Jari Tiihonen

11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)

BACKGROUNDnThe introduction of second-generation antipsychotic drugs during the 1990s is widely believed to have adversely affected mortality of patients with schizophrenia. Our aim was to establish the long-term contribution of antipsychotic drugs to mortality in such patients.nnnMETHODSnNationwide registers in Finland were used to compare the cause-specific mortality in 66 881 patients versus the total population (5.2 million) between 1996, and 2006, and to link these data with the use of antipsychotic drugs. We measured the all-cause mortality of patients with schizophrenia in outpatient care during current and cumulative exposure to any antipsychotic drug versus no use of these drugs, and exposure to the six most frequently used antipsychotic drugs compared with perphenazine use.nnnFINDINGSnAlthough the proportional use of second-generation antipsychotic drugs rose from 13% to 64% during follow-up, the gap in life expectancy between patients with schizophrenia and the general population did not widen between 1996 (25 years), and 2006 (22.5 years). Compared with current use of perphenazine, the highest risk for overall mortality was recorded for quetiapine (adjusted hazard ratio [HR] 1.41, 95% CI 1.09-1.82), and the lowest risk for clozapine (0.74, 0.60-0.91; p=0.0045 for the difference between clozapine vs perphenazine, and p<0.0001 for all other antipsychotic drugs). Long-term cumulative exposure (7-11 years) to any antipsychotic treatment was associated with lower mortality than was no drug use (0.81, 0.77-0.84). In patients with one or more filled prescription for an antipsychotic drug, an inverse relation between mortality and duration of cumulative use was noted (HR for trend per exposure year 0.991; 0.985-0.997).nnnINTERPRETATIONnLong-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use. Second-generation drugs are a highly heterogeneous group, and clozapine seems to be associated with a substantially lower mortality than any other antipsychotics. Restrictions on the use of clozapine should be reassessed.nnnFUNDINGnAnnual EVO Financing (Special government subsidies from the Ministry of Health and Welfare, Finland).

Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study

Abstract Objective To study the association between prescribed antipsychotic drugs and outcome in schizophrenia or schizoaffective disorder in the community. Design Prospective cohort study using national central registers. Setting Community care in Finland. Participants Nationwide cohort of 2230 consecutive adults hospitalised in Finland for the first time because of schizophrenia or schizoaffective disorder, January 1995 to December 2001. Main outcome measures Rates of discontinuation of drugs (all causes), rates of rehospitalisation, and mortality associated with monotherapy with the 10 most commonly used antipsychotic drugs. Multivariate models and propensity score methods were used to adjust estimates of effectiveness. Results Initial use of clozapine (adjusted relative risk 0.17, 95% confidence interval 0.10 to 0.29), perphenazine depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to 0.71), and clozapine (0.64, 0.48 to 0.85) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3, 6.0 to 24.1) and the risk of suicide was high (37.4, 5.1 to 276). Conclusions The effectiveness of first and second generation antipsychotics varies greatly in the community. Patients treated with perphenazine depot, clozapine, or olanzapine have a substantially lower risk of rehospitalisation or discontinuation (for any reason) of their initial treatment than do patients treated with haloperidol. Excess mortality is seen mostly in patients not using antipsychotic drugs.

Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis

OBJECTIVEnTo evaluate the efficacy of glutamatergic drugs, acting agonistically on the N-methyl-D-aspartate (NMDA) or the non-NMDA receptors, in schizophrenia.nnnMETHODnAll relevant randomized controlled trials of glutamatergic drugs for schizophrenia were obtained from the Cochrane Schizophrenia Groups Register of Trials without any language or year limitations. Trials were classified according to their methodological quality. For binary and continuous data, relative risks and weighted (WMD) or standardized mean differences (SMD) were calculated, respectively.nnnRESULTSnEighteen short-term trials with 343 randomized patients were included in the meta-analysis. In all of these trials, glycine, D-serine, D-cycloserine or ampakine CX516 was used to augment antipsychotics. NMDA receptor co-agonists glycine and D-serine are effective in reducing negative symptoms (N = 132, fixed effect model SMD = -0.66, 95% CI -1.02 to -0.29, p = 0.0004) of schizophrenia, the magnitude of the effect is moderate. D-Cycloserine, a partial agonist of NMDA receptors, is less effective towards negative symptoms (N = 119, fixed effect model SMD = -0.11, 95% CI -0.48 to 0.25, p = 0.6). Positive symptoms fail to respond to glutamatergic medication. Available derived data on cognitive functioning do not indicate a significant effect of glycine or D-serine (N = 80, random effect model WMD = -2.79, 95% CI -6.17 to 0.60, p = 0.11).nnnCONCLUSIONSnIn the current limited data set, a moderate amelioration of negative symptoms of schizophrenia was found, but no other statistically significant beneficial effects on symptoms of schizophrenia.

Lamotrigine in treatment-resistant schizophrenia: A randomized placebo-controlled crossover trial

BACKGROUNDnThere is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine.nnnMETHODSnThirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period.nnnRESULTSnIn intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms.nnnCONCLUSIONSnThese results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia.

Polypharmacy With Antipsychotics, Antidepressants, or Benzodiazepines and Mortality in Schizophrenia

CONTEXTnPolypharmacy is widely used in the treatment of schizophrenia, although it is believed to have major adverse effects on the well-being of patients.nnnOBJECTIVEnTo investigate if the use of benzodiazepines, antidepressants, or multiple concomitant antipsychotics is associated with increased mortality among patients with schizophrenia.nnnDESIGNnRegistry-based case linkage study.nnnSETTINGnAcademic research.nnnPATIENTSnWe linked national databases of mortality and medication prescriptions among a complete nationwide cohort of 2588 patients hospitalized in Finland for the first time with a diagnosis of schizophrenia between January 1, 2000, and December 31, 2007.nnnMAIN OUTCOME MEASURESnHazard ratios (HRs) were computed for all-cause mortality during the use of antipsychotics, antidepressants, or benzodiazepines in outpatient care, adjusting for the effects of sociodemographic and clinical variables, geographic location, and current and past pharmacological treatments.nnnRESULTSnCompared with antipsychotic monotherapy, concomitant use of 2 or more antipsychotics was not associated with increased mortality (HR, 0.86; 95% CI, 0.51-1.44). Similarly, antidepressant use was not associated with a higher risk for mortality (HR, 0.57; 95% CI, 0.28-1.16) and was associated with markedly decreased suicide deaths (HR, 0.15; 95% CI, 0.03-0.77). However, benzodiazepine use was associated with a substantial increase in mortality (HR, 1.91; 95% CI, 1.13-3.22), and this was attributable to suicidal deaths (HR, 3.83; 95% CI, 1.45-10.12) and to nonsuicidal deaths (HR, 1.60; 95% CI, 0.86-2.97). In total, 826 of 904 patients (91.4%) who used benzodiazepines had purchased prescriptions that contained more than 28 defined daily doses, violating treatment guidelines.nnnCONCLUSIONSnBenzodiazepine use was associated with a marked increase in mortality among patients with schizophrenia, whereas the use of an antidepressant or several concomitant antipsychotics was not. Antidepressant use was associated with decreased suicide deaths. The literature indicates that long-term use of benzodiazepines among patients with schizophrenia is more prevalent in other countries (eg, the United States) compared with Finland, which suggests that benzodiazepine use may contribute to mortality among this patient population worldwide.

Prefrontal volumes in habitually violent subjects with antisocial personality disorder and type 2 alcoholism

Pathology of the prefrontal cortices has been suggested to be a part of neural networks underlying deviant behavioral patterns. Recently, reduced overall prefrontal cortical volumes have been proposed in subjects with antisocial personality disorder (ASP). It is not known whether there are specific patterns of volume loss within the prefrontal regions. Nor is it known if there are correlations between the prefrontal volumes and degree of psychopathology. In this study, total prefrontal, prefrontal white, and cortical (dorsolateral, orbitofrontal, medial frontal) prefrontal volumes were measured from magnetic resonance images in 24 non-psychotic, violent male subjects who had a diagnosis of ASP in combination with type 2 alcoholism, and 33 age-matched control males. The degree of psychopathy in the ASP subjects was assessed using the Psychopathy Checklist-Revised (PCL-R). Compared with the controls, the ASP subjects had significantly smaller volumes of all three cortical regions on the left, but this significance disappeared after controlling for differences in education and duration of alcoholism. For the dorsolateral and orbitofrontal cortices, only duration of alcoholism was significantly associated with the observed volume deficit, and for the medial frontal cortex it was the difference in education. Thus, the observed volume deficits in this sample were related more to alcoholism or differences in education rather than to the diagnosis of ASP. Moreover, no significant correlations between any of the volumes and the degree of psychopathy were found.

A volumetric MRI study of the entorhinal cortex in first episode neuroleptic-naive schizophrenia

BACKGROUNDnImaging studies have frequently reported volume loss of limbic structures in schizophrenia, yet there appears to be no quantitative data on entorhinal cortex volumes in patients with neuroleptic naive first-episode schizophrenia.nnnMETHODSnThe volume of the entorhinal cortices of 22 control subjects and 18 patients with neuroleptic-naïve first-episode schizophrenia were measured from magnetic resonance images (MRI) scans using recently designed anatomic criteria for MRI anatomy of the entorhinal cortex.nnnRESULTSnSmaller entorhinal volumes were found bilaterally in the schizophrenic patients. This volume loss did not correlate with items on the Positive and Negative Syndrome Scale.nnnCONCLUSIONSnThese data suggest early involvement of the entorhinal cortex in schizophrenia.

The amygdala and schizophrenia: a volumetric magnetic resonance imaging study in first-episode, neuroleptic-naive patients

BACKGROUNDnThe attempts to evaluate amygdaloid volumes using magnetic resonance imaging (MRI) in patients with schizophrenia have yielded highly divergent results.nnnMETHODSnVolumes of the amygdala were measured in 22 healthy participants and 18 neuroleptic-naive patients with first-episode schizophrenia, while controlling for intracranial area, gender, age, and handedness.nnnRESULTSnPersons with schizophrenia presented significantly lower amygdaloid volumes bilaterally. No significant correlations were found between the amygdaloid volumes and either the duration of the disease or the symptom severity.nnnCONCLUSIONSnAmygdaloid volume anomalies are already present in the early phases of schizophrenia.

Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: A double-blind, randomized, placebo- controlled trial

BACKGROUNDnMirtazapine, an antidepressant with a broad spectrum of receptor affinity may, if combined with first generation antipsyhotics (FGAs), improve clinical profile of the FGAs. However, potentiation of the antipsychotic effect by mirtazapine has not been reported thus far. We explored the efficacy of adjunctive mirtazapine on symptoms of schizophrenia in patients having an insufficient response to different FGAs.nnnMETHODSnSchizophrenia-diagnosed patients with a prolonged disease and a history of a poor response to numerous antipsychotics, who were at least moderately ill despite their FGAs treatment, received add-on mirtazapine (n=20) or placebo (n=19) in a 6-week double-blind randomized controlled trial (RCT). The analysis was made on a Modified Intent-to-Treat (MITT) basis with Last Observations Carried Forward (LOCF).nnnRESULTSnMirtazapine outranged placebo on almost all measures. The clear-cut clinical relevance of this finding was demonstrated by a large effect size of 1.00 (95% CI 0.23-1.67, p=0.003) on the total Positive and Negative Syndrome Scale (PANSS) scores (the primary outcome). The PANSS positive subscale scores decreased by 17.2% with mirtazapine vs. 1.6% with placebo (p<0.001), and the PANSS negative subscale scores by 12% and 3% (p<0.001), correspondingly.nnnCONCLUSIONSnThis is the first RCT reporting a robust additive antipsychotic effect of an adjunctive antidepressant. Mirtazapine-FGAs combination appears to be a safe, well-tolerated and efficacious treatment option in this challenging population. These findings are important due to the current re-emerging attention to FGAs. The focus of further studies should be expanded to include combinations with or switching to novel antipsychotics, different subpopulations of patients with schizophrenia, finding of optimal doses, and comparison with clozapine.

Premorbid Personality Factors in Schizophrenia and Bipolar Disorder: Results From a Large Cohort Study of Male Conscripts

The present study explored the premorbid personality traits Neuroticism, Extraversion, and Disinhibition in individuals later diagnosed with psychotic disorders. Results on personality questionnaires and intellectual performance tests were obtained for 213,443 apparently healthy male subjects (mean age: 20.1 years) conscripted into the Finnish Defence Forces during the period 1982-1987. Linkage with the Finnish Hospital Discharge Register (mean follow-up time: 14.1 years, SD = 1.7) identified conscripts later diagnosed with schizophrenia (N = 1,328), bipolar disorder (N = 98), or other psychoses (N = 456). Both before and after controlling for intellectual performance, high Neuroticism predicted future onset of schizophrenia and other psychoses, and high Extraversion predicted future onset of bipolar disorder. The data of the present research showed for the 1st time that premorbid personality traits predict heightened risk for psychotic disorders beyond intellectual performance and also showed for the 1st time an association between premorbid Extraversion and bipolar disorder.