyweight loss in healthy obese subjects, patients with bipolar disorder, and patients with eating disorder. However, there are very few reports about the efficacy of topiramate for weight management in schizophrenic patients. We present the cases of three Taiwanese patients with schizophrenia whose bodyweight increased as a result of atypical antipsychotics treatment, then was controlled by topiramate without aggravation of their psychotic symptoms.     

SNAP-25 gene polymorphisms and weight gain in schizophrenic patients

Drug induced weight gain is a serious side effect of several atypical antipsychotics. As genetic factors play an important role in the homeostasis of hunger/satiety we tried to replicate a preliminary previous finding about an impact of three polymorphisms in the synaptosomal-associated protein of 25kDa (SNAP-25; sites MnlI, TaiI and DdelI in the 3(')-UTR) on clinical response and antipsychotic induced weight gain. We genotyped 162 schizophrenic patients being treated in monotherapy with atypical antipsychotics and 312 healthy control subjects for the three polymorphisms in the SNAP-25 gene using PCR. PANSS scores and weight were measured weekly for a minimum of five weeks. We found significant associations between the TaiI and MnlI polymorphisms and serum triglyceride levels at baseline and for the DdelI polymorphism and weight gain. In conclusion our study can at least partly replicate the previous findings concerning the impact of SNAP-25 gene polymorphisms on weight gain during antipsychotic treatment.     

抗精神病药对精神分裂症患者体重的影响

目的 为了探讨抗精神病药对精神分裂症患者体重的影响。方法 295例服用抗精神病药的精神分裂症患者进行了临床调查。结果 67．12％患者出现体重增加；体重增加从多到少的药物依次是氯氮平、奥氮平、氯氮平合并利培酮、氯丙嗪、利培酮、氯氮平合并舒必利；氯氮平、氯丙嗪、利培酮体重增加较人组前有显著差异；女性患者、初次服抗精神病药者、合并心境稳定剂者体重增加亦明显。结论 大部分抗精神病药可导致体重增加，应在治疗前及治疗中定期进行体重监测。     

Acute weight gain, gender, and therapeutic response to antipsychotics in the treatment of patients with schizophrenia

Background

This study was designed to evaluate the psychiatrists' level of recognition of somatic symptoms associated to a major depressive episode (MDE) (DSM-IV-TR criteria) and the impact of those somatic symptoms on the treatment effectiveness.

Methods

This non-interventional study was conducted in 25 medical offices in Puerto Rico from February to December 2003. It had 2 visits separated by 8 weeks. The level of recognition was determined by: the correlation between the physician clinical evaluation and their patients' self-evaluations through different validated instruments using kappa statistics. Chi-square test was used to evaluate the impact of somatic symptoms on treatment antidepressants' effectiveness.

Results

All the 145 recruited patients reported the presence of at least one somatic symptom associated with their current MDE. In the two visits covered by the study, a fair agreement between the psychiatrists' and the patients' reports was noted for headache, abdominal pain and upper limb pains (0.4003 ≤ κ ≥ 0.6594). For other painful symptoms and painless somatic symptoms, the Kappa values obtained were non-significant. Slight but significant reductions in depression and painful symptoms severity were observed after 8 weeks of treatment. A proportional relationship between the pain and depression severity was observed (p < 0.0001).

Conclusion

The study results show that somatic symptoms: are very common in depressed Puerto Rican patients; are significant under-reported by psychiatrists; and have a significant impact on the antidepressant effectiveness.     

第二代抗精神分裂症药物对体重与代谢的影响

目的评价首发精神分裂症单一使用第二代抗精神病药物治疗对体重和代谢的影响。方法采用历史性队列研究方法评估62例首发精神分裂症单一使用抗精神病药物治疗2,4周末体重和代谢改变,并且对这些患者2年后的体重和代谢情况进行随访。结果62例患者随着治疗延长,体重迅速明显增加,平均体重从基线时的（55．5±15．6）kg,第2周末增加至（56．2±15．1）kg,第4周末进一步增加至（57．3±15．0）kg。第二代抗精神病药物对体重均有影响,其中奥氮平（增加5．24％）最为突出,利培酮（增加2．6％）、喹硫平（增加2．1％）次之。治疗第4周末,部分患者的糖脂代谢出现异常。在治疗2年后共随访到47例患者,其中27例继续治疗,20例因各种原因中断治疗,其中6例患者因为体重增加而停药。持续治疗的患者中,体重全部增加,半数体重增加10％～30％,1例患者体重增加50％。结论第二代抗精神病药物在首发精神分裂症急性期治疗会影响体重和糖脂代谢,进而影响患者的躯体健康和服药依从性。     

Serum melatonin levels in schizophrenic and schizoaffective hospitalized patients

Conflicting results on changes of the diurnal melatonin rhythms of patients with affective disorders have been reported in the literature. The heterogeneous data may derive from the great discrepancy in the diagnostic criteria of different authors. A study of 12 schizoaffective and chronic schizophrenic psychotic patients found a constant pattern of an obliterated nocturnal melatonin rise only in the latter group. The presence or absence of the nocturnal melatonin rise was determined in drug-free hospitalized patients and remained unchanged despite 2 months of drug treatment including large doses of neuroleptics. This finding, when confirmed in a larger number of patients, could possibly serve as a marker for the type of mental disorder, drug to be applied and response expected.     

Switching antipsychotics as a treatment strategy for antipsychotic-induced weight gain and dyslipidemia

Patients taking antipsychotic medications for psychiatric disorders also have many risk factors for medical comorbidities and early death. While these risk factors were present before the arrival of the newer antipsychotic medications, the overall risk factor burden is exacerbated for those high-risk patients whose antipsychotic therapy causes or aggravates obesity or dyslipidemia. Therefore, there is an urgent need for effective interventions to address problems related to the additional iatrogenic burden from weight gain and dyslipidemias caused by antipsychotic medications. For patients with schizophrenia, complete discontinuation of antipsychotic therapy is not advisable and, therefore, pharmacologic options are narrowed to dose adjustments, adding adjunctive agents to induce weight loss, discontinuation of other adjunctive agents associated with weight gain, or changing the antipsychotic medication ("switching"). This article reviews the evidence showing that relative to other possible treatment options, switching to an antipsychotic with a lower propensity to induce weight gain or dyslipidemia can be effective for reversing the weight gain and dyslipidemia caused by previous antipsychotic treatment.     

Serum homocysteine and folate levels in korean schizophrenic patients

Objective

This study was conducted to confirm the results of the authors'' previous research on schizophrenia manifesting high serum homocysteine and low folate levels. This study is anchored on a theory that a high serum homocysteine concentration affects schizophrenia by virtue of a neurotoxic mechanism, and on a report that some schizophrenia patients with high homocysteine levels benefited from high folate ingestion.

Methods

The serum homocysteine, folate, and vitamin B₁₂ levels of 236 normal-control-group subjects and 234 schizophrenia subjects who met the diagnostic criteria based on DSM-IV-TR were compared. The homocysteine levels were measured via fluorescence polarization immunoassay, and the folate and vitamin B₁₂ levels were determined via radioimmunoassay.

Results

The homocysteine levels of the patient group were significantly higher than those of the normal control group. The homocysteine level was more negatively correlated with the folate level in the schizophrenia group than in the control group. The percentages of female and male schizophrenia subjects manifesting high homocysteine levels were 33.8 and 51.5%, respectively. The percentage of schizophrenia subjects with low folate levels was 66.2%. In the low- and normal-folate-level groups, the patient group showed significantly higher homocysteine levels than the normal control group. The low-folate-level patient group particularly showed significantly higher homocysteine levels than the low-folate-level normal control group.

Conclusion

Some schizophrenia patients with high serum homocysteine levels may have the genetic defect of having low folate serum levels. In such cases, folate ingestion may be a good management modality for clinical improvement.