Biomarkers for the effects of benzodiazepines in healthy volunteers

Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose-response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose (r2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low.     

The effect of antipsychotic treatment on hormonal,inflammatory, and metabolic biomarkers in healthy volunteers: A systematic review and meta-analysis

Antipsychotic medications demonstrate a variable range of efficacy and side effects in patients with mental illness. Research has attempted to identify biomarkers associated with antipsychotic effects in various populations. Research designs utilizing healthy volunteers may have the added benefit of measuring the effect of antipsychotics on a given biomarker (s) independent of the varied environmental and clinical factors that often accompany patient populations. The aim of this systematic review and meta-analysis was to synthesize the current evidence of hormonal, inflammatory, and metabolic biomarker studies of antipsychotic treatment in study designs using healthy volunteers. The systematic review was performed according to established guidelines and a random effects meta-analysis of biomarkers appearing in at least three studies was performed while biomarkers in two or less studies were qualitatively summarized. A total of 28 studies including 28 biomarkers were identified. Meta-analyses were carried out for 14 biomarkers, showing significant effects within six biomarkers (cortisol, C-peptide, free fatty acids, leptin, thyroid-stimulating hormone, and prolactin). Many of these effects were associated with olanzapine, the most used antipsychotic amongst the trials, observed on sub-analyses. When combining biomarkers into categories, some additional effects were observed, for example, when grouping inflammatory biomarkers. These findings suggest that antipsychotics exert potentially strong effects on several biomarkers of interest independent of psychiatric disease which could be used to spur future investigations, however, replication work is needed for many biomarkers included in this review.     

Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects

AIMS: Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. This paper provides a systematic overview of CNS-tests used with SSRIs in healthy subjects. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. METHODS: These criteria were applied to all individual tests found in studies of selective serotonin reuptake inhibitors (SSRIs), performed in healthy subjects since 1966, identified with a systematic MedLine search. Separate databases were created to evaluate the effects of single or multiple dose SSRI-studies, and for amitriptyline whenever the original report included this antidepressant as a positive control. Doses of the antidepressant were divided into high- and low-dose ranges, relative to a medium range of therapeutic doses. For each test, the drug effects were scored as statistically significant impairment/decrease (-), improvement/increase (+) or no change (=) relative to placebo. RESULTS: 56 single dose studies and 22 multiple dose studies were identified, investigating the effects of 13 different SSRIs on 171 variants of neuropsychological tests, which could be clustered into seven neuropsychological domains. Low single doses of SSRIs generally stimulated tests of attention and memory. High doses tended to impair visual/auditory and visuomotor systems and subjective performance, while showing an acceleration in motor function. The most pronounced effects were observed using tests that measure flicker discrimination (improvement at low doses: 75%, medium doses: 40%, high doses: 43% of studies); REM sleep (inconsistent decrease after medium doses, decrease in 83% of studies after high doses); and EEG recordings, predominantly in alpha (decrease in 60% and 43% of studies after low and medium doses, respectively) and in theta activity (increase in 43% and 33% of studies after medium and high doses, respectively). Amitriptyline generally impaired central nervous system (CNS) functions, which increased with doses. Multiple doses caused less pronounced effects on the reported tests. The most responsive tests to amitriptyline appeared to be EEG alpha and theta, and REM sleep duration. CONCLUSIONS: SSRIs in healthy subjects appear to cause slight stimulating effects after low doses, which tend to diminish with dose. The most consistent effects were observed with flicker discrimination tests, EEG (alpha and beta bands), REM sleep duration, and subjective effects at higher doses. These effects are small compared with amitriptyline and other CNS-active drugs. Multiple dosing with SSRIs caused even fewer measurable differences from placebo, probably due to adaptive processes. SSRI-effects are best detected with a test battery that is sensitive to general CNS-stimulation, but such tests only comprise a very small portion of the close to 200 different methods that were found in current review.     

Biomarkers for the effects of cannabis and THC in healthy volunteers

An increasing number of novel therapeutic agents are targeted at cannabinoid receptors. Drug development programmes of new cannabinoid drugs may be facilitated by the identification of useful biomarkers. This systemic literature review aims to assess the usefulness of direct biomarkers for the effects of cannabis and tetrahydrocannabinol (THC) in healthy volunteers. One hundred and sixty-five useful articles were found that investigated the acute effects of cannabis or THC on the central nervous system (CNS) and heart rate in healthy volunteers. Three hundred and eighteen tests (or test variants) were grouped in test clusters and functional domains, to allow their evaluation as a useful biomarker and to study their dose–response effects. Cannabis/THC affected a wide range of CNS domains. In addition to heart rate, subjective effects were the most reliable biomarkers, showing significant responses to cannabis in almost all studies. Some CNS domains showed indications of depression at lower and stimulation at higher doses. Subjective effects and heart rate are currently the most reliable biomarkers to study the effect of cannabis. Cannabis affects most CNS domains, but too many different CNS tests are used to quantify the drug–response relationships reliably. Test standardization, particularly in motor and memory domains, may reveal additional biomarkers.     

Delusions of pregnancy associated with increased prolactin concentrations produced by antipsychotic treatment

Treatment of psychotic symptoms has traditionally involved conventional antipsychotics. While efficacious, their side-effects have been problematic and the approval by the Food and Drug Administration of the newer antipsychotics with improved side-effects profiles heralded important advances in treating psychoses. Prolactin elevation has been associated with all classical and some atypical antipsychotics. We present cases where elevation of prolactin concentrations secondary to antipsychotic treatment was associated with delusions of pregnancy. Risperidone was the antipsychotic employed and elevation of prolactin concentrations were noted each time. The delusions abated and prolactin concentrations decreased when the drug was discontinued. Rechallenge with risperidone resulted in re-elevation of prolactin levels along with recurrent delusions. Substituting risperidone with another antipsychotic (either olanzapine or quetiapine) also led to abatement of the delusions and lowering of prolactin. Although no direct psychotogenic effects of prolactin are known, it is contended that delusions of pregnancy reported during antipsychotic treatment might be associated with rising prolactin concentrations.     

Sertindole: efficacy and safety in schizophrenia

Sertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level. The active substance has a long half-life. Oral administration once daily yields highly stable plasma levels. These features may explain the clinically observed low frequency of extrapyramidal side effects, including tardive dyskinesia. In contrast to most antipsychotics, sertindole seems to be void of sedative effects. However, although not strictly proven by objective neuropsychological tests, this asset of sertindole does not add to the cognitive problems inherent in schizophrenia. Administration of sertindole is more often associated with prolongation of QTc compared with most other currently used antipsychotics. However, large cohort analyses do not suggest that all-cause mortality is higher with sertindole than with, for example, risperidone or olanzapine. The effective antipsychotic dose range of sertindole is 12-20 mg/day, with small variations among patients. The frequency of most adverse events, for example extrapyramidal symptoms and somnolence, with such a dose does not differ from placebo. Three side effects have been more common than with placebo/haloperidol in short-term studies: weight gain, rhinitis and a decreased ejaculation volume. Two head-to-head comparisons (one in treatment-resistant patients) of sertindole and risperidone showed equivalent effects on positive symptoms. For negative symptoms, one study obtained equivalent effects and one a superior effect of sertindole. Sertindole should not be used as first-line treatment for first-episode patients with schizophrenia because of the QTc prolongation. It has a side-effect profile that makes it an interesting alternative for many patients who do not respond well to the initial choice of antipsychotic drug.     

Improvement of prefrontal brain function in endogenous psychoses under atypical antipsychotic treatment.

Typical and atypical antipsychotics are thought to exert their effects on different neurotransmitter pathways with specific action of atypical compounds on the prefrontal cortex, but studies directly investigating the effect of those drugs on neurophysiological measures of prefrontal brain function are sparse. We therefore investigated the influence of different antipsychotics on an electrophysiological marker of prefrontal brain function (NoGo anteriorization, NGA) and neuropsychological test scores. For this purpose, 38 patients with endogenous psychoses were investigated at the beginning of a stationary psychiatric treatment and at a 6-week-follow-up. Patients were treated with typical or atypical antipsychotics, or a combination of both. They underwent psychopathological diagnostic and neuropsychological testing, as well as electrophysiological investigations during a Continuous Performance Test. The results indicate that typical and atypical antipsychotics differentially affected the development of the NGA over the course of the treatment, typical antipsychotics tending to result in decreased values at follow-up, and atypical antipsychotics stabilizing, or increasing this parameter. Performance in tests of frontal lobe function generally declined under typical antipsychotics and improved with atypical compounds, changes in Stroop interference correlated with changes in the NGA. We conclude that typical and atypical antipsychotics differ regarding their effect on prefrontal brain function in schizophrenia, atypical neuroleptics often showing a more favorable impact than conventional antipsychotics on respective parameters.     

Risperidone-associated hyperprolactinemia: evaluation in twenty psychiatric outpatients.

Despite the lack of extrapyramidal side effects, some atypical antipsychotics can induce an increase in prolactinemia, as the conventional neuroleptics do. We decided to evaluate the effects of risperidone on serum prolactin levels and prolactin-related adverse effects in 20 outpatients of an Italian community psychiatric service. Patients enrolled in this study were on risperidone (2-8 mg per day; mean dose=4.15+/-0.4 mg per day) treatment in the period May-November 2002. The 20 patients, 13 women and 7 men (mean age=36.38+/-3.2 years for women and 29.7+/-2.2 for men) who accomplished inclusion criteria, participated in the study after giving informed written consent. Raised prolactin levels were observed in 13 (9 women and 4 men) out of 20 patients, but only 8 patients presented prolactin-related adverse effects, libido reduction being the most frequent. In this observational study, risperidone enhanced serum prolactin in 65% of patients. A good correlation was found between age and prolactin levels in pre-menopausal women, although no clear correlation among duration of treatment, dose used, prolactin levels and prolactin-related adverse effects could be established.     

Dopamine and serotonin receptor binding and antipsychotic efficacy.

The relationship between clinically effective antipsychotic drug dosage and binding affinity to cloned dopamine (DA) and serotonin receptor subtypes was analyzed in an effort to elucidate the contribution of individual receptor subtypes to medication response. Clinically effective dose and binding affinity to D(2) DA receptor were modestly correlated for typical antipsychotic medications (r=0.54, p=0.046), but surprisingly were not correlated for atypical antipsychotics (r=0.41, p=0.31). For typical antipsychotics, a more robust inverse relationship was observed between medication dose and 5-HT(2C) affinity (r=-0.68, p=0.021). The strongest correlation for typical antipsychotics was observed between drug dosage and 5-HT(2C)/D(2) binding affinity ratio (r=-0.81, p=0.003). For atypical antipsychotics, no significant correlations were identified between medication dosage and 5-HT(2C), 5-HT(2A), 5-HT(2C)/D(2), or 5-HT(2A)/D(2) receptor-binding affinities. In contrast, atypical antipsychotic medication dosage was highly correlated with the ratios of D(2) (5-HT(2A)/5-HT(1A)) (r=0.80, p=0.031), and D(2) (5-HT(2C)/5-HT(1A)) (r=0.78, p=0.038) binding affinities. These observations demonstrate an interaction between D(2) and 5-HT(2C) receptor effects contributing to positive symptom response for typical antipsychotic medications, suggesting that signaling through 5-HT(2C) receptors interacts with and improves antipsychotic effects achieved via D(2) receptor blockade. This analysis also demonstrates that, in contrast to typical antipsychotics, therapeutic effects of atypical antipsychotic medications are determined by opposing interactions among three different domains: (1) increasing D(2) DA receptor-binding affinity enhances antipsychotic potency. (2) Increasing 5-HT(2C) and 5-HT(2A) receptor-binding affinities also facilitate antipsychotic efficacy. (3) Increasing 5-HT(1A) receptor-binding affinity, in contrast, reduces antipsychotic efficacy.     

Review of quetiapine and its clinical applications in schizophrenia

Preclinical studies have shown that quetiapine (Seroquel?, AstraZeneca) is an atypical antipsychotic with many similarities to clozapine. Both placebo-controlled and comparative studies in patients with schizophrenia have demonstrated that quetiapine has long-term efficacy in both positive and negative domains, as well as beneficial effects on affective and cognitive symptoms. Comparative clinical studies confirm that quetiapine is at least as effective as the standard antipsychotics, chlorpromazine and haloperidol and response rates with quetiapine are similar to those reported with other atypical antipychotics. Quetiapine has also demonstrated superior efficacy to haloperidol in partially responsive patients, who can be particularly difficult to treat. Quetiapine has a wide clinical dosing range (150 - 750 mg/day), although doses of 400 mg or above should be used in patients who do not fully respond to lower doses of the drug. Quetiapine is generally well tolerated with no requirement for routine ECG or blood monitoring and it has minimal effects on weight. Uniquely among other first-line atypical antipsychotics, quetiapine is associated with a placebo-level incidence of extrapyramidal side-effects (EPS) and an indistinguishable effect from placebo on plasma prolactin at all doses. Thus, clinicians can confidently increase the dose of quetiapine, without increasing the risk of EPS or hyperprolactinaemia. A number of studies have also shown that quetiapine is well-tolerated and effective in patients who are particularly susceptible to EPS, including elderly and adolescent patients and those with pre-existing dopaminergic pathology, such as Alzheimer’s disease and Parkinson’s disease. The consistent efficacy in treating all schizophrenic domains and good tolerability, particularly placebo-level EPS, make quetiapine acceptable to patients, as demonstrated in a survey of patient satisfaction. Thus quetiapine is a suitable first-line therapy for the treatment of schizophrenia and psychosis.     

EGYT-2509 a novel neuroleptic agent without extrapyramidal and endocrine side effects

The dibenzodioxazocine derivative EGYT-2509 was effective in neuropsychopharmacological tests characteristic for neuroleptics and antiparkinsonian drugs. It interacted with dopaminergic compounds similarly to chlorpromazine and haloperidol, but in certain tests it showed different activity. Similarly to chlorpromazine and haloperidol it inhibited the lethal effect of amphetamine in grouped mice. The apomorphine-induced stereotypy was potentiated by lower, and antagonized by higher doses of EGYT-2509. The compound did not show cataleptogenic activity and even antagonized the catalepsy evoked by bulbocapnine. The in vitro potency of EGYT-2509 to block dopamine-mediated inhibition of prolactin release was weaker by three orders of magnitude than that of haloperidol. In preliminary human studies it did not affect the plasma prolactin level. It is concluded that EGYT-2509 is a new potential antipsychotic agent with minimal risk of extrapyramidal and endocrine side effects.     

Amisulpride a selective dopamine antagonist and atypical antipsychotic: results of a meta-analysis of randomized controlled trials

The pharmacological profiles of the atypical antipsychotics, clozapine, olanzapine, quetiapine and risperidone, all show a combined serotonin (5-HT2) and dopamine type-2 (D2) receptor antagonism. Amisulpride, a highly selective dopamine D2/D3 receptor antagonist that binds preferentially to receptors in the mesolimbic system, is also an 'atypical' antipsychotic despite having a different receptor-affinity profile. A meta-analysis of 18 clinical trials was undertaken to compare the efficacy and safety of amisulpride with conventional antipsychotics. The improvement in mental state was assessed using the Brief Psychiatric Rating Scale (BPRS) or the Scale for the Assessment of Negative Symptoms (SANS). In a pooled analysis of 10 studies of acutely ill patients, amisulpride was significantly more effective than conventional neuroleptics with regard to improvement of global symptoms. Amisulpride is, to date, the only atypical antipsychotic for which several studies on patients suffering predominantly from negative symptoms have been published. In four such studies, amisulpride was significantly superior to placebo. Three small studies with conventional neuroleptics as a comparator showed only a trend in favour of amisulpride in this regard. Amisulpride was associated with fewer extrapyramidal side-effects and fewer drop-outs due to adverse events than conventional neuroleptics. These results clearly show that amisulpride is an 'atypical' antipsychotic, and they cast some doubt on the notion that combined 5-HT2-D2 antagonism is the only reason for the high efficacy against negative symptoms and fewer extrapyramidal side-effects.     

Effects of the atypical antipsychotics olanzapine and risperidone on plasma prolactin levels in male rats: a comparison with clinical data

Rationale Hyperprolactinaemia is a common side effect of antipsychotic treatment and the clinical consequences associated with this, e.g. sexual dysfunction, can have a negative impact on patient compliance. Objectives The aim of this study was to investigate the effect of the atypical antipsychotics olanzapine and risperidone on prolactin levels in rats using different treatment regimes and to compare these data with those reported clinically. Methods: All experiments were carried out in male CD rats. In separate studies, the effects of acute, sub-chronic (7 days) and chronic (28 days) olanzapine and risperidone administration on prolactin levels were determined. Further studies investigated the time course of the prolactin response following olanzapine and risperidone treatment over 24 h. Results Both drugs significantly increased prolactin levels in a similar manner following acute administration, in keeping with clinically reported data. However, this elevation was still present following sub-chronic and chronic treatment, contrasting with clinical data with respect to olanzapine but not risperidone. Over 24 h, olanzapine demonstrated a more transient elevation of prolactin levels, whereas risperidone caused a robust and persistent increase in prolactin up to 24 h post-dose, closely mimicking clinical results. Conclusions The present study has demonstrated that olanzapine and risperidone display similar effects on prolactin levels in the rat following acute and chronic administration but differ in their prolactin response over a 24-h period. In conclusion, prolactin levels in rats following atypical antipsychotic treatment may not be fully predictive of the clinical situation.     

Review of quetiapine and its clinical applications in schizophrenia

Preclinical studies have shown that quetiapine (Seroquel, AstraZeneca) is an atypical antipsychotic with many similarities to clozapine. Both placebo-controlled and comparative studies in patients with schizophrenia have demonstrated that quetiapine has long-term efficacy in both positive and negative domains, as well as beneficial effects on affective and cognitive symptoms. Comparative clinical studies confirm that quetiapine is at least as effective as the standard antipsychotics, chlorpromazine and haloperidol and response rates with quetiapine are similar to those reported with other atypical antipychotics. Quetiapine has also demonstrated superior efficacy to haloperidol in partially responsive patients, who can be particularly difficult to treat. Quetiapine has a wide clinical dosing range (150-750 mg/day), although doses of 400 mg or above should be used in patients who do not fully respond to lower doses of the drug. Quetiapine is generally well tolerated with no requirement for routine ECG or blood monitoring and it has minimal effects on weight. Uniquely among other first-line atypical antipsychotics, quetiapine is associated with a placebo-level incidence of EPS and an indistinguishable effect from placebo on plasma prolactin at all doses. Thus, clinicians can confidently increase the dose of quetiapine, without increasing the risk of EPS or hyperprolactinaemia. A number of studies have also shown that quetiapine is well-tolerated and effective in patients who are particularly susceptible to EPS, including elderly and adolescent patients and those with pre-existing dopaminergic pathology, such as Alzheimer's disease and Parkinson's disease. The consistent efficacy in treating all schizophrenic domains and good tolerability, particularly placebo-level EPS, make quetiapine acceptable to patients, as demonstrated in a survey of patient satisfaction. Thus quetiapine is a suitable first-line therapy for the treatment of schizophrenia and psychosis.     

Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management

Hyperprolactinaemia is an important but neglected adverse effect of antipsychotic medication. It occurs frequently with conventional antipsychotics and some atypical antipsychotics (risperidone and amisulpride) but is rare with other atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, ziprasidone). For this reason the terms 'prolactin-sparing' and 'prolactin-raising' are more useful than 'atypical' and 'conventional' when considering the effect of antipsychotic drugs on serum prolactin. During antipsychotic treatment prolactin levels can rise 10-fold or more above pretreatment values. In a recent study approximately 60% of women and 40% of men treated with a prolactin-raising antipsychotic had a prolactin level above the upper limit of the normal range. The distinction between asymptomatic and symptomatic hyperprolactinaemia is important but is often not made in the literature. Some symptoms of hyperprolactinaemia result from a direct effect of prolactin on target tissues but others result from hypogonadism caused by prolactin disrupting the normal functioning of the hypothalamic-pituitary-gonadal axis. Symptoms of hyperprolactinaemia include gynaecomastia, galactorrhoea, sexual dysfunction, infertility, oligomenorrhoea and amenorrhoea. These symptoms are little researched in psychiatric patients. Existing data suggest that they are common but that clinicians underestimate their prevalence. For example, well conducted studies of women treated with conventional antipsychotics have reported prevalence rates of approximately 45% for oligomenorrhoea/amenorrhoea and 19% for galactorrhoea. An illness-related under-function of the hypothalamic-pituitary-gonadal axis in female patients with schizophrenia may also contribute to menstrual irregularities. Long-term consequences of antipsychotic-related hypogonadism require further research but are likely and include premature bone loss in men and women. There are conflicting data on whether hyperprolactinaemia is associated with an increased risk of breast cancer in women. In patients prescribed antipsychotics who have biochemically confirmed hyperprolactinaemia it is important to exclude other causes of prolactin elevation, in particular tumours in the hypothalamic-pituitary area. If a patient has been amenorrhoeic for 1 year or more, investigations should include bone mineral density measurements. Management should be tailored to the individual patient. Options include reducing the dose of the antipsychotic, switching to a prolactin-sparing agent, prescribing a dopamine receptor agonist and prescribing estrogen replacement in hypoestrogenic female patients. The efficacy and risks of the last two treatment options have not been systematically examined. Antipsychotic-induced hyperprolactinaemia should become a focus of interest in the drug treatment of psychiatric patients, particularly given the recent introduction of prolactin-sparing antipsychotics. Appropriate investigations and effective management should reduce the burden of adverse effects and prevent long-term consequences.     

Discriminative stimulus properties in rats of the novel antipsychotic quetiapine

Rats discriminated the novel antipsychotic quetiapine (Seroquel). Full generalization was seen with the novel ("atypical") antipsychotics, clozapine, olanzapine, and risperidone. Generalization was not seen with the older "typical" antipsychotics, haloperidol, chlorpromazine, and loxapine, or with the novel atypical antipsychotic, amisulpride. The pattern of generalization resembled that seen in rats trained to discriminate a low dose (1.25 mg/kg) of clozapine, which dissociates most novel antipsychotics from typical antipsychotics. However, the failure of the novel antipsychotic amisulpride to generalize demonstrates that this bioassay does not detect all novel antipsychotics. These data suggest that the discrimination of antipsychotics such as quetiapine may be of value in the development of novel antipsychotics, although the relationship between the discriminative properties of such drugs and their clinical actions is unclear.     

Pharmacotherapy of first-episode psychosis

Early intervention in psychosis has attracted more attention in the last few years. The treatment of this phase of the disorders requires a specific and adapted approach. The issue of engaging the patient is so critical that it influences not only the choice of medication, but also the context and the way in which it is administered. In the case of a first admission, patients should be observed for 24-48 h without any antipsychotic treatment, in order to clarify the diagnosis and exclude the possibility that symptoms are caused by acute intoxication with illicit substances, for example. The diagnosis is often difficult and unstable. A dimensional, rather than a categorical approach, is usually more likely to be adopted. In recent years, atypical antipsychotics have become the most frequently used first-line treatment. They are less likely to cause secondary negative symptoms, cognitive impairments and dysphoria. They also appear to influence the course of depression and hostility/aggression better than conventional neuroleptics, have possibly mood-stabilising properties and, subjectively, are often better accepted by patients. On the risk side, prevalence of acute extrapyramidal side effects and possibly tardive dyskinesia are lower, compared to the older neuroleptics. Although, the risk for short-term weight gain, cardiovascular, and especially hyperglycaemic complications are somewhat higher for some of these antipsychotics. Finally, the dose should be adapted as it has been shown that patients presenting a first psychotic episode respond to a lower dose of antipsychotic. This article focuses on the pharmacotherapy of first-episode psychosis, on the basis of a computerised and a manual search for articles dealing with antipsychotic treatment of these patients. Findings are discussed and combined in clinical guidelines for first-episode affective and non-affective psychosis, for patients with incomplete recovery or treatment resistance, for cases of emergency and for side effects associated with antipsychotic treatment.     

Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics.

There is now some evidence that schizophrenia may be accompanied by an activation of the inflammatory response system (IRS) and that typical antipsychotics may suppress some signs of IRS activation in that illness. This study was carried out to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA) and Clara Cell protein (CC16), an endogenous anticytokine, in nonresponders to treatment with typical neuroleptics and (ii) the effects of atypical antipsychotics on the above IRS variables. The above parameters were determined in 17 patients with treatment-resistant schizophrenia (TRS) to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. Patients with TRS had repeated measurements of the IRS variables before and 2 and 4 months after treatment with atypical antipsychotics. Serum IL-6 was significantly higher in schizophrenic patients, irrespective of their response to typical antipsychotics, than in normal controls. Serum IL-1RA was significantly higher in the TRS patients than in controls, whereas responders took up an intermediate position. The serum concentrations of CC16 were significantly lower after treatment with atypical antipsychotics during 4 months than before treatment. It is concluded that (i) schizophrenia and, in particular, TRS is characterized by an activation of the monocytic arm of cell-mediated immunity and (ii) atypical antipsychotics may decrease the anti-inflammatory capacity of the serum in TRS patients.