Björn M. Nilsson

Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33 000 women from the general population

BackgroundLow intake of fish, polyunsaturated fatty acids (PUFA) and vitamin D deficiency has been suggested to play a role in the development of schizophrenia. Our aim was to evaluate the association between the intake of different fish species, PUFA and vitamin D and the prevalence of psychotic-like symptoms in a population-based study among Swedish women.MethodsDietary intake was estimated using a food frequency questionnaire among 33 623 women aged 30-49 years at enrolment (1991/92). Information on psychotic-like symptoms was derived from a follow-up questionnaire in the years 2002/03. Participants were classified into three predefined levels: low, middle and high frequency of symptoms. The association between diet and psychotic-like symptoms was summarized in terms of relative risks (RR) and corresponding 95% confidence intervals and was evaluated by energy-adjusted multinomial logistic regression.Results18 411 women were classified as having a low level of psychotic-like symptoms, 14 395 as middle and 817 as having a high level. The risk of high level symptoms was 53% (95% CI, 30-69%) lower among women who ate fish 3-4 times per week compared to women who never ate fish. The risk was also lower for women with a high intake of omega-3 and omega-6 PUFA compared to women with a lower intake of these fatty acids. The effect was most pronounced for omega-6 PUFAs. The RR comparing the highest to the lowest quartile of omega-6 PUFAs intake was 0.78 (95% CI, 0.64-0.97). The associations were J-shaped with the strongest reduced risk for an intermediate intake of fish or PUFA. For fatty fish (herring/mackerel, salmon-type fish), the strongest inverse association was found for an intermediate intake (RR: 0.81, 95% CI, 0.66-0.98), whereas a high intake of fatty fish was associated with an increased risk of psychotic-like symptoms (RR: 1.90, 95% CI, 1.34-2.70). Women in the highest compared with the lowest quartile of vitamin D consumption experienced a 37% (95% CI, 22-50%) lower risk of psychotic-like symptoms.ConclusionOur findings raise a possibility that adult women with a high intake of fish, omega-3 or omega-6 PUFA and vitamin D have a lower rate of psychotic-like symptoms.

The design and pharmacology of novel selective muscarinic agonists and antagonists

The muscarinic pharmacology of C1-methyl-substituted chiral compounds related to McN-A-343 and of (R)- and (S)-dimethindene has been studied. Among the McN-A-343 analogues, the (S)-enantiomers were more potent and had higher affinity than the (R)-isomers. The quaternary compound (S)-BN 228 was found to be the most potent M1-selective agonist known today (pEC50: M1/rabbit vas deferens = 7.83; M2/guinea-pig atria = 6.35; M3/guinea-pig ileum = 6.29). In both the atria and ileum the tertiary carbamate, (S)-4-F-MePyMcN, was a competitive antagonist (pA2 value = 7.39 and 6.82, respectively). In contrast, in rabbit vas deferens (S)-4-F-MePyMcN was a potent partial agonist (pEC50 = 7.22; apparent efficacy = 0.83). These results indicate that (S)-4-F-MePyMcN might be a useful tool to study M1 receptor-mediated effects involved in central cholinergic function. (S)-Dimethindene was a potent M2-selective antagonist (pA2 = 7.86/atria; pKi = 7.8/rat heart) with lower affinities for the M1 (pA2 = 6.36/rat duodenum; pKi = 7.1/NB-OK 1 cells), M3 (pA2 = 6.92/guinea-pig ileum; pKi = 6.7/rat pancreas) and M4 receptors (pKi = 7.0/rat striatum). It was more potent (up to 41-fold) than the (R)-isomer. In contrast, the stereoselectivity was inverse at ileal H1 receptors (pA2: (R)-isomer = 9.42; (S)-isomer = 7.48). Thus, (S)-dimethindene could be a valuable agent to test the hypothesis that M2 antagonists show beneficial effects in the treatment of cognitive disorders. It might also become the starting point for the development of diagnostic tools for quantifying M2 receptors in the CNS with PET imaging.

Cognition and autonomic function in schizophrenia : Inferior cognitive test performance in electrodermal and niacin skin flush non-responders

BACKGROUND Patients with schizophrenia suffer from a broad range of cognitive disturbances. The impact in terms of functional outcome is significant. There are also several reports of disturbed autonomic regulation in the disease. The present study examined cognitive function as well as psychophysiological parameters in patients with schizophrenia and healthy controls. METHODS Twenty-five patients and 14 controls were investigated with electrodermal activity (EDA), an oral niacin skin flush test and a comprehensive neurocognitive test program including the Wechsler battery (WAIS-R), Fingertapping Test, Trail Making Test, Verbal Fluency, Benton Visual Retention Test, Wisconsin Card Sorting Test and Rey Auditory Verbal Learning Test. RESULTS The patients generally had inferior test results compared to controls. Further analysis revealed that the EDA non-responding patient group explained this variation with significant lower test results than controls. On executive tests, EDA non-responders also performed significantly worse than EDA responding patients. The small group of niacin non-responding patients exhibited an even lower overall test performance. Delayed niacin flush also correlated inversely with psychomotor function and IQ in the patients. CONCLUSION The findings support the hypothesis of a neurodevelopment disturbance affecting both autonomic function and higher cortical function in schizophrenia.

Test–retest stability of the oral niacin test and electrodermal activity in patients with schizophrenia

In schizophrenia, well-replicated findings support an attenuated niacin skin-flush response. We have previously reported a delayed skin-flush after niacin ingestion and also an association between niacin non-responding and electrodermal non-responding in schizophrenia. The stability of the niacin and electrodermal tests was now studied in a test-retest design. An additional aim was to assess the association previously found. Twenty-three patients with schizophrenia underwent two sessions 3 months apart during which an oral niacin test was conducted and electrodermal activity was measured. Despite similar values for niacin outcome variables at the group level, there was high intraindividual variation. Test-retest stability for the oral niacin test was thus low, although a trend toward correlation for the dichotomous response criterion was found. Most electrodermal measures correlated between baseline and retest. A significant association between the tests was again found; niacin non-responding implied electrodermal non-responding, providing further support for a common underlying aberration in schizophrenia.

3-Heteroarylquinuclidin-2-ene derivatives as muscarinic antagonists: synthesis, structure-activity relationships and molecular modelling.

Publisher Summary This chapter examines a variety of C-5 substituted analogs in an attempt to determine what physicochemical properties influence the M 1 receptor affinity. The new compounds are tested in receptor binding and functional assays as previously reported. A series of achiral muscarinic antagonists with structures related chiral quinuclidine derived agonists. The most potent antagonist is the 2-benzofuranyl derivative. Replacing the 2-benzofuranyl with a 3-benzofuranyl-, furanyl-, thienyl-, 2- or 3-benzothienyl, or a 2-benzoxazolyl moiety gives less potent antagonists. In general, the antagonists display low selectivity for the investigated muscarinic receptor subtypes (M 1 , M 2 and M 3 ). An analysis of the structure-affinity relationships among the benzo-fused five-membered heteroaromatic analogs demonstrates that the magnitude of the negative electrostatic potential in the benzene moiety correlates with M 1 receptor affinity. In an attempt to determine what physicochemical properties of the substituted benzofuran derivatives influence the M 1 -receptor affinity, the chapter performs a QSAR analysis of the 9 derivatives.

Karolinska Scales of Personality, cognition and psychotic symptoms in patients with schizophrenia and healthy controls

Background: Studies on both personality dimensions and cognition in schizophrenia are scarce. The objective of the present study was to examine personality traits and the relation to cognitive function and psychotic symptoms in a sample of patients with schizophrenia and healthy controls. Method: In total 23 patients with schizophrenia and 14 controls were assessed with the Karolinska Scales of Personality (KSP). A broad cognitive test programme was used, including the Wechsler Adult Intelligence Scales, the Finger-Tapping Test, the Trail Making Test, the Verbal Fluency Test, the Benton Visual Retention Test, the Wisconsin Card Sorting Test and Rey Auditory Verbal Learning Test . Results: Compared with controls, the patients exhibited prominent elevations on KSP scales measuring anxiety proneness and neuroticism (P = 0.000005–0.0001), on the Detachment scale (P < 0.00009) and lower value on the Socialization scale (P < 0.0002). The patients also scored higher on the Inhibition of Aggression, Suspicion, Guilt and Irritability scales (P = 0.002–0.03) while the remaining five scales did not differ between patients and controls. KSP anxiety-related scales correlated with the Positive and Negative Symptoms Scale (PANSS) general psychopathology subscale. Cognitive test results were uniformly lower in the patient group and correlated with PANSS negative symptoms subscale. There was no association between KSP scale scores and PANSS positive or negative symptoms. Conclusion: The patients revealed a highly discriminative KSP test profile with elevated scores in neuroticism- and psychoticism-related scales as compared to controls. Results support previous findings utilizing other personality inventories in patients with schizophrenia. Cognitive test performance correlated inversely with negative symptoms.

Quinuclidin-2-ene-based muscarinic antagonists.

A series of achiral 3-heteroaryl substituted quinuclidin-2-ene derivatives and related compounds have been synthesized by facile methods. The compounds were evaluated for muscarinic and antimuscarinic properties in receptor binding studies using (-)-[3H]-QNB as the radioligand and in a functional assay using isolated guinea pig urinary bladder. 3-(2-Benzofuranyl)-quinuclidin-2-ene (15) displayed the highest M1-receptor affinity in the present series (Ki = 9.6 nM).

Acute and Maintenance Electroconvulsive Therapy for Treatment of Severely Disabling Obsessive-compulsive Symptoms in a Patient With Asperger Syndrome

We report successful treatment with electroconvulsive therapy of a comorbid condition including severe obsessive-compulsive symptoms and hypochondriacal delusions in a 38-year-old man with Asperger syndrome. His condition deteriorated into a severely disabled chronic state that was refractory to different pharmacological and psychological treatments but was completely reversed after electroconvulsive therapy. Although typical obsessive-compulsive symptoms were predominant, the case also exhibits differences compared with regular obsessive-compulsive disorder regarding onset and course that are discussed in the report.

Tachycardia in patients treated with clozapine versus antipsychotic long-acting injections.

Tachycardia is a known adverse effect during clozapine treatment. However, prevalence reported differs widely between studies and hitherto there are no studies comparing clozapine-treated patients with a similar control group. The present study was carried out to assess the prevalence of tachycardia in patients treated with clozapine and antipsychotic long-acting injections (LAI). Data on heart rate (HR), concomitant medication, and relevant anthropometric and laboratory measurements were collected for all clozapine-treated patients (n=174) in a defined catchment area and compared with data on patients treated with LAI (n=87). In total, 33% of patients on long-term clozapine treatment had tachycardia (HR>100) compared with 16% in the LAI group (P<0.001). The mean HR was 91 in the clozapine group and 82 in the LAI group (P<0.001). Clozapine dose correlated with HR. The majority of patients with HR more than 100 received no specific treatment for tachycardia. In conclusion, the prevalence of tachycardia was twice as high in patients treated with clozapine as in a similar patient group with severe schizophrenia spectrum disorder. The tachycardia was in many cases clinically unnoticed. Tachycardia during antipsychotic treatment is a common phenomenon that must be monitored for actively and, when noticed, further investigated and treated.

Persistent tachycardia in clozapine treated patients: A 24-hour ambulatory electrocardiogram study

Tachycardia is associated with cardiovascular mortality. Tachycardia is also a known clozapine adverse effect. However, whether clozapine-associated tachycardia is persistent is not known. Thirty clozapine-treated patients with clinical tachycardia were investigated with 24-hour ambulatory electrocardiography (ECG). Baseline peripheral heart rate (HR) was 106.7±7.8. The ambulatory ECG 24-hour-HR was 98.7±9.7. Baseline HR and 24-hour-HR correlated strongly (r=0.74, p=0.000003). Daytime HR was 106.4±9.9 and nighttime HR 89.2±12.0. Low dose bisoprolol reduced HR significantly. The high 24-hour-HR indicates a persistent tachycardia. Tachycardia should not discourage from clozapine use but the findings indicate a need of guidelines for detection and treatment of clozapine-associated tachycardia.