Roni Shiloh

Evaluation of the neurotoxic activity of typical and atypical neuroleptics: relevance to iatrogenic extrapyramidal symptoms.

Typical neuroleptic therapy often results in extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Recent reports reveal neurotoxic activity in some neuroleptics. We hypothesized that neurotoxicity might be implicated in EPS. This study aims to evaluate the neurotoxic activity of typical and atypical neuroleptics and to determine the possible role of neurotoxicity in neuroleptic-induced EPS. Perphenazine, haloperidol, clozapine, sulpiride, and risperidone (10–100 μM) were administered, either alone or combined with dopamine, to primary mouse neuronal or intact brain culture and to a human neuroblastoma (NB) cell line (SK-N-SH). Cell viability (measured by neutral red and alamar blue), DNA fragmentation (flow cytometry–NB) were determined. Neuroblastoma: perphenazine, clozapine, and haloperidol (100 μM) decreased viability by 87, 43, and 34% respectively. Sulpiride and risperidone were not toxic. At 10 μM, toxicity decreased markedly. Dopamine (125 μM) potentiated the perphenazine-induced toxicity. Flow cytometry of NB cells treated with perphenazine (2.5–40 μM) showed an increase (perphenazine 20 μM, 40 μM, 48 h) in fragmented DNA (74.7% and 95.0% vs. 8.7% in controls). Lower concentrations increased the G1 phase and decreased S phase in the cell cycle. In primary neurons, perphenazine, haloperidol, and clozapine, but not risperidone and sulpiride, induced a significant neurotoxic effect, which, in intact brain culture, was absent (haloperidol and clozapine) or lowered (perphenazine). Dopamine (0.5 mM) did not modify the effect of the drugs in the primary cultures. Neuroleptics possess differential neurotoxic activity with higher sensitivity of neoplasm tissue (NB compared to primary cultures). The order of toxicity was perphenazine > haloperidol = clozapine; sulpiride and risperidone were not toxic. Neurotoxicity is independent of dopamine and is associated with cell cycle arrest and apoptosis. With the exception of clozapine, neurotoxicity seems relevant to neuroleptic-induced EPS and TD.

Abnormal thermoregulation in drug-free male schizophrenia patients

Schizophrenia patients may develop various thermoregulatory disturbances. We hypothesized that a standardized exercise-heat tolerance test [two 50-min bouts of walking a motor-driven treadmill at 40 degrees C (relative humidity=40%)] would reveal abnormal thermoregulation in drug-free schizophrenia patients. Six drug-free schizophrenia outpatients and seven healthy comparison subjects participated in this study. The schizophrenia patients exhibited significantly higher baseline and exertion-related rectal temperature. The relevance of these findings to the pathophysiology of schizophrenia-related thermoregulatory disorders is as yet unclear.

High serum creatinine kinase level: possible risk factor for neuroleptic malignant syndrome.

High creatinine kinase (CK) levels and leukocytosis are known to be associated with neuroleptic malignant syndrome (NMS). The authors sought to determine if their presence during non-NMS psychotic episodes is predictive of the later development of NMS. Sixteen psychotic inpatients who met the criteria for NMS were included. For statistical comparison, two control groups were formed by matching each study patient with two non-NMS patients for age, gender, ethnicity, and year and ward of hospitalization (n = 32). The maximal individual serum levels of CK, lactate dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), and white blood cell count (WBC) during all non-NMS psychotic episodes (Brief Psychiatric Rating Scale 40) were averaged. To normalize the distribution, the individual averages were transformed to natural logarithms (Ln). Mean Ln (average [CK]) in the patients with NMS was found to be 6.46 ± 0.91 IU/L, and in the non-NMS patients, 5.24 ± 0.90 IU/L (actual serum CK levels, 911 ± 747 IU/L and 343 ± 620 IU/L, respectively). This difference was statistically significant (F [2,15] = 10.5, p < 0.0001). In addition, CK levels above the upper limit of normal were noted in 76% of psychotic episodes in the patients with NMS and in only 30% of psychotic episodes in the non-NMS patients (p < 0.0001). There was no significant difference between the NMS and non-NMS groups in Ln(LDH), Ln(SGOT), or Ln(WBC) (F [2,15] = 1.4, 2.1, and 0.9, respectively). The authors concluded that high serum CK level during non-NMS psychotic episodes seems to be a risk factor for future NMS. Therefore, CK measurement may be justified on admission of acutely psychotic patients who have other risk factors and a history of psychosis-associated CKemia.

Mianserin or placebo as adjuncts to typical antipsychotics in resistant schizophrenia.

The beneficial effect of atypical antipsychotic drugs (APDs) in treatment-resistant schizophrenia patients has been attributed, mostly, to their relatively high serotonergic (5-HT)2 to dopaminergic (D)2 receptor blockade ratio. We hypothesized that a combination of typical APDs (D2 antagonists) and mianserin, a potent 5-HT2 antagonist, might also exert superior efficacy in this population. Eighteen inpatients with treatment-resistant schizophrenia who had an acute psychotic exacerbation of the disorder received, in a double-blind design, 30 mg/day mianserin (n =9) or placebo (n =9) in conjunction with typical neuroleptics [haloperidol (n =9) or perphenazine (n =9)]. Clinical status was evaluated before, during, and at the end of 6 weeks of combined treatment with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms and Hamilton Rating Scale for Depression. The typical APD/mianserin group exhibited significantly greater improvement in total BPRS scores (17.6% versus 5.5%;P =0.03) and a trend towards greater improvement in SAPS scores (35.3% versus 13.0%;P =0.07). Our study indicates that patients with chronic treatment-resistant schizophrenia who have an acute psychotic exacerbation (‘acute-on-chronic’) may benefit from the addition of a potent 5-HT2 blocker, such as mianserin, to typical antipsychotics. Our findings may further emphasize the contribution of enhanced 5-HT2 blockade to the ‘atypicality’ of the atypical APDs and to their greater efficacy in alleviating symptoms of chronic treatment-resistant schizophrenia.

Increased corneal temperature in drug-free male schizophrenia patients.

Schizophrenia patients may exhibit altered body temperature. We hypothesized that drug-free patients may have a higher corneal temperature than normal subjects. The corneal temperature of seven remitted drug-free schizophrenia outpatients and seven healthy volunteers was evaluated with a flir thermal imaging camera. A significantly higher corneal temperature was observed in the patient group (34.60+/-1.89 vs. 33.05+/-0.58 degrees C; P=0.005) and it correlated with their BPRS score (r=0.82; P=0.024). The relevance of these preliminary findings merit further investigation.

Sulpiride adjunction to clozapine in treatment-resistant schizophrenic patients: a preliminary case series study

Six chronic neuroleptic-resistant schizophrenic patients, partial responders to clozapine, were co-administered 600 mg/day of sulpiride (a selective D(2) dopaminergic antagonist) as an augmentation to clozapine (a relatively weak D(2) blocker), for 10 weeks, open-labeled. A remarkable reduction in positive and negative symptoms was observed in four of the six patients.

Altered thermoregulation in ambulatory schizophrenia patients: A naturalistic study

Background. Schizophrenia patients may exhibit alterations in core/body temperature. Hence, we intended to examine the potential existence of thermoregulatory abnormalities in ambulatory schizophrenia patients. Methods. Anonymous electronic patient record data of the Leumit Health Fund (Israel) were screened for all schizophrenia patients who have no other apparent chronic co-morbidity (mental or non-mental) and had their oral temperature assessed during routine follow-ups (Schiz-rFUs) or for various transitory infectious/inflammatory processes (Schiz-Infect) during the years 1999–2005 (n = 535). The comparison group consisted of a comparable sample (n = 560) of healthy subjects (Control-rFUs and Control-Infect). Results. The sub-group of Schiz-rFUs (n = 216) exhibited significantly lower mean oral temperature compared to the matched group of Control-rFUs (n = 140) (36.72±0.54 vs. 36.94±0.64°C, respectively; P<0.05). There was no significant difference in mean oral temperatures between the Schiz-Infect (n = 319) and the Control-Infect (n = 420) (37.32±0.92 vs. 37.28±0.98°C, respectively; NS). Conclusions. Ambulatory schizophrenia patients without a concomitant infectious/inflammatory process exhibit altered thermoregulation manifested by a substantial (about 0.2°C) and significantly lower oral temperature compared to healthy comparison subjects as well as a potential exaggerated increase in oral temperature during transitory infectious/inflammatory processes. The relevance of these phenomena to the pathophysiology of schizophrenia as well as the potential immune-mediated pathologies in schizophrenia merit further investigation.

Acute antipsychotic drug administration lowers body temperature in drug-free male schizophrenic patients

We examined, in a controlled design, potential alterations in body temperature of male schizophrenic patients following acute antipsychotic drug (APD) administration. Fourteen drug-free (study group) and seven schizophrenic patients maintained on APDs (comparison group) initiated or received higher dose of their APD, respectively, for 27 days. Initial body temperature was 0.36 degrees C higher in the study group (P=0.01) and decreased within 24 h to values comparable to that of the comparison group (all within normal range).

Zolmitriptan compared to propranolol in the treatment of acute neuroleptic-induced akathisia: A comparative double-blind study

Neuroleptic-induced akathisia (NIA) is a common, sometimes incapacitating adverse effect of anti-psychotic medication. Zolmitriptan is a selective 5-HT(1D) agonist. We aimed to determine its anti-NIA efficacy in comparison to propranolol. Thirty-three neuroleptic-treated patients were randomly allocated in a double-blind design to receive either 7.5 mg/d of zolmitriptan or 120 mg/d of propranolol for 3 consecutive days, followed by 3 days without any anti-NIA treatment. Patients were assessed at baseline and on days 3 and 7 by the Barnes Akathisia Rating Scale (BARS), PANSS, HAMD, HAMA, Pulse, and Blood Pressure. Both groups showed improvement of akathisia (BARS) along the treatment period, with significant effect for time but not for group. No significant differences were found between the groups in all other measurements. Taken together, zolmitriptan was found to be as effective as propranolol for the treatment of NIA. Further placebo-controlled studies are warranted.

Corneal temperature in schizophrenia patients

Most data imply that dopaminergic transmission is essential for proper hypothalamic-mediated core temperature regulation. Altered central dopaminergic transmission is suggested to be involved in the pathophysiology of schizophrenia. Thus, hypothetically, schizophrenia patients might be at increased risk of developing thermoregulatory dysregulation manifested by alterations in core temperature, as well as in peripheral tissue, the temperature of which has been shown to correlate with core temperature (e.g. cornea). Previous small pilot studies of ours showed that schizophrenia patients may exhibit corneal temperature abnormalities. Hence, we assessed corneal temperature in a controlled sample of drug-free ( n =11) and medicated ( n =28) schizophrenia patients compared to healthy comparison subjects ( n =9), using a FLIR thermal imaging camera. Drug-free schizophrenia patients exhibited significantly higher corneal temperature compared to healthy subjects, typical antipsychotic drug (APD)-treated patients ( n =16) and atypical APD-treated patients ( n =12) (37.08+/-1.46 degrees C vs. 33.37+/-2.51 degrees C, 31.08+/-1.43 degrees C and 31.67+/-0.44 degrees C respectively, p <0.0001; p <0.001 vs. each group separately). The healthy comparison subjects and the atypical APD-treated patients exhibited comparable corneal temperatures and these two groups exhibited higher corneal temperatures compared to the typical APD-treated patients ( p <0.01 and p =0.051 respectively). In conclusion, this study indicates that drug-free schizophrenia patients exhibit substantially higher corneal temperature compared to healthy comparison subjects or medicated patients, and that APDs may decrease corneal temperature either to normal (atypical APD) or to subnormal (typical APD) values. The relevance of these phenomena to the pathophysiology of schizophrenia, the biological mechanism underlying drug-induced corneal temperature alterations, the possible role of temperature-lowering drugs (neuroleptics or non-neuroleptics) on schizophrenic psychosis as well as the role of corneal temperature as a tool to evaluate adherence to APD treatment merit further investigation via larger samples of both medicated and drug-free schizophrenia patients compared to matched controlled subjects.