Second-generation antipsychotic effect on cognition in patients with schizophrenia--a meta-analysis of randomized clinical trials.

OBJECTIVE: To investigate the effect of second-generation antipsychotics on cognitive function in patients diagnosed with schizophrenia or schizoaffective disorder. METHOD: Multiple-treatments meta-analysis model. RESULTS: On cognitive composite score, sertindole was superior to clozapine, effect size (ES) 0.87; 95% CI: 0.12-1.63, quetiapine, ES 0.75; 95% CI: 0.00-1.49, and first-generation antipsychotics (FGAs), ES 0.89; 95% CI: 0.14-1.64. Analyses on each cognitive domain showed clozapine, ES 0.37; 95% CI: 0.00-0.74, olanzapine, ES 0.31; 95%CI: 0.02-0.59, quetiapine, ES 0.34; 95% CI: 0.03-0.64, and FGAs, ES 0.51; 95% CI: 0.18-0.83 performing poorer on verbal working memory than ziprasidone, as well as FGAs performing poorer than risperidone, ES 0.31; 95% CI: 0.04-0.58. On executive function, sertindole performed better than clozapine, ES 0.82; 95% CI: 0.06-1.58, olanzapine, ES 0.81; 95% CI: 0.07-1.55, quetiapine, ES 0.76; 95% CI: 0.02-1.51, ziprasidone, ES 0.90; 95% CI: 0.14-1.67, and FGAs, ES 0.83; 95% CI: 0.08-1.58. On processing speed, FGAs performed poorer than sertindole, ES 0.97; 95% CI: 0.02-1.91, and quetiapine, ES 0.36; 95% CI: 0.01-0.72. On long-term verbal working memory, clozapine performed poorer than olanzapine, ES 0.41; 95% CI: 0.06-0.76. On verbal fluency, FGAs performed poorer than olanzapine, ES 0.26; 95% CI: 0.01-0.50, and clozapine, ES 0.44; 95% CI: 0.06-0.81. Lastly, FGAs, ES 0.41; 95% CI: 0.04-0.78, and clozapine, ES 0.44; 95% CI: 0.05-0.83, performed poorer on visuospatial skill compared to olanzapine. CONCLUSION: The meta-analysis was able to detect some trends in the data analyzed, but did not show any drug having a uniform positive cognitive profile.

Effects of sertindole on cognition in clozapine-treated schizophrenia patients.

OBJECTIVE: To assess the cognitive effects of sertindole augmentation in clozapine-treated patients diagnosed with schizophrenia. Cognition is secondary outcome of the trial. METHOD: A 12-week, double-blinded, randomized, placebo-controlled, augmentation study of patients treated with clozapine. Participants were randomized 1:1 to receive 16 mg of sertindole or placebo as adjunctive treatment to clozapine. RESULTS: Participants displayed substantial cognitive deficits, ranging from 1.6 standard deviation below norms at baseline to more than three standard deviations on tests of response readiness and focused attention. There were no significant differences between sertindole augmentation and placebo groups at study end. Correlation analysis of Positive and Negative Syndrome (PANSS) subscales, Global Assessment of Functioning subscale (GAF-F) and Clinical Global Impression (CGI) with 20 neurocognitive indices was conducted, but no significant correlations were found. Second, we tested change from baseline to endpoint for the PANSS, GAF-F, and CGI, vs. the concomitant changes in cognitive test performance, and found no significant correlations. CONCLUSION: The clozapine-treated patients displayed marked cognitive deficits at baseline. Adding sertindole did not improve or worsen cognitive functioning, which is in line with previous negative studies of the effect on cognition of augmenting clozapine treatment with another antipsychotic drug.

Skin conductance habituation and cerebrospinal fluid 5-hydroxyindoleacetic acid in suicidal patients.

The concentration of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and psychophysiologic variables, such as habituation of the skin conductance response, were measured in 35 drug-free, suicidal inpatients. Twenty-four patients were hospitalized after a suicide attempt, and another 11 had suicidal ideation. The suicide attempters were classified into nonviolent (drug overdoses taken orally, or a single wrist cut) and violent (all other methods). As in previous studies, the suicide attempters had significantly lower CSF concentrations of 5-HIAA compared with healthy, matched controls. The distribution of habituation rate was bimodal (slow and fast habituators). All violent attempters were fast habituators, as were all four patients who in a one-year follow-up were found to have completed a suicide (all by violent methods). The lowest frequency of fast habituators was found in the group of patients with suicidal ideation. There was no correlation between CSF 5-HIAA and habituation rate. A combination of these two variables yielded a highly significant correlation with type of suicide behavior, both retrospectively and prospectively.

Smooth pursuit eye movements, clinical symptoms, CSF metabolites, and skin conductance habituation in schizophrenic patients.

Smooth pursuit eye movements (SPEM) for two stimulus velocities (sinusoidal and triangular) were studied by visual inspection in 12 unmedicated RDC-diagnosed schizophrenic patients and in 13 matched controls. SPEM was worse in the patient group and their performance deteriorated with repeated presentations of the task. Patients with previous antipsychotic medication, previous hospitalization, higher age, late onset of manifest psychotic symptoms, and few positive psychotic symptoms had worse SPEM according to the Comprehensive Psychopathological Rating Scale. Subjects with poor SPEM showed slower habituation of skin conductance responses. There were no correlations between SPEM ratings and levels of CSF monoamine metabolites HVA, 5-HIAA, and MHPG.

New insights into the second generation antihistamines.

Second generation antihistamines are recognised as being highly effective treatments for allergy-based disease and are among the most frequently prescribed and safest drugs in the world. However, consideration of the therapeutic index or the benefit/risk ratio of the H1 receptor antagonists is of paramount importance when prescribing this class of compounds as they are used to treat non-life threatening conditions. There are many second generation antihistamines available and at first examination these appear to be comparable in terms of safety and efficacy. However, the newer antihistamines in fact represent a heterogeneous group of compounds, having markedly differing chemical structures, adverse effects, half-life, tissue distribution and metabolism, spectrum of antihistaminic properties, and varying degrees of anti-inflammatory effects. With regard to the latter, there is growing awareness that some of these compounds might represent useful adjunct medications in asthma therapy. In terms of safety issues, the current second generation grouping includes compounds with proven cardiotoxic effects and others with the potential for adverse drug interactions. Moreover, some of the second generation H1 antagonists have given cause for concern regarding their potential to cause a degree of somnolence in some individuals. It can be argued, therefore, that the present second generation grouping is too large and indistinct since this was based primarily on the concept of separating the first generation sedating compounds from nonsedating H1 antagonists. Although it is too early to talk about a third generation grouping of antihistamines, future membership of such a classification could be based on a low volume of distribution coupled with a lack of sedating effects, drug interactions and cardiotoxicity.

Clonazepam and imipramine in the treatment of panic attacks: a double-blind comparison of efficacy and side effects.

Data from 12 patients (in two control study groups) provide preliminary results of an ongoing double-blind comparison of clonazepam and imipramine in the treatment of panic disorder. In both treatment groups, the patients' global improvement was substantial over the first few weeks and persisted over the 6-month treatment period based on assessments by the therapist and the patient; side effects were mild. Faintness was slightly more prevalent among patients on clonazepam treatment but disappeared after the first few weeks. Mild, persistent tachycardia was reported among patients receiving imipramine. No tolerance emerged, and discontinuation was successful in 2 patients from each group after 6 months of treatment. Eight patients needed continued medication (25-50 mg/day of imipramine, 0.5-2.0 mg/day of clonazepam) to maintain substantial improvement. Findings confirm earlier reports from open studies that low doses of both drugs eliminate panic attacks (about 50 mg/day for imipramine and 1.5 mg/day for clonazepam).

Smoking and vigilance. The effects of tobacco smoking on CFF as related to personality and smoking habits.

The effects of tobacco smoking on vigilance (Critical Flicker Fusion, CFF) measured by a computerized forced-choice interactive technique, was studied in a group of 28 male moderate smokers. Subjects participated in a Smoking (S) and a Non-Smoking (NS) condition each of 1 h duration. CFF performance was measured during fifteen 2-min trials in each condition. In the S condition subjects smoked three puffs during each of five pauses between five successive trials. Vigilance was significantly improved by smoking. An initial sharp increase in CFF performance was noticed with a maximum 8 min after the first puff. Performance was significantly higher in the S condition compared to the NS condition up to 20 min after the last puff. Two extreme groups, based on differences in CFF performance between the S and NS condition were compared by questionnaires on personality and smoking habits. The most improved group had significantly higher scores in an extraversion scale. Ratings of the effect of smoking on level of alertness indicated that the objective effect of increased vigilance had no counterpart on the subjective level.

Metipranolol and propranolol: no CNS effects of a single oral dose.

Effects of single oral doses of the beta-blocking drugs propranolol (40 mg) and metipranolol (Disorat, Boehringer, Mannheim, FRG, 5 and 20 mg), in comparison with placebo, on mental performance and psychophysiological measures were investigated in a double-blind crossover study comprising 12 healthy volunteers. Effects were evaluated using a battery of highly reliable and sensitive computerized indices of mental performance and a comprehensive range of psychophysiological measures. Propranolol and metipranolol had no effects on mental performance, in contrast to findings in a previous study for bunitrolol (Stresson, Boehringer, Ingelheim, FRG). There were marked effects on some autonomic functions; dose-dependent for heart rate and heart rate response, and dose-independent for blood pressure and finger tremor. In the previous study bunitrolol had no effect on tremor and blood pressure and a less marked effect on heart rate. The lack of psychotropic effects for metipranolol and propranolol as compared to bunitrolol cannot be predicted from pharmacokinetic properties or peripheral effects of the three drugs, arguing for the need for systematic screening using psychometric and psychophysiological methods of current and new beta-blocking drugs. A comparison between the effect of propranolol given in a single oral dose and findings in a previous study with repeated administration suggested that the differences in effect profile between acute and chronic administration of the drug are small.

Smoking, pain tolerance, and physiological activation.

The effects of tobacco smoking and beta-blockade on psychophysiological measures, i.e., heart rate (HR), blood pressure (BP), skin conductance (SC), and sensitivity to electrical pain stimulation was studied in a group of 33 male moderate smokers. Using a method of limits threshold determination technique, measures of pain threshold (PT), and tolerance level (TL) were obtained. The results were analyzed in relation to smoking habits, personality measures, and subjective effects. There was no significant effect of smoking on pain sensitivity. Smoking caused a physiological activation as indicated by an increase in HR and systolic BP. beta-Blockade counteracted the smoking-induced increase in HR and systolic BP, but did not influence PT or TL. Subjective effects of smoking were not affected by beta-blockade. The findings suggest that physiological activation is not related to effects of smoking on pain.

Birth stress, handedness and cognitive performance.

Information regarding conditions during pregnancy and delivery was obtained by extensive interviews with mothers to left-handed and right-handed students. Using the same criterion as van Strien, Bouma and Bakker (1987) for defining birth stress, the present study did not replicate their findings of higher frequency of reported birth stress in left-handers. The difference in outcome was ascribed to differences in recruitment of subjects, the present sample constituting a majority of left hand writers from a population of 921 students, while the van Strien sample was less well defined. The present study was extended by comparing left-handed and right-handed subjects (separated for sex) with and without birth stress, on verbal and nonverbal abilities, and on eye dominance, early learning difficulties and familial sinistrality. Left eye dominance was more frequent in male left-handers with birth stress. Birth stress alone had negative effects on cognitive performance, different for males and females.

Neuropsychological correlates of platelet monoamine oxidase (MAO) activity in female and male subjects.

Platelet monoamine oxidase (MAO) activity has been found to have behavioral (psychiatric and personality) correlates and is assumed to be linked to central transmitter systems and thus presumably to neuropsychological processes. In the present study, computerized neuropsychological tests, a reaction time (RT) test and a visuo-spatial problem solving test, the Perceptual Maze Test (PMT), were given to 32 female and 29 male students, each sex group divided into three subgroups on the basis of platelet MAO activity. The tests yield measures of laterality (reaction time for left- versus right-sided stimuli) and different aspects of cognitive strategy and skill, e.g. time used for inspection of the maze, for processing the stimulus pattern, and for checking the correctness of solutions. Low MAO female subjects had shorter RTs, pronounced for left-sided stimuli, and shorter inspection times in the PMT compared to other female subjects. Low and high MAO males had difficulties in inhibiting responses, when required, and low MAO males were more rapidly prepared to respond to new stimuli after short intervals than other males. In the PMT, high MAO male subjects spent a smaller part of the total time on inspection in relation to other male groups and had more rubouts than low MAO males, whose maze solving behavior indicated higher visuo-spatial ability. The results are discussed in terms of possible neurochemical bases of impulsivity and psychopathy, and of spatial skill.

Bilateral skin conductance activity, clinical symptoms and CSF monoamine metabolite levels in unmedicated schizophrenics, differing in rate of habituation.

Bilateral skin conductance (SC) and heart rate (HR) were recorded for 18 RDC-diagnosed unmedicated recently admitted psychotic patients (13 schizophrenic and 5 paranoid) and for age- and sex-matched controls, during rest and tone stimulation (85 dBA, 1000 Hz, 1 sec duration and 0.25 msec rise time). Schizophrenics had more SC spontaneous fluctuations and faster HR, indicating higher arousal. SC spontaneous fluctuations were more frequent in left hand and showed an increasing trend over the session. Several SC measures indicated higher responsivity and a more irregular responding pattern in schizophrenics. These patients had higher levels of the noradrenaline metabolite (MHPG). Paranoid psychotic patients had a more stable SC habituation course than controls, and higher levels of the dopamine (HVA) and serotonin metabolites (5-HIAA). Schizophrenic nonhabituators had fewer positive psychotic symptoms than habituators, suggesting that poor habituation is not due to interference by symptoms. It may be related to higher arousal, or to deficient information processing.

Smooth pursuit eye tracking, neuropsychological test performance, and computed tomography in schizophrenia.

Smooth pursuit eye movements (SPEM) were measured in 18 patients who met Research Diagnostic Criteria for schizophrenia. Some degree of SPEM impairment was present in most patients. Deviant eye tracking was not related to ratings of severity of illness, but was related to recurrent episodes of hospitalization, antipsychotic medication, and lower ratings in anxiety and delusions. Worse SPEM tended to be associated with larger lateral ventricles as assessed on computed tomography. Three patients with reversed occipital asymmetry had more deviant eye tracking than the remaining patients. Eye movement impairment was related to worse performance in Finger Tapping and in the Trail-Making Test, and to fewer perceived alternations of a Necker cube, suggesting that frontoparietal disturbances are related to poor pursuit eye tracking in schizophrenia.

Dopamine D2-receptor density in humans as assessed with SPET and the new high-affinity ligand 123I-NCQ298: a pilot study.

Astra (S)-3-[123I]iodo-5,6-dimethoxyl-N-[(1-ethyl-2-pyrrolidinyl)methyl] -salicylamide (123I-NCQ298) is a new high-affinity D2-receptor ligand for use in single photon emission tomography (SPET) studies. We have studied the biodistribution and absorbed radiation dose of 123I-NCQ298 in humans. The mean effective dose for adults was 0.055 mSv MBq(-1). Brain uptake and clearance was measured with a head dedicated SPET camera. 123I-NCQ298 showed specific uptake in the basal ganglia with a low clearance rate (time constant of 9-34 h). The extrastriatal binding was variable (average 30%, maximum 60% of that in the basal ganglia at 1 h), but with a clearance rate twice that of the basal ganglia. The fairly high level of extrastriatal binding precluded the use of a quotient between the basal ganglia and cerebellum-to-frontal cortex 123I-NCQ298 concentration as a measure for basal ganglia D2-receptor density. Chronic schizophrenic patients treated with conventional neuroleptics had a decreased affinity for 123I-NCQ298 in the basal ganglia in the range 10-60% of the median value for the control, untreated subjects.

Temperament traits in male suicide attempters and violent offenders.

With the purpose of comparing temperament traits in subjects who have been violent towards others and with subjects who have shown self-directed violence, 34 male suicide attempters and 34 male violent offenders were matched for age and psychiatric diagnosis. Violent offenders with a history of suicide attempts were excluded. Temperament traits were assessed by means of the Karolinska Scales of Personality. The temperament profiles of suicide attempters and violent offenders were very similar, with high trait anxiety and very low socialization. Violent offenders displayed significantly higher social desirability (P < 0.001). Suicide attempters tended to have higher indirect aggression and monotony avoidance. Impulsiveness, verbal aggression, and inhibition of aggression were within the normal range in both groups. There were substantial temperamental similarities between suicide attempters and violent offenders. In order to disentangle the differential mechanisms behind aggression towards self and others, we probably need to consider historical as well as current situation factors in a systematic way.

Sandra: successful psychotherapeutic work with a schizophrenic woman.

This presentation concerns a young woman who gradually developed a schizophrenic picture on the basis of a borderline personality, and who recovered after more than 20 years of incapacitating symptoms. Today she sees her psychotherapy as decisive for the outcome. The material was collected from case records as well as from interviews with the patient and her therapist. Special emphasis is laid on the attitude and working methods of the therapist as these were viewed retrospectively by the two participants in the therapeutic process.

Interventions in the nurse-patient relationship in forensic psychiatric nursing care: a Swedish survey.

Nurses (Registered nurses, RN, and Licensed Mental Nurses, LMN) working in five Swedish forensic psychiatric units filled in a questionnaire designed for general psychiatric nursing, but modified for forensic use. In this report, data concerning the extent to which treatment interventions included verbal elements, and the focus of these nurse--patient verbal interactions, were analysed. The most commonly used interventions were 'social interaction', 'regular communication' and 'social skills training'. The most common focus in verbal nurse--patient interaction were 'explaining consequences, confronting and encouraging the patient to talk about his/her crime/behaviour', 'interpretative communications with the patient', and 'communication about functions in daily life'. The salient findings were: (1) seven of the fifteen interventions used by the nurses included verbal elements to a great extent; (2) nurses often used confronting interventions, despite the fact that the large EE (expressed emotion) literature suggest that hostility and critical remarks may provoke a worsening of symptoms among psychotic patients; (3) there was only little correspondence between actual practice and theoretical models; and (4) there were unexpectedly small differences between the two professional groups (RN and LMN), suggesting that the roles are not distinct.

Attention deficit hyperactivity disorder, reading disability, and personality disorders in a prison population.

Attention Deficit Hyperactivity Disorder (ADHD) has long been recognized in children, and for many the disorder persists into adulthood. There is a growing concern that the adults with ADHD who have the least favorable outcome, are among those who end up in prison. The aim of this study was to assess childhood ADHD and its persistence into adulthood among a representative sample of Norwegian prison inmates, as well as personality disorders and reading difficulties, which in previous studies have been linked to ADHD. The results indicate that persistent ADHD is very common among prison inmates. Personality disorders and reading difficulties are also common. Psychiatric comorbidity complicates the diagnosis of ADHD in adults. A greater awareness about ADHD in adults certainly is warranted, especially within the prison system because of the risk of misdiagnosing psychiatric disorders and also the risk of missing a condition possibly amenable to treatment.

Regional cortical dysfunction in schizophrenic patients studied by computerized neuropsychological methods.

18 RDC-diagnosed schizophrenic patients (11 men, 7 women) were compared to 84 normal men with three computerized neuropsychological methods, assumed to reflect lateralized and frontal cortical functions: (1) Bilateral Finger Tapping and Finger Alternation, (2) Bilateral Trail Making, and (3) passively perceived Necker cube reversals. Schizophrenics differed from normals by (1) inferior Tapping/Alternation but only in the right hand, (2) inferior Trail Making, most pronounced for Form B, and (3) lower frequency of Necker cube reversals. Patients with previous neuroleptic medication and prior psychiatric hospitalizations were inferior in Trail Making and had fewer Necker cube reversals. The findings were interpreted in line with recent models of schizophrenia involving a left-hemisphere dysfunction/over-activation and a frontal dysfunction.

Cognitive sex differences: speed and problem-solving strategies on computerized neuropsychological tasks.

Skill, strategy, and laterality measures obtained through computerized neuropsychological tasks, a reaction time (RT) test, and a visuospatial problem-solving test, the Perceptual Maze Test, were analyzed in relation to sex and handedness of 56 high-school students. Boys were significantly faster than girls on most RT subtasks (including a response-inhibition task) and made more two-choice RT response errors for right-sided stimuli, which may be interpreted as resulting from a less cautious strategy. In maze performance, boys were superior to girls. An analysis of separate phases of the maze-solution process suggested that boys preferentially used an impulsive-global strategy. Girls, using a more reflective-sequential task-solving strategy, were significantly slower, without hitting more targets. Compared to all other groups, left-handed girls (strongly left-handed) had lower performance on maze tasks with no target information, particularly in left-sided solution pathways. Results were interpreted as reflecting differences in hemispheric competence and activation patterns between the sexes. Signs of a less differentiated lateralization and slight dysfunction of visuospatial skills in the left-handed girls were discussed.