Leif Lindström

Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia

Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate-receptor. Mounting evidence indicate that the compound is significantly involved in basal neurophysiological processes in the brain. In the present investigation, cerebrospinal fluid (CSF) level of kynurenic acid was analyzed in 28 male schizophrenic patients and 17 male healthy controls by means of high pressure liquid chromatography and fluorescence detection. Schizophrenic patients showed elevated CSF levels of kynurenic acid (1.67+/-0.27 nM) compared to the control group (0.97+/-0.07 nM). Furthermore, CSF levels of kynurenic acid in schizophrenic patients were also found to correlate with age. The present finding is indicative of a contribution of kynurenic acid in the pathogenesis of schizophrenia.

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET

BACKGROUND The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. METHODS PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled L-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate L-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. RESULTS In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of L-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. CONCLUSIONS The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia.

Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine : evidence from a therapeutic drug monitoring service

Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups—patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5–10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.

Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene

Previous research has demonstrated that a polymorphism in the serotonin transporter gene (5-HTTLPR) and adverse psychosocial circumstances interact to predict depression. The purpose of the present study was to explore the extent to which sex modulates these effects. Eighty-one boys and 119 girls (16-19 years old) were interviewed about psychosocial background variables and genotyped for the 5-HTT promoter polymorphism. There were two main results. First, boys and girls carrying the short 5-HTTLPR allele react to different kinds of environmental factors. Whereas males were affected by living in public housing rather than in own owned homes and by living with separated parents, females were affected by traumatic conflicts within the family. Second, the responses of males and females carrying the short 5-HTTLPR allele to environmental stress factors go in opposite directions. Thus, whereas females tend to develop depressive symptoms, males seem to be protected from depression. The results suggest that both the molecular and the psychosocial mechanisms underlying depression may differ between boys and girls.

NEUROPEPTIDE Y AND PEPTIDE YY AS POSSIBLE CEREBROSPINAL FLUID MARKERS FOR MAJOR DEPRESSION AND SCHIZOPHRENIA, RESPECTIVELY

Neuropeptide Y (NPY)-like and peptide YY (PYY)-like immunoreactivities were measured in cerebrospinal fluid (CSF) from patients with major depressive disorder or schizophrenia and from healthy volunteers without physical or mental illness. NPY-like material was significantly lower (P less than 0.001) in CSF of patients with depressive disorders than in schizophrenic patients or healthy controls. Treatment with the antidepressant, amiflamine, a selective MAO-A inhibitor, did not alter CSF peptide concentrations. In drug-free schizophrenic patients, normal NPY but reduced PYY concentrations in CSF were observed. Treatment with neuroleptics did not affect the levels of NPY or PYY in the CSF. The finding of reduced CSF concentrations of NPY in patients with major depression and of reduced PYY concentrations in schizophrenia may reflect disturbed synthesis, turnover or degradation of the peptides. These findings suggest that the reduced concentrations of NPY or PYY in the CSF may be used as trait markers of the respective illnesses.

Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity

BACKGROUND A number of important sociological, psychological, and biological predictors of adolescent criminal behavior have been identified during the most recent decades. The aim of this study was to replicate recent findings that interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter region and psychosocial factors might predict male adolescent criminal activity. METHODS A cross-sectional study with a randomized sample from the total population of 16- and 19-year-olds from the county of Västmanland, Sweden. Eighty-one male adolescents, who volunteered to participate, were randomly selected from groups representing different degrees of deviant risk behavior. RESULTS The present study strongly supports the notion that carrying the 3-repeat allele of the MAO-A-gene promoter increases the risk of male adolescent criminal behavior, when interacting with psychosocial factors. No effects at all of the MAO-A genotype on adolescent criminal activity were found when MAO-A genotype was considered alone (i.e., without its psychosocial context). The explained variance of the bio-psychosocial model (controlling for MAO-A) in this study exceeded the psychosocial model by 12%. CONCLUSIONS The findings support the notion that genotype and psychosocial factors interact to precipitate male adolescent criminal behavior.

The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years

ABSTRACT— A retrospective study was performed to evaluate the effect of long‐term treatment with clozapine in 96 schizophrenic or schizoaffective patients hospitalized at the Psychiatric Research Center in Uppsala during the period 1974‐1986. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The mean duration of the disorder at the start of clozapine treatment was 8 years and 9 months and the mean duration of the treatment 3 years and 11 months. Clozapine treatment was discontinued in 36 % of the patients, mainly due to lack of efficacy, poor compliance or temporary withdrawal of the drug from the market in 1975. In two patients the reason was leukopenia or agranulocytosis. In another 10 patients a transient decrement of WBC was seen, which was normalized during ongoing treatment. Four patients died when on clozapine during the follow‐up period, but no causal relationship to the treatment could be established. Eighty‐five per cent of the patients could be discharged from the hospital. Of the 62 patients who were still on clozapine after 2 years, 18% had full time and 21 % half‐time employment. A global evaluation of the clinical efficacy revealed a significant improvement in 43 % and a moderate improvement in 38 % of the patients compared to previous neuroleptic treatments. Common but usually mild side effects were sedation, hypersalivation, weight gain, and obstipation. Four patients had grand mal seizures. No extrapyramidal side effects were observed during clozapine treatment. It is concluded that clozapine is an effective antipsychotic drug that offers particular advantages for many schizophrenic patients compared to classical neuroleptics and that the risk/benefit ratio should be re‐evaluated in the light of recent long‐term studies.

Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients.

Several lines of evidence suggest that D-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia. The purpose of this study was to determine whether levels of D- and L-serine or D-serine ratio (D-serine/total serine) in cerebrospinal fluid (CSF) were altered in first episode and drug-naive schizophrenic patients. The CSF levels of D- and L-serine in 25 male first episode and drug-naive schizophrenic patients and 17 age-matched male healthy subjects were measured using a column-switching high performance liquid chromatography system. The percentage of D-serine in the total serine of patients was significantly (z = -2.01, p = 0.044) lower than that of controls. This study suggests that synthetic or metabolic pathways of D-serine may be abnormal in the brain of drug-naive schizophrenic patients, supporting the NMDA receptor dysfunction hypothesis of schizophrenia.

Increased CSF levels of endorphines in chronic psychosis

The levels of two endorphines, endogenously occurring morphinomimetic peptides, were measured in serial samples of CSF from seven psychiatric patients. Four cases with chronic schizophrenia were studied before and after treatment with the antipsychotic agent clozapine (Leponex). Supernormal fraction II levels were found on at least one sampling occasion in each patient. Two patients, who responded well to clozapine treatment, showed a clear-cut drop in fraction II levels, whereas two patients showed increased levels which paralleled a deterioration of the schizophrenic symptoms. Three manic-depressive cases showed abnormally high levels of endorphine fraction I in the manic phase which declined during normal or depressed phases. Levels of fraction II varied in a less consistent manner and appeared to be at maximum during the apparently normal phases. Although preliminary, the data indicate that endorphines may reach supernormal levels in patients with chronic psychoses.

Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia

Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n=49) and male patients with schizophrenia (n=90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM+/-0.10 vs. 1.06 nM+/-0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM+/-0.19, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM+/-0.17, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM+/-0.10, n=19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.