Sedation, an unpleasant, undesirable and potentially dangerous side-effect of many psychotropic drugs

Sedation is a property of many psychotropic drugs. It can be defined as a decrease in psychomotor and cognitive performance. Many of the earlier neuroleptic, anxiolytic, antidepressant and antihistamine drugs were extremely sedative and sedation came to be considered as an integral part of the activity of these compounds. Newer, far less sedative, examples of each of these classes have shown that sedation is not required for their efficacy. Sedation is now increasingly considered as an adverse effect which should be avoided rather than a desirable effect especially when treating disorders such as anxiety or depression. This article discusses the sedative properties and mechanisms of different classes of psychotropic drugs.     

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.     

Current schizophrenia drugs: efficacy and side effects

Over the course of the past decade, the acceptance of several second-generation antipsychotics (SGAs) as effective medication for the treatment of schizophrenia has led to some changes. SGAs have a lower risk of inducing extrapyramidal side effects and tardive dyskinesia compared with first-generation antipsychotics, and have been said to be more successful in long-term treatment and tolerability. They also significantly improve the quality of life of schizophrenic patients. However, during treatment with SGAs other adverse effects can occur, such as weight gain, metabolic changes, sexual dysfunction and QTc-prolongation, significantly affecting the patient’s physical health. Consequently, these side effects might be the reason that a high proportion of patients discontinue treatment with SGAs. Thus, from the authors’ view, optimising individualised treatment implies increasing the efficacy of current schizophrenia drugs. This can be achieved by finding clinical or pharmacogenetic predictors for the most appropriate drug or drug combination, and by improving side-effect management in combination with non-pharmacological interventions in order to increase patients’ quality of life and treatment compliance, possibly resulting in a better long-term outcome.     

All-cause mortality associated with atypical and typical antipsychotics in demented outpatients

PURPOSE: To estimate the association between use of typical and atypical antipsychotics and all-cause mortality in a population of demented outpatients. METHODS: The study cohort comprised all demented patients older than 65 years and registered in the Integrated Primary Care Information (IPCI) database, during 1996-2004. First, mortality rates were calculated during use of atypical and typical antipsychotics. Second, we assessed the association between use of atypical and typical antipsychotics and all-cause mortality through a nested case-control study in the cohort of demented patients. Each case was matched to all eligible controls at the date of death by age and duration of dementia. Odds ratios were estimated through conditional logistic regression analyses. RESULTS: The crude mortality rate was 30.1 (95%CI: 18.2-47.1) and 25.2 (21.0-29.8) per 100 person-years (PY) during use of atypical and typical antipsychotics, respectively. No significant difference in risk of death was observed between current users of atypical and typical antipsychotics (OR = 1.3; 95%CI: 0.7-2.4). Both types of antipsychotics were associated with a significantly increased risk of death as compared to non-users (OR = 2.2, 1.2-3.9 for atypical antipsychotics; OR=1.7, 1.3-2.2 for typical antipsychotics). CONCLUSIONS: Conventional antipsychotic drug should be included in the FDA's Public Health advisory, which currently warns only of the increased risk of death with the use of atypical antipsychotics in elderly demented persons.     

Within-session behavioral decrement of atypical antipsychotics: Role of novelty

In order to gain a better understanding of the characteristics of antipsychotic-induced within-session decrements in unconditioned behavioral responses of mice, and whether they are sensitive to novel environmental stimuli, we studied the acute effects of haloperidol and atypical antipsychotic drugs (sulpiride, thioridazine, clozapine, and remoxipride) in familiar and novel open-field conditions in mice. The results show that familiarized controls and antipsychotic-treated groups had a progressive reduction in ambulation and rearing during the 10-minute open-field session. By manipulating the configuration of the open-field situation, familiarized controls as well as mice treated with typical or atypical antipsychotic drugs were able to exhibit an enhanced response to the presentation of novel stimuli. It may be noted that both the maintenance and the initiation of ambulation were affected by antipsychotic treatment. Furthermore, when comparing novel versus familiar groups during the 10-minute session, the increase in ambulation induced by atypical antipsychotic treatment was maintained longer (6–8 minutes) than that induced by haloperidol (4 minutes). In summary, these findings show that an important feature in the reinstatement of both typical and atypical antipsychotic-induced behavioral decrement may be a change in the stimulus conditions. Drug Dev. Res. 42:71–75, 1997. © 1997 Wiley-Liss, Inc.     

Additive effects of clonidine and antidepressant drugs in the mouse forced-swimming test

In the mouse forced-swimming model, dose-dependent reversal of immobility was induced by the alpha-agonist clonidine given IP 30 min before testing. In addition, three preferential inhibitors of 5-HT uptake (citalopram, indalpine and fluvoxamine) had similar activity in the dose range 8–16 mg/kg as did the 5-HT1 agonist 8-OH-DPAT (1–4 mg/kg). Pretreatment with alpha-methyl-para-tyrosine (100 mg/kg) did not prevent clonidine (1 mg/kg) action, suggesting that there was mediation by alpha post-junctional receptors. The effect of clonidine was unaltered by prazosin (2 mg/kg) and reversed by yohimbine (4 mg/kg) and 5-MeODMT (1 mg/kg), whereas it was potentiated by reserpine (2.5 mg/kg), methysergide (2 mg/kg) and ketanserin (8 mg/kg). Moreover, an ineffective dose of clonidine (0.06 mg/kg at 45 min pre-testing) made active subthreshold doses of various antidepressants (given at 30 min pre-testing): imipramine (4 mg/kg), amitriptyline (1 mg/kg), maprotiline (8 mg/kg), citalopram (2 mg/kg), indalpine, fluvoxamine and mianserin (4 mg/kg), viloxazine (2 mg/kg). Similar interactions were found with iprindole and nialamide (32 mg/kg), which were inactive alone up to 64 mg/kg, and 8-OH-DPAT (0.5 mg/kg) but not with major and minor tranquillizers. It is suggested that one effect of antide-pressants might be the triggering of different relationships between alpha-2 and 5-HT mechanisms.     

Evaluation of a behavioural weight management programme for patients with severe mental illness: 3 year results

Excess weight is a common problem in the general population and in those with severe mental illness and is associated with a range of adverse consequences. The evidence base for managing excess weight in those with severe psychiatric illness is small. We report the outcome of a weight management programme provided in a community mental health centre. The programme consisted of group sessions, held weekly and lasting one hour. Participants self-referred and attended as many sessions as they wished. Sessions included weighing, feedback from participants and education on a range of issues including healthy eating and exercise. Over a 3-year period 70 patients, predominantly with schizophrenia, attended the programme. Length of follow-up ranged from 2 weeks to 3 years. Data for all 70 patients was evaluated. The mean BMI at entry to the programme was 32.5 kg/m2. The mean number of sessions attended was 34. Patients achieved a mean weight loss of 4.97 kg. The mean BMI at last attendance was 30.7 kg/m2. Weight loss correlated with number of sessions attended (p = 0.0001). This study demonstrates the long-term value of a weight management programme at 3 years and supports the hypothesis that weight loss can be achieved using a simple behavioural intervention in motivated psychiatric patients.     

Use of benzodiazepines and benzodiazepine-related drugs in the Nordic countries between 2000 and 2020

Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000–2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55–78% of BZ use in 2020, followed by BZ sedatives at 20–44%, BZ-hypnotics at <1–5%, and clonazepam at <1–2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups—despite warnings against their use in this population.     

Prevention of “learned helplessness” in the rat by hydroxyzine

The effects of hydroxyzine (8, 16, and 32 mg/kg i.p.), administered either 30 min before exposing rats to a series of inescapable shocks (preventive treatment) or during the subsequent acquisition of a shuttle box avoidance response (curative treatment), wereinvestigated. In these conditions untreated rats, previously exposed to inescapable shocks (“stress” ), show a marked increase in escape failures in the shuttle box when compared with nonshocked control animals (“ learned helplessness” ). Control experiments examined the effects of hydroxyzine on memory (passive avoidance test) and on electric shock sensitivity. Diazepam (2 mg/kg i.p.) was used as a reference compound. Hydroxyzine, when administered before “ stress,” clearly decreased at 8 and 32 mg/kg the number of escape failures observed but was without effect when administered after “stress” during the subsequent shuttle box avoidance learning. Similar results were observed with diazepam. Unlike diazepam, hydroxyzine at 32 mg/kg^?1 induced no amnesia in the passive avoidance test, whereas clear amnesia was observed with diazepam. Neither compound altered the rats' sensitivity to shock. These results suggest that hydroxyzine decreases the effects of “ stress” and that these effects cannot be attributed either to impaired memory for the aversive stimulation or to diminished shock sensitivity.     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.     

新型抗精神病药的研发进展

现存的各类抗精神病药物的不良反应繁多，且控制症状的效能仍有很大局限，致使相当数量的患者成为难治性案例。本文对近年国外研究出的新型药物的进展进行系统探讨，以期提高现有治疗水平。     

Discontinued psychiatric drugs in 2008

During the past several decades, neuropsychiatric agents have been one of the fastest growing classes of medicinal agents. This expansion is in part due to the increased recognition of the prevalence and burden of illness associated with disparate neuropsychiatric disorders, increased public awareness and possibly reduced stigma associated with mental illness, as well as extensive marketing of neuropsychiatric agents to healthcare providers. Most of the agents reviewed herein represent modifications and/or refinements of pre-existing agents and/or theoretical approaches (e.g., monoamine hypothesis). There remains a relative paucity of agents with genuinely novel mechanisms targeting effector systems implicated in contemporary models of disease pathophysiology in mood and psychotic disorders (e.g., glutamate, insulin, brain derived neurotrophic factor and other growth factors, immunoinflammatory systems and oxidative stress).     

高效液相色谱法测定血浆中常用精神病治疗药物

用高效液相色谱法对氟哌啶醇、氯氮平、阿普唑仑、丙咪嗪、阿米替林、氯丙嗪、泰尔登、氟奋乃静、地西泮等９种常用精神病治疗药物过量中毒进行定量分析。标本经一步液－液提取后，在Ｃ８柱上进行分离，流动相为甲醇－乙腈－水，紫外检测波长为２５４ｎｍ，９种药物在１７ｍｉｎ内即可实现良好分离，线性范围为０．５～１６μｇ／ｍｌ，绝对回收率为７６．８％～９３．３％，最低检测浓度为０．１～０．４μｇ／ｍｌ，日内和日间精密度小于７．５％。本法具有简便灵敏、快速准确的优点，适合于临床检测。     

Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs

Cytochrome P450 CYP2D6 is the most extensively characterized polymorphic drug-metabolizing enzyme. A deficiency of the CYP2D6 enzyme is inherited as an autosomal recessive trait; these subjects (7% of Caucasians, about 1% of Orientals) are classified as poor metabolizers. Among the rest (extensive metabolizers), enzyme activity is highly variable, from extremely high in ultrarapid metabolizers, to markedly reduced in intermediate metabolizers. The CYP2D6 gene is highly polymorphic, with more than 70 allelic variants described so far. Of these, more than 15 encode an inactive or no enzyme at all. Others encode enzyme with reduced, "normal" or increased enzyme activity. The CYP2D6 gene shows marked interethnic variability, with interpopulation differences in allele frequency and existence of "population-specific" allelic variants, for instance among Orientals and Black Africans. The CYP2D6 enzyme catalyses the metabolism of a large number of clinically important drugs including antidepressants, neuroleptics, some antiarrhythmics, lipophilic beta-adrenoceptor blockers and opioids. The present-day knowledge on the influence of the genetic variability in CYP2D6 on the clinical pharmacokinetics and therapeutic effects/adverse effects of psychotropic drugs is reviewed.     

Cilobamine in the treatment of atypical depression

Sixteen patients meeting our criteria for atypical depression were treated in a 7-week single-blind pilot study with cilobamine mesylate, an investigational antidepressant structurally distinct from tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI). Nine patients (56 per cent) responded to cilobamine. Cilobamine patients were compared with a group of similar patients receiving placebo for 6 weeks in a separate double-blind study. The response rate to cilobamine was superior to that of placebo. Cilobamine patients also showed significantly greater improvement in Hamilton Depression Scale scores than did placebo patients. Previous studies have demonstrated the efficacy of MAOIs in atypical depression. This study suggests that certain antidepressants which are not MAOIs, and are free of dietary restrictions and the risk of hypertensive crises, may also be effective in atypical depression.     

Use of anxiolytic or hypnotic drugs and total mortality in a general middle-aged population

PURPOSE: The aim of the study was to evaluate the effect of the consumption of anxiolytic or hypnotic drugs on total mortality in a general population. METHODS: We followed a cohort of 7225 men and 7726 women aged 40-42 years who underwent health surveys in 1985-1989 in two Norwegian counties, with respect to deaths. Mean follow-up period was 18 years. The subjects were categorised according to frequency of anxiolytic or hypnotic drug use during the last month: daily, every week, less than every week and not used during the last month. RESULTS: The proportion of anxiolytic or hypnotic drug users was 6.6% among men and 16.2% among women. Altogether 402 men and 290 women died. There was an increase in risk of death with an increase in frequency of use. Crude hazard ratios for men and women daily using anxiolytics or hypnotics were 3.1 (95%CI 2.0, 4.8) and 2.7 (1.9, 4.0), respectively, as compared with non-users last month. After adjusting painkiller use and smoking the hazard ratios were lowered, being 2.4 (1.5-4.0) (men) and 2.1 (1.4-3.2) (women). After additional adjustments for other possible confounders the hazard ratios were further attenuated to 1.5 (0.9-2.7) for men and 1.7 (1.1-2.6) for women. CONCLUSIONS: Daily users of anxiolytic or hypnotic drugs in our study showed higher crude mortality than non-users. However, after adjusting lifestyle and socio-economic variables the difference was markedly reduced suggesting that the remaining excess mortality is due to residual confounding.