Actions of typical and atypical antipsychotics on tuberoinfundibular dopamine neurons

The activity of tuberoinfundibular dopamine neurons, as judged from the accumulation of dihydroxyphenylalanine (DOPA) after the inhibition of decarboxylase activity, was unaltered following the acute administration of the typical antipsychotics haloperidol, cis-flupentixol, chlorpromazine, or fluphenazine. In contrast, a significant increase in the activity of tuberoinfundibular dopamine neurons was elicited by the purported atypical antipsychotics clozapine, melperone, thioridazine, setoperone, and RMI 81582. The clozapine-induced increase in the activity of tuberoinfundibular dopamine neurons was antagonized by the D1 agonist SKF 38393, but not by the D2 agonist quinpirole. The stimulatory effects of atypical antipsychotics on the activity of these hypothalamic dopamine neurons was mimicked by neurotensin and its analogue [D-Trp11]-neurotensin. Moreover, like typical antipsychotics, neurotensin and its analogue also increased serum concentrations of corticosterone. The production of an acute activation of tuberoinfundibular dopamine neurons, which is sensitive to D1 receptor activation and may be mediated by neurotensin, appears to be an effect that distinguishes typical and atypical antipsychotics.     

Gray and white matter changes and their relation to illness trajectory in first episode psychosis

Previous works have studied structural brain characteristics in first-episode psychosis (FEP), but few have focused on the relation between brain differences and illness trajectories. The aim of this study is to analyze gray and white matter changes in FEP patients and their relation with one-year clinical outcomes. A sample of 41 FEP patients and 41 healthy controls (HC), matched by age and educational level was scanned with a 3 T MRI during the first month of illness onset. One year later, patients were assigned to two illness trajectories (schizophrenia and non-schizophrenia). Voxel-based morphometry (VBM) was used for gray matter and Tract-based spatial statistics (TBSS) was used for white matter data analysis. VBM revealed significant and widespread bilateral gray matter density differences between FEP and HC groups in areas that included the right insular Cortex, the inferior frontal gyrus and orbito-frontal cortices, and segments of the occipital cortex. TBSS showed a significant lower fractional anisotropy (FA) in 8 clusters that included segments of the anterior thalamic radiation, the left body and forceps minor of corpus callosum, the right anterior segment of the inferior fronto-occipital fasciculus and the anterior segments of the cingulum. The sub-groups comparison revealed significant lower FA in the schizophrenia sub-group in two clusters: the anterior thalamic radiation and the anterior segment of left cingulum. These findings are coherent with previous morphology studies. The results suggest that gray and white matter abnormalities are present at early stages of the disease, and white matter differences may distinguish different illness prognosis.     

Effects of acute antipsychotic treatment on brain activation in first episode psychosis: an fMRI study.

This study aimed to assess the neurophysiological effects of acute atypical antipsychotic treatment on cognitive functioning in subjects presenting with a first episode of psychosis. We used functional MRI to examine the modulatory effects of acute psychopharmacological intervention on brain activation during four different cognitive tasks: overt verbal fluency, random movement generation, n-back and a spatial object memory task. Treatment with atypical antipsychotics was associated with alterations in regional activation during each task and also when task demands were manipulated within paradigms. The initial treatment of psychosis with atypical antipsychotics thus appears to be associated with modifications of the neurofunctional correlates of executive and mnemonic functions. These effects need to be considered when interpreting group differences in activation between medicated patients and controls.     

Effects of modafinil on cognitive functions in first episode psychosis

Rationale  

Cognitive impairments are important determinants of functional outcome in psychosis, which are inadequately treated by antipsychotic medication. Modafinil is a wake-promoting drug that has been shown to improve attention, memory and executive function in the healthy population and in patients with schizophrenia.     

Sex difference in effects of typical and atypical antipsychotics on glucose-insulin homeostasis and lipid metabolism in first-episode schizophrenia

OBJECTIVE: The present study was to investigate the sex difference in effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia. METHOD: One hundred twelve patients with schizophrenia were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index, waist-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol and triglyceride levels. All measures were collected at baseline and at the end of the 8-week treatment. RESULTS: After treatment, waist-hip ratio and triglyceride and IRI levels of men were increased higher than that of women in clozapine and olanzapine groups. In sulpiride group, body mass index and triglyceride, insulin, and IRI levels of women increased higher than those of men. There was no significant sex difference for all assessments in risperidone group. Insulin, C-peptide, and IRI, but not fasting glucose levels, were significantly increased in the 4 groups. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. CONCLUSIONS: These results suggest that clozapine, olanzapine, and sulpiride had effects on glucose and lipid metabolism in first-episode schizophrenia with sex difference. Clozapine and olanzapine seem to have the greatest potential to induce glucose and lipid metabolism abnormalities, and risperidone has the least.     

Disruption of conditioned reward association by typical and atypical antipsychotics

Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward-predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 µg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3-30 µg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward-predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward-predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia.     

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.     

Adverse effects of atypical antipsychotics in the elderly: a review

Use of antipsychotic medication is very common in the elderly and often an essential therapy. However, successful treatment in the elderly requires appropriate multidimensional assessment of the patient, knowledge of possible multiple co-morbidities, and awareness of the complexities of polypharmacy, age-dependent changes in pharmacokinetics and pharmacodynamics, and drug-drug interactions in this age group. Antipsychotics are known to have a number of adverse effects. New antipsychotics, such as amisulpride, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, zotepine and aripiprazole, may interact with both dopamine and serotonin receptors. However, compared with conventional antipsychotics, they are less likely to cause extrapyramidal symptoms and are better tolerated in the elderly. At the same time, consistent differences between atypical antipsychotics have been demonstrated. Use of clozapine, for example, is limited by the risk of agranulocytosis, whereas this is not a disadvantage of olanzapine, risperidone, quetiapine and, more recently, ziprasidone, which are being widely used with good results in schizophrenia. However, use of the latter agents to treat the behavioural and psychological symptoms of dementia has been restricted because of recent observations of increased cardiovascular events in patients taking risperidone and olanzapine treatment. Nonetheless, careful review of the literature suggests that the available evidence does not support any causal relationship between use of risperidone or olanzapine and cardiovascular events. This article focuses on some of the main adverse effects commonly reported during administration of atypical antipsychotics to elderly patients. Such effects may be partly explained by age-related changes in pharmacokinetics and pharmacodynamics, and partly by the characteristics of the drugs themselves and their different receptor binding profiles.     

Chlorpromazine as a discriminative stimulus in rats: Generalization to typical and atypical antipsychotics

The discriminative stimulus properties of the typical antipsychotic chlorpromazine were examined in a two‐lever drug discrimination procedure for food reward. Six of nine rats readily acquired the discrimination between 1.0 mg/kg chlorpromazine (i.p.) and vehicle in a mean of 29.7 training sessions. The chlorpromazine generalization curve was dose‐dependent and yielded an ED₅₀ of 0.305 mg/kg (95% confidence interval (CI) = 0.201–0.463 mg/kg). The chlorpromazine cue generalized to the atypical antipsychotics clozapine (ED₅₀ for the clozapine curve was 0.258 mg/kg [95% CI = 0.047–1.420 mg/kg]) and olanzapine (ED₅₀ for the olanzapine curve was 0.199 mg/kg [95% CI = 0.076–0.522 mg/kg]) and to the typical antipsychotic thioridazine (ED₅₀ for the thioridazine curve was 3.103 mg/kg [95% CI = 1.993–4.832 mg/kg]). Haloperidol (a typical antipsychotic) and raclopride (an atypical antipsychotic) did not substitute for chlorpromazine. It is clear from the present results that the discriminative stimulus properties of chlorpromazine share similarities both with the atypical antipsychotics clozapine and olanzapine and with the typical antipsychotic thioridazine. The extent to which the discriminative stimulus properties of antipsychotic drugs reflect or are predictive of their therapeutic effects in schizophrenic patients remains unclear. Drug Dev. Res. 48:38–44, 1999. © 1999 Wiley‐Liss, Inc.     

Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat.

Some atypical antipsychotic drugs appear to improve cognitive function in schizophrenia and since acetylcholine (ACh) is of importance in cognition, we used in vivo microdialysis to examine the effects of antipsychotics administered acutely (SC or IP) at pharmacologically comparable doses on ACh outflow in the hippocampus of the rat. The atypical antipsychotics olanzapine and clozapine produced robust increases in ACh up to 1500% and 500%, respectively. The neuroleptics haloperidol, thioridazine, and chlorpromazine, as well as the atypical antipsychotics risperidone and ziprasidone produced modest increases in ACh by about 50-100%. Since most atypical antipsychotics affect a variety of monoaminergic receptors, we examined whether selective ligands for some of these receptors affect hippocampal ACh. Antagonists for the 5-HT(2A) (MDL 100,907), the 5-HT(2C) (SB 242,084), the 5-HT(6) (Ro 04-6790), the D(2) (raclopride) receptors, and the alpha(1)-adrenoceptors (prazosin) modestly increased ACh by about 50%. The 5-HT(1A) agonist R-(+)-8-OH-DPAT and the alpha(2)-adrenoceptor antagonist yohimbine significantly increased ACh by about 100% and 50%, respectively. Thus, olanzapine and clozapine increased ACh to a greater extent than other tested antipsychotics, explaining perhaps their purported beneficial effect in cognitive function in schizophrenia. It appears that selective activity at each of the monoaminergic receptors studied is not the sole mechanism underlying the olanzapine and clozapine induced increases in hippocampal ACh.     

Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics.

In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic Bax, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of Bax and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (p<0.001), 40% higher with clozapine (p<0.05), and 48% higher with quetiapine (p<0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (p<0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects.     

Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects.

Although it is generally accepted that atypical antipsychotics differ in their risk for diabetic side effects, the underlying pharmacological mechanisms are unknown. Studies on the mechanisms of antipsychotic-induced hyperglycemia or insulin resistance are often confounded by the concomitant weight gain and dyslipidemia, known diabetic risk factors. To investigate whether antipsychotics can acutely cause metabolic effects before any change in body composition, we studied the effects of four atypical antipsychotics on whole-body insulin resistance. Using the hyperinsulinemic, euglycemic clamp technique in conscious rats, insulin and somatostatin were infused at a constant rate to provide constant hyperinsulinemia and to suppress pancreatic insulin secretion. Glucose was infused at a variable rate, adjusted to maintain euglycemia. At steady state, animals were administered vehicle (V) or antipsychotic and the glucose infusion rate was monitored as an index of insulin sensitivity. Clamp experiments using radiotracers and studies on glucose uptake into isolated skeletal muscle were conducted to differentiate between effects on hepatic glucose production (HGP) and on peripheral glucose uptake. Olanzapine (OLAN) and clozapine (CLOZ) acutely impaired whole-body insulin sensitivity in a dose-dependent manner (P<0.001 vs V), whereas ziprasidone and risperidone had no effect. CLOZ also induced profound insulin resistance after dosing 10 mg/kg/day for 5 days (P<0.05 vs V). Tracer studies indicated that acute changes mainly reflect increased HGP, consistent with the lack of effect on glucose uptake. OLAN and CLOZ can thus rapidly induce marked insulin resistance, which could contribute to the hyperglycemia and ketoacidosis reported for patients receiving those therapies.     

Adverse effects of atypical antipsychotics : differential risk and clinical implications

Antipsychotic drugs can be of great benefit in a range of psychiatric disorders, including schizophrenia and bipolar disorder, but all are associated with a wide range of potential adverse effects. These can impair quality of life, cause stigma, lead to poor adherence with medication, cause physical morbidity and, in extreme cases, be fatal. A comprehensive overview of tolerability requires a review of all available data, including randomised controlled trials (RCTs), observational studies and postmarketing surveillance studies. Assessing the relative tolerability of atypical antipsychotics is hampered by the paucity of RCTs that compare these drugs head-to-head, and limited and inconsistent reporting of adverse effect data that makes cross-study comparisons difficult.Despite methodological problems in assessment and interpretation of tolerability data, important differences exist between the atypical antipsychotics in the relative risk of acute extrapyramidal symptoms (highest risk: higher doses of risperidone), hyperglycaemia and dyslipidaemia (highest risk: clozapine and olanzapine), hyperprolactinaemia (highest risk: amisulpride and risperidone), prolongation of heart rate-corrected QT interval (QTc) [highest risk: ziprasidone and sertindole] and weight gain (highest risk: clozapine and olanzapine). Sedation, antimuscarinic symptoms, postural hypotension, agranulocytosis and seizures are more common with clozapine than with other atypical antipsychotics. The variation in their tolerability suggests that it is misleading to regard the atypical antipsychotics as a uniform drug class, and also means that the term 'atypical antipsychotic' has only limited usefulness. Differences between the atypical agents in terms of efficacy and pharmacodynamic profiles also support this view. As tolerability differs between specific conventional and atypical drugs, we conclude that broad statements comparing the relative risk of specific adverse effects between 'atypical' and 'conventional' antipsychotics are largely meaningless; rather, comparisons should be made between specific atypical and specific conventional drugs. Adverse effects are usually dose dependent and can be influenced by patient characteristics, including age and gender. These confounding factors should be considered in clinical practice and in the interpretation of research data. Selection of an antipsychotic should be on an individual patient basis. Patients should be involved in prescribing decisions and this should involve discussion about adverse effects.     

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.     

Effects of typical and atypical antipsychotics on the prepulse inhibition of the startle reflex in patients with schizophrenia

Patients with schizophrenia show a loss of sensory (motor) gating, which is reflected in a reduced prepulse inhibition (PPI) of the startle reflex. Furthermore, patients with schizophrenia habituate less than healthy subjects. From previous studies, it is clear that typical antipsychotics have little or no effect on either sensorimotor gating or habituation, while only limited data is available on the effects of atypical antipsychotics on these processes.Forty-four schizophrenic patients (27 stable on typical and 17 stable on atypical antipsychotics) and 35 healthy control subjects were tested in a PPI paradigm. The prepulse and startle stimuli were pure tones of 1500 Hz (duration 40 ms, intensity 80 dB and 110 dB respectively), with a fixed interstimulus interval of 120 milliseconds. Block effects in PPI and startle amplitude to the pulse alone trials (habituation) were analyzed over the three groups, using comedication (i.e., benzodiazepines) as a covariate.Main effect for block was found for startle amplitude (habituation), while main effects for group and block were found for percentage PPI. Further analysis displayed significant differences in PPI between the patients treated with typical antipsychotics and the healthy control group, while patients treated with atypical antipsychotics did not differ from either the healthy control group, or the patients treated with typical antipsychotics. Furthermore, post-hoc division of the patients treated with atypical antipsychotics in patients treated with clozapine and risperidone revealed that this superiority from atypical antipsychotics over typical antipsychotics appeared to be mainly based on the effects of clozapine.Patients with schizophrenia who are treated with atypical antipsychotics appear to have levels of sensorimotor gating that are more consistent with healthy controls than patients who are treated with typical antipsychotics. Furthermore, within the class of atypical antipsychotics, clozapine appears most potent in restoring this process.     

Clozapine versus typical antipsychotics a retro- and prospective study of extrapyramidal side effects

Schizophrenic patients in long-term neuroleptic monotherapy with clozapine (n=100) and perphenazine, flupenthixol or zuclopentixol (controls,n=100) were evaluated for extrapyramidal side effects (EPS) (blind) as well as other side effects and mental condition (non-blind). In both groups the patients had received neuroleptic treatment for a total of 14 years (median) and the present antipsychotic (clozapine or control drug) for 5 years. Thus the clozapine-treated patients had previously received traditional neuroleptics for 9 years (median). The study was both retrospective (0.3–19 years for clozapine, 0.3–24 years for control drug, by means of chart information) and prospective (1 year, with video-controlled evaluation of EPS). There was a significantly lower prevalence of tardive dyskinesia (TD) in clozapine treated patients than control patients, although prior to this treatment there were more TD patients in the clozapine group (P<0.05). This lower level of TD in the clozapine group was related to a lower induction of new cases (P<0.001) and a tendency towards greater disappearance of TD in the clozapine than in the control group (P=0.07). Clozapine treated patients without TD had started clozapine and ceased traditional neuroleptics at an earlier age than those with TD. Parkinsonian signs were seen in 33% of the clozapine patients versus 61% of the control patients, mainly as hypokinesia; tremor in 3% versus 11% and rigidity in 0 versus 19%. Psychic akathisia was found in 14% versus 40% and motor akathisia in 7% versus 29% of the patients, all differences significantly in favor of clozapine. Clozapine treated patients also had less neuroleptic-induced emotional indifference and depression, but more autonomic side effects than controls.     

Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial

The role of olanzapine in treatment-resistant schizophrenia is still unresolved. This article presents an open-label, prospective, 14-week trial with olanzapine in patients with schizophrenia and schizoaffective disorder selected for unambiguous resistance to either clozapine or risperidone and to typical antipsychotics. Forty-three inpatients (mean age, 41.6 years; mean duration of illness, 21.7 years) were enrolled and treated after cross-titration from their previous antipsychotic treatment with olanzapine 10 to 40 mg daily without any concomitant antipsychotic medication. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale, and the Extrapyramidal Symptom Rating Scale. The change with olanzapine treatment was associated with a PANSS total score improvement of 3.7 (SD = 15.6; not significant). There was a significant improvement for the PANSS cognitive and depression/anxiety factors, whereas the PANSS excitement factor worsened. The improvement rate was superior in patients receiving olanzapine doses higher than 20 mg. A total of 16.7% of patients reached response criteria set forth by a previous study. There was a significant decrease in extrapyramidal side effects (t = 2.04; p < 0.05) and statistically significant, yet modest, weight gain. These results indicate that olanzapine is only modestly effective in these severely treatment-resistant patients with schizophrenia. However, a trial with olanzapine can be recommended in these patients before moving to augmentation strategies, given the lack of proven alternatives and the observation that 16.7% of patients reached the response criteria.