Samarthji Lal

Monoamine metabolites in lumbar CSF: The question of their origin in relation to clinical studies

Abstract The sources of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and 5-hydroxyindoleacetic acid (5HIAA) in lumbar CSF of man are discussed. Although HVA in lumbar CSF is derived from the brain, and MHPG seems to be mainly from the spinal cord, the origin of 5HIAA is uncertain. The evidence for and against a brain contribution to 5HIAA of the lumbar CSF is evaluated. It is concluded that the brain can contribute 5HIAA to lumbar CSF under some circumstances. Measurement of 5HIAA concentrations in lumbar CSF can be of clinical value in detecting changes of 5-hydroxytryptamine (5HT) metabolism in the CNS if the changes are general throughout the CNS.

Nicotine and Behavioral Markers of Risk for Schizophrenia: A Double-Blind, Placebo- Controlled, Cross-Over Study

We investigated the effect of nicotine on three behavioral markers of risk for schizophrenia: sustained attention (using the Continuous Performance Task (CPT)), antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in two conditions, one in which attention was enhanced (monitoring target changes) and one in which attention was not enhanced (no monitoring). Patients with schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in a double-blind, placebo-controlled, crossover design and plasma nicotine concentrations were monitored. Nicotine concentrations were similar in both groups. A Group × Drug interaction (p < .02) on CPT hits indicated that nicotine improved sustained attention in patients but not in controls. Nicotine significantly decreased antisaccade errors (p < .01) in both groups. A Drug × Monitoring condition interaction (p < .01) on pursuit gain indicated that nicotine significantly increased pursuit gain in the no-monitoring condition in patients and controls equally, but did not improve pursuit in the monitoring condition. Thus, improvement in pursuit may have been mediated via an effect on attention rather than by an effect on oculomotor function per se. In patients, the magnitude of improvement in attention on nicotine was correlated with the improvement on eye movement tasks. Thus, nicotine improves performance on both attention and oculomotor markers of risk for schizophrenia, possibly via common mechanisms.

Cognitive and clinical moderators of recognition memory in schizophrenia: a meta-analysis

Recognition memory performance in schizophrenia has been shown to vary greatly across studies. To identify the conditions under which recognition memory is significantly impaired, we used a meta-analytic strategy to quantify the moderating effects of several cognitive and clinical variables. Eighty-four studies (from 1965 to July 2003) provided recognition memory data for both a schizophrenia and control group. The overall group comparison for recognition memory yielded a significant mean weighted effect size of d=0.76. Material specificity was the most significant cognitive variable found, with patients exhibiting greater impairment for figural than verbal recognition. A yes-no recognition format and auditory encoding also led to significantly greater effect sizes for recognition memory relative to forced-choice recognition tests and visual encoding, respectively. Furthermore, the effect size for recognition memory as measured by false alarm was smaller than the effect size as measured by hit rate or by d-prime and its related measures. Among clinical variables that were associated with higher effect sizes, chronicity was the most significant, but different trends linking poor performance to negative symptoms and general symptomatology were also observed. Thus, a recognition memory deficit moderated by both cognitive and clinical variables is clearly present in schizophrenia.

Amygdala–hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients

Verbal memory deficits have been related to reduced volume of medial temporal structures in several neurological and psychiatric populations, including schizophrenic patients. Impairments in verbal memory have been proposed to be a marker of risk for schizophrenia. Recently, relatives of schizophrenic patients have been reported to have reduced volume of the amygdala-hippocampal complex. In this study, we evaluate the possibility that amygdala-hippocampal volume reductions may constitute one neural substrate of verbal memory deficits in first-degree relatives. Subjects were 20 healthy first-degree relatives of schizophrenic patients and 14 demographically similar controls. Verbal memory was assessed with the Logical Memory Test. Subjects were scanned with high-resolution MRI and the images were transformed into Talairach space. Volumes of interest were amygdala-anterior hippocampus and posterior hippocampus. Relatives of schizophrenic patients had intact immediate verbal memory but significantly poorer delayed verbal memory than controls. Relatives also had significantly reduced amygdala-anterior hippocampus volumes. Across all subjects, delayed verbal memory was significantly correlated with amygdala-anterior hippocampus volume. The magnitude of the correlation did not differ between the groups. These data provide an empirical link between memory performance and volumetric abnormalities in the amygdala-hippocampal complex in the relatives of schizophrenic patients.

Apomorphine-induced penile tumescence in impotent patients — preliminary findings

Apomorphine (Apo), a short acting dopamine (DA) receptor agonist induces penile erections in normal subjects. The erectile response to one or more doses of Apo HCl (0.25, 0.5, 0.75, 1.0 mg sc) or placebo was investigated in eight impotent subjects and penile tumescence monitored using a mercury strain gauge and strip chart recording. Four patients showed a full erection with Apo and one a partial response. Distressing side effects (nausea, sweating) were associated with non-response or partial response. Three responders to Apo were treated with low doses of the long acting DA receptor agonist, bromocriptine (2.5-3.75 mg/d po); all three showed complete recovery of erectile function within two weeks. A subgroup of impotent patients may have impaired central DA function. Testing with Apo may provide a diagnostic and predictive test to identify such patients who may respond to treatment with low doses of bromocriptine or other DA receptor agonist.

Effect of apomorphine on growth hormone and prolactin secretion in schizophrenic patients, with or without oral dyskinesia, withdrawn from chronic neuroleptic therapy.

Serum growth hormone (GH) and prolactin (PRL) concentrations were measured after administration of the dopamine receptor agonist, apomorphine HC1 (0.75 mg subcutaneously), to 17 chronic schizophrenic patients, four of whom had an oral dyskinesia, who were withdrawn from chronic neuroleptic therapy for periods of two to 15 weeks, and in 21 control subjects (normal volunteers or physically healthy alcoholics not exposed to neuroleptics). Six of the schizophrenic patients, but none of the controls, had raised baseline levels of GH (greater than 6 ng/ml). After apomorphine all controls showed an increase in serum GH with a peak concentration of 9 ng/ml or more, whereas eight subjects withdrawn from neuroleptics showed an inadequate response (peak less than 6 ng/ml) and in two others an inadequate response was obtained on one of two trials. The peak GH concentration was significantly less after apomorphine in patients withdrawn from neuroleptics (11.90 +/- 3.19 ng/ml) compared with controls (20.80 +/- 2.11 ng/ml) (P less than 0.05). Among patients withdrawn from neuroleptics, those with an oral dyskinesia had significantly lower peak GH concentration 2.46 +/- 0.93 ng/ml) after apomorphine compared with those without (14.85 +/- 3.83 ng/ml) (P less than 0.05). There were no differences in serum PRL concentrations, before or after apomorphine administration, between patients withdrawn from neuroleptics and controls. In uncontrolled observations none of the four patients with an oral dyskinesia showed any worsening of the movement disorder after apomorphine. These data provide no evidence for supersensitivity of dopamine receptors in chronic schizophrenic patients withdrawn from chronic neuroleptic therapy.

Cholecystokinin and Schizophrenia

Publisher Summary This chapter presents some of the evidence from animal and clinical studies, implicating cholecystokinin (CCK)-peptides in the pathophysiology of schizophrenia. CCK pathways are extensively distributed throughout the CNS. CCK-immunoreactivity (CCK-IR) is co-localized with dopamine (DA) in some DA neurons projecting to limbic structures. The extent of the co-localization is species dependent. The co-existence of CCK and DA is of interest in view of the DA hypothesis of schizophrenia and the putative role of limbic dysfunction in the pathophysiology of this disorder. Several biochemicals, electrophysiological, and behavioral studies point to an interaction between CCK and DA. Some studies point to an inhibitory effect of CCK peptides on DA function, which would be compatible with a potential antischizophrenic action, others point to an enhancement. CCK peptides show a neuroleptic-like profile in several screening tests for neuroleptics but not in all studies. Cerebrospinal fluid (CSF) CCK-IR is described as being unchanged or decreased in schizophrenia. Autopsy studies have shown significant decreases, increases, or no change in brain CCK-IR in schizophrenia.

Relationships between tryptophan in serum and CSF, and 5-hydroxyindoleacetic acid in CSF of man: effect of cirrhosis of liver and probenecid administration.

Tryptophan was measured in the lumbar CSF and serum of patients undergoing neurological investigation (controls) and in patients with hepatic cirrhosis. Samples were taken from the fasting patients at 8:00 a.m. Under these conditions, in the controls the mean CSF, free )mpm-albumin-bound) and total serum tryptophan were in the approximate ratio 1:4:24. In this cross-sectional study, for the controls, CSF tryptophan was correlated significantly and positively with the total serum but not with the free serum tryptophan. In patients with advanced hepatic cirrhosis the mean CSF tryptophan concentration was greatly elevated. However, the mean total serum tryptophan was unchanged and the free serum tryptophan only slightly elevated. Administration of probenecid, which displaces tryptophan from binding sites on serum albumin, and thereby increases the proportion of serum tryptophan in the free form, did not affect CSF tryptophan.

Associative Memory Encoding and Recognition in Schizophrenia: An Event-Related fMRI Study

BACKGROUND We used an event-related functional Magnetic Resonance Imaging (fMRI) approach to examine the neural basis of the selective associative memory deficit in schizophrenia. METHODS Fifteen people with schizophrenia and 18 controls were scanned during a pair and item memory encoding and recognition task. During encoding, subjects studied items and pairs of visual objects. In a subsequent retrieval task, participants performed an item recognition memory test (old/new decisions) and an associative recognition test (intact/rearranged decisions). The fMRI analysis of the recognition data was restricted to correct items only and a random effects model was used. RESULTS At the behavioral level, both groups performed equally well on item recognition, whereas people with schizophrenia demonstrated lower performance on associative recognition relative to the control group. At the brain level, the comparison between associative and item encoding revealed greater activity in the control group in the left prefrontal cortex and cingulate gyrus relative to the schizophrenia group. During recognition, greater left dorsolateral prefrontal and right inferior prefrontal activations were observed in the control group relative to the schizophrenia group. CONCLUSION This fMRI study implicates the prefrontal cortex among other brain regions as the basis for the selective associative memory encoding and recognition deficit seen in schizophrenia.

Effects of aporphine and emetine alkaloids on central dopaminergic mechanisms in rats.

Abstract A series of aporphine and emetine alkaloids was studied for induction of stereotyped behaviour (SB), antagonism of reserpine sedation, and effect on the cerebral concentrations of homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in the rat. Apomorphine (5 mg/kg) induced SB, reversed the reserpine syndrome and lowered the concentration of cerebral HVA. Apocodeine (10-O-methylapomorphine) and methylenedioxyaporphine (both injected in a dose of 20 mg/kg) induced intermittent SB, reversed the reserpine syndrome and reduced cerebral HVA, whereas 10,11-dimethoxyaporphine had none of these effects. Methylenedioxyaporphine decreased the level of 5-HIAA slightly. The results suggest that apocodeine and methylenedioxyaporphine have similar sites of action to those affected by apomorphine, but that the first 2 alkaloids are less potent agonists than apomorphine. 6 other analogues of apomorphine, including 1,2,10,11-tetrahydroxyaporphine (the N-methyl derivative of a compound theoretically derivable from tetrahydropapaveroline), were tested at doses of 20 mg/kg, but none induced SB. Cephaeline and emetine did not influence the concentrations of HVA or 5-HIAA in the brain, nor did they induce SB.