Шизофрения и курение

The self-medication hypothesis of smoking in schizophrenia

There is a discrepancy in the literature, with numerous animal studies suggesting that nicotine should help negative symptoms but scarce clinical data suggesting that this may be true in those with schizophrenia (Hughes, 2000). Two main sub-hypotheses are usually included in the self-medication hypothesis: smoking reduces the side-effects of antipsychotics; and nicotine may improve schizophrenic symptoms, particularly the negative, cognitive and/or depressive symptoms (Taiminen et al, 1998).

Two mechanisms have been implicated in the reduction of antipsychotic side-effects: a release of dopamine resulting from the administration of nicotine, a notion supported by both acute administration of nicotine in animal models (Drew et al, 2000) and in vivo human studies (Salokangas et al, 2000); and a decrease in antipsychotic blood levels through enzymatic induction. Individuals with schizophrenia who smoke tend to receive consistently higher doses of antipsychotics than non-smokers (Ziedonis et al, 1994; de Leon et al,1995, 2002a). The inductive effect of smoking in antipsychotic metabolism therefore is inadvertently corrected by psychiatrists, because smokers tend to be treated with higher daily doses of antipsychotics than non-smokers. When compared with others with severe mental illness in three epidemiological studies in psychiatric hospitals, the effect of antipsychotic medication did not explain the association between schizophrenia and smoking (de Leon et al,1995, 2002a; Llerena et al, 2003). Some cross-sectional studies have suggested that smoking reduces antipsychotic side-effects and others have not (Dalack et al, 1998); yet all of these studies are hampered by the lack of control for confounding factors. Longitudinal studies with small samples suggest that, when compared with atypical antipsychotics, typical antipsychotics are associated with increased smoking in some individuals (McEvoy et al, 1995) and with a greater difficulty for quitting smoking (Georgeet al, 2000). Anticholinergic medication was not associated significantly with smoking in this or in previous studies (de Leon et al, 1995, 2002a, b).

In spite of the hypothesis from animal studies (Drew et al, 2000), very limited clinical data support an association between smoking and a reduction in negative symptoms (Dalack et al, 1998). Data indicating that nicotine may improve sensory gating abnormalities and smooth pursuit eye movements in schizophrenia or cognitive abnormalities induced by antipsychotics are somewhat stronger. Nicotine may have antidepressant qualities in individuals with depression (Salin-Pascual et al, 1996), but this is not well established in those with schizophrenia.

The literature appears to suggest that those with severe forms of schizophrenia may smoke more frequently, and more heavily, than those with less severe forms (Lohr & Flynn, 1992). The possible beneficial effect of nicotine (and smoking) on schizophrenic symptoms and antipsychotic side-effects may be obscured by this association between smoking and severe forms of schizophrenia. In summary, a critical reading of the literature lends very limited support to the self-medication hypothesis, but this effect may be obscured by the association between severe forms of schizophrenia and heavy smoking.

Nicotine dependence and symptoms in schizophrenia 

Исследование вторичной негативной симптоматики при приёме антипсихотиков

OBJECTIVE: Despite the clinical observation that antipsychotics can produce negative symptoms, no previous controlled study, to our knowledge, has evaluated this action in healthy subjects. The present study assessed observer-rated and self-rated negative symptoms produced by conventional and second-generation antipsychotics in healthy volunteers. METHOD: The authors used a double-blind, placebo-controlled trial of single doses of haloperidol (5 mg) and risperidone (2.5 mg) in normal subjects. Thirty-two subjects were administered haloperidol, risperidone, and placebo in a random order. Motor variables and observer-rated negative symptoms were assessed after 3–4 hours and subjective negative symptoms and drowsiness after 24 hours. RESULTS: Neither of the active drugs caused significant motor extrapyramidal symptoms after administration. Haloperidol caused significantly more negative signs and symptoms than placebo on the Scale for the Assessment of Negative Symptoms (SANS) and two self-rated negative symptom scales: the Subjective Deficit Syndrome Scale total score and an analog scale that evaluates subjective negative symptoms. Risperidone caused significantly more negative signs and symptoms than placebo on the Brief Psychiatric Rating Scale (BPRS), the SANS, the Subjective Deficit Syndrome Scale total score, and the analog scale for subjective negative symptoms. After control for drowsiness, risperidone but not haloperidol produced more negative symptoms than placebo on the BPRS and the SANS. Significance was lost for the subjective negative symptoms with both drugs. CONCLUSIONS: Single doses of both haloperidol and risperidone produce negative symptoms in normal individuals. Drowsiness may be an important confounding factor in the assessment of negative symptoms in antipsychotic trials.

Negative Signs and Symptoms Secondary to Antipsychotics: A Double-Blind, Randomized Trial of a Single Dose of Placebo, Haloperidol, and Risperidone in Healthy Volunteers

Монотерапия рисперидоном в сравнении с терапией комбинацией низких доз рисперидона и галоперидола

Monotherapy is recommended for schizophrenia treatment, but the risk-benefit issue of antipsychotic drug combination (except for clozapine) remains unclear. Risperidone, an atypical antipsychotic drug, has a lower incidence of extrapyramidal syndrome but higher risks of prolactinemia and metabolic syndrome than haloperidol, a typical agent. This study compared efficacy and safety of risperidone monotherapy versus low-dose risperidone plus low-dose haloperidol in schizophrenia. In this 6-week, double-blind study, patients were randomized to the combination group (2-mg/d risperidone plus 2-mg/d haloperidol, n = 46) or the monotherapy group (4-mg/d risperidone, n = 42). Efficacy assessments included Clinical Global Impression-Severity, Positive and Negative Syndrome Scale and subscales, Calgary Depression Scale, Global Assessment of Functioning, and Medical Outcomes Study Short-Form 36. Safety was rigorously monitored. Response was defined as 30% reduction in the Positive and Negative Syndrome Scale total score. The 2 treatment groups were similar in (1) demographic and clinical characteristics at baseline, (2) response rate, and (3) improvement in various psychopathological measures and quality of life at end point. The monotherapy group had a higher increase in prolactin levels (P = 0.04) and Simpson-Angus Scale scores (P = 0.04) and a higher percentage of biperiden use (P = 0.045). There were no significant between-group difference in changes in weight, vital signs, corrected QT interval, liver/renal function, fasting glucose level, and lipid profiles. The findings suggest that risperidone monotherapy may yield higher prolactin levels than a combination of low-dose risperidone plus low-dose haloperidol. The 2 treatment groups are similar in efficacy, life quality, and other safety profiles. Future long-term studies are warranted.

A randomized, double-blind comparison of risperidone versus low-dose risperidone plus low-dose haloperidol in treating schizophrenia.

Дисфагия при приёме палиперидона

Paliperidone-Induced Dystonic Dysphagia

пролонгированная форма рисперидона vs кветиапин

Chronic management of schizophrenia and schizoaffective disorders is frequently complicated by symptomatic relapse. An open-label, randomized, active-controlled, 2-year trial evaluated 710 patients with schizophrenia or related disorders who were switched from stable treatment with oral risperidone, olanzapine, or conventional neuroleptics to risperidone long-acting injectable (RLAI) or oral quetiapine. Primary effectiveness evaluation was time-to-relapse. Safety evaluations included adverse events (AEs) reported for the duration of the study, Extrapyramidal Symptom Rating Scale (ESRS), clinical laboratory tests, and vital signs. A total of 666 patients (n=329 RLAI, n=337 quetiapine) were evaluable for effectiveness measures. Baseline demographics were similar between treatment groups. Kaplan–Meier estimate of time-to-relapse was significantly longer with RLAI (p < 0.0001). Relapse occurred in 16.5% of patients with RLAI and 31.3% with quetiapine. RLAI and quetiapine were both safe and well tolerated. Weight gain affected 7% of patients with RLAI and 6% with quetiapine, with mean end point increases of 1.25±6.61 and 0±6.55 kg, respectively. There were no significant between-group differences in weight gain. ESRS total scores decreased similarly after randomization to either RLAI or quetiapine. Extrapyramidal AEs occurred in 10% of patients with RLAI and 6% with quetiapine. Treatment-emergent potentially prolactin-related AEs were reported in 15 (5%) patients with RLAI and 5 (2%) patients with quetiapine; hyperprolactinemia was reported in 43 (13.1%) patients with RLAI and 5 (1.5%) patients with quetiapine. Somnolence occurred in 2% of patients with RLAI and 11% with quetiapine. To our knowledge, this is the first report of a randomized clinical trial directly comparing relapse prevention with a second-generation long-acting injectable antipsychotic and oral therapy. Time-to-relapse in stable patients with schizophrenia or schizoaffective disorder was significantly longer in patients randomized to RLAI compared with those randomized to oral quetiapine. Both antipsychotics were generally well tolerated.

Relapse Prevention in Schizophrenia and Schizoaffective Disorder with Risperidone Long-Acting Injectable vs Quetiapine: Results of a Long-Term, Open-Label, Randomized Clinical Trial

Fast-Off эффект

"Mode of Action

Quetiapine binds to a number of potentially relevant neurotransmitter receptors. Quetiapine has a greater affinity for serotonin 5HT2 receptors than for dopamine D, receptors. Together with considerable activity at histamine receptors and a-adrenoceptors, that explains somnolence and orthostatic hypotension caused by it. Quetiapine has less affinity for dopamine D2 receptors than dopamine itself, as a result It is rapidly dissociated from D2 receptor which results into several beneficial effects such as absence of EPS, absence of tardive dyskinesia and no effect on serum prolactin levels. This phenomena is known as "Fast-off",

Fast – off Effect

Typical antipsychotic drugs such as haloperidol, chlorpromazine, and fluphenazine have higher affinity for D2 receptor and bind more tightly than dopamine itself to D2 receptors. Prolonged occupancy of D2 receptors by typical antipsychotic drug result into several side effects such as extrapyramidal symptoms, elevated levels of serum prolactin and after a period of time tardive dyskinesia. It has been demonstrated that haloperidol, chlorpromazine dissociate very slowly over a 30 minutes time span, while quetiapine and clozapine dissociate rapidly from D2 receptors in less than 60 seconds.¹²"

Quetiapine: A Novel Anti Schizophrenic Drug