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In 1992, our esteemed colleagues Alan Breier, Orlando Davis, Robert Buchanan, Samuel J. Listwak, Courtney Holmes, David Pickar, and David S. Goldstein published a seminal scientific paper titled “Effects of Alprazolam on Pituitary-Adrenal and Catecholaminergic Responses to Metabolic Stress in Humans.” In it, they described with high accuracy the effects of benzodiazepines on stress-induced activation of the three classic “stress” systems: Pituitary-adrenal, adrenal medullary, and sympathoneural systems. The results provided an answer to a question that is still being asked today: Why is alprazolam so much more effective than all other benzodiazepines for certain anxiety-related conditions, especially panic attacks? The colleagues found the answer to that question, but although the work was impeccable, their findings never made it into medical textbooks. What Breier et al. found was this: Alprazolam is able to attenuate 2DG-induced activation of the HPA axis and adrenomedullary activity, as evidenced by attenuated responses of plasma levels of ACTH and epinephrine, respectively, without clinically affecting other important responses of two indices of sympathoneural activity. For the treatment of patients whose adrenal glands are working in a highly dysfunctional or centrally dysregulated manner due to rare diseases such as NTBI induced H63D syndrome, alprazolam is still the first drug of choice - despite its dependence potential - to protect the organism of the affected person from dangerous adrenaline excesses that are way more dangerous than any well-monitored use of alprazolam.

It is difficult to come away from review of pharmacologic and metabolite studies without concluding that dopaminergic mechanisms play a significant role in mediating both negative and positive symptoms. Nevertheless, the characteristics of dopaminergic involvement are unclear. Whereas compelling evidence continues to link the mechanism of action of neuroleptic drugs, including therapeutic effects on negative and positive symptoms, to blockade of D2 receptors, neuroleptic-induced alterations in dopaminergic function are time-dependent and may include reductions in variability as well as in net dopamine activity. Moreover, pharmacologic enhancement of dopaminergic function may at least transiently improve symptomatology (negative greater than positive) and levels of CSF HVA appear to be reduced or are negatively correlated with symptoms in some schizophrenic patients. Thus, there is support for both increased and decreased dopamine function in schizophrenia. Functional brain imaging has, after only a few years of application, made significant contributions to our understanding of the pathophysiology of schizophrenia. Studies of cerebral metabolism and regional CBF have shown remarkable consistency in their identification of abnormal function of the frontal cortex in schizophrenia. It should be pointed out, however, that agreement across studies remains largely conceptual with significant discrepancies still existing with regard to the precise localization of dysfunction and its relationship to cognitive activation. Although less well documented than 'hypofrontality' itself, negative symptomatology appears to bear some relationship to this defect. The idea that positive symptoms might be associated with increased subcortical and/or metabolism is less well supported. The recent advances in our understanding of structure and function of CNS dopaminergic systems may help to integrate these two bodies of data into more dynamic models of dopaminergic defects in schizophrenia. For example, the concept that diminished mesocortical coupled with increased subcortical dopaminergic activity might be a 'substrate' for psychosis is compatible with neurochemical evidence suggesting both diminished and enhanced dopaminergic processes as well as with metabolic hypofrontality. Better understanding of the regulatory mechanisms involved in establishing functional balance between cortical and subcortical systems might, therefore, identify new possibilities for biological dysfunction in schizophrenia. The recent study by Weinberger et al. which correlates CSF HVA levels with neuropsychologically induced frontal CBF is an example of how neurochemistry can enhance brain imaging data.(ABSTRACT TRUNCATED AT 400 WORDS)

It is the goal of pharmacogenomics in psychiatry to establish predictive relationships between polymorphisms of candidate genes and therapeutic response to drug treatment. Polymorphisms of candidate genes related to drug mechanisms and pathophysiology of illness and defined clinical phenotype are the foundations for pharmacogenomic studies. Pharmacogenomic studies of antipsychotic response have focused on polymorphisms of genes for dopamine and serotonin receptors with most positive results reported for polymorphisms of genes of the 5HT2a and 5HT2c serotonin receptor subtypes. Although the goal of establishing individualized medicine predicated on an individual patient's genetic code has yet to be achieved, the fundamentals are now in place for second-generation investigation and more application to health care.

Despite widespread abuse of anabolic-androgenic steroids (AAS), the endocrine effects of supraphysiologic doses of these compounds remain unclear. We administered the AAS methyltestosterone (MT) to 20 normal volunteers in an in-patient setting, examined its effects on levels of pituitary-gonadal, -thyroid, and -adrenal hormones, and examined potential relationships between endocrine changes and MT-induced psychological symptoms.Subjects received MT (three days of 40 mg/day, then three days of 240 mg/day) or placebo in a fixed sequence with neither subjects nor raters aware of order. Samples were obtained at the ends of the baseline, high-dose MT and withdrawal phases. Potential relationships between hormonal changes and visual analog scale measured mood changes were examined.Significant decreases in plasma levels of gonadotropins, gonadal steroids, sex hormone binding globulin, free T3 and T4, and thyroid binding globulin (Bonferroni t, p0.01 for each) were seen during high-dose MT; free thyroxine and TSH increased during high-dose MT, with TSH increases reaching significance during withdrawal. No significant changes in pituitary-adrenal hormones were observed. Changes in free thyroxine significantly correlated with changes in aggressiveness (anger, violent feelings, irritability) (r=0.5,p=0.02) and changes in total testosterone correlated significantly with changes in cognitive cluster symptoms (forgetfulness, distractibility) (r=0.52,p=0.02). Hormonal changes did not correlate with plasma MT levels.Acute high-dose MT administration acutely suppresses the reproductive axis and significantly impacts thyroid axis balance without a consistent effect on pituitary-adrenal hormones. Mood and behavioral effects observed during AAS use may in part reflect secondary hormonal changes.

OBJECTIVE: Childhood onset of “adult” psychiatric disorders may be caused, in part, by more salient genetic risk. In this study, the rates of schizophrenia spectrum disorders among parents of patients with childhood-onset and adult-onset schizophrenia and parents of community comparison subjects were compared. METHOD: To assess the presence of axis I and axis II disorders associated with schizophrenia, parents of patients with childhood-onset schizophrenia (95 parents), patients with adult-onset schizophrenia (86 parents), and community comparison subjects (123 parents) were interviewed directly by using semistructured instruments. Information on 19 additional parents (parents of childhood-onset patients, N=2; parents of adult-onset patients, N=11; parents of community comparison subjects, N=6) was obtained by using a family history interview with the same instruments. Transcribed interviews were scored by a rater blind to group membership, and the morbid risks for schizophrenia spectrum disorders in the ...

Several lines of evidence suggest that changes in dopamine release and/or post-synaptic sensitivity may be involved in the pathogenesis of tardive dyskinesia (TD). Preclinically, increased D(2) receptor sensitivity and dopamine turnover are associated with D(2) receptor antagonism. Clinically, development of TD is associated with D(2) receptor antagonist administration. Eight patients with mild evidence of TD (AIMS ratings > or =14) and six without (AIMS = 10), underwent [(11)C]raclopride PET scans. Baseline and amphetamine-induced decrements in striatal specific binding were assessed. Baseline and amphetamine-induced decrements in specific binding did not differ between patients with and without evidence of mild TD (p =.53). AIMS ratings did not significantly correlate with baseline (p =.76) or decrements in specific binding (p =.45). This study provides evidence that TD is not associated with increased amphetamine-induced presynaptic dopamine release and/or D(2) receptor binding as measured by [(11)C]raclopride PET. More research is needed to unravel the neurobiology of this debilitating disorder.

Pharmacogenomics, the utilization of genetic information to predict outcome of drug treatment (therapeutic and side-effects), holds great promise for clinical medicine. The pharmacotherapy of psychiatric disorders exhibits wide variability in therapeutic response with little scientific guidance for treatment on a patient-by-patient basis. The emerging field of pharmacogenomics holds great potential for refining and optimizing psychopharmacology. Key components for future development of the pharmacogenomics of psychiatric disorders include understanding the mechanism of drug action, identification of candidate genes and their variants, and well-conducted clinical trials. In this article, data from recent studies are examined with particular emphasis on methodological requirements and direction for future research.

Schizophrenia has been linked to abnormal dopamine function, recently to excessive amphetamine-induced release of striatal dopamine, and also to pathology of prefrontal cortical neurons. It has been hypothesized that prefrontal pathology is a primary condition that leads to dopamine dysregulation. We evaluated in vivo the relationship between neuronal integrity in dorsolateral prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations measured with proton magnetic resonance spectroscopic imaging, and amphetamine-induced release of striatal dopamine, assessed with 11C-raclopride Positron Emission Tomography (PET) in patients with schizophrenia and in healthy subjects. In the patients, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C-raclopride after amphetamine infusions (rho = − 0.76, p < .02). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.

Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents.After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents.Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone.The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.

Elevated plasma norepinephrine (NE) levels is a relatively consistent clinical effect of clozapine. Plasma NE levels reflect an interplay of release, reuptake, metabolism, and excretion. To explore the mechanism of clozapine-induced plasma NE elevation, we measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in schizophrenic patients treated with clozapine, fluphenazine, or placebo. Clozapine-treated patients had markedly higher levels of NE than did the patients treated with fluphenazine or placebo. NE spillover averaged more than three times higher in clozapine-treated patients; whereas NE clearance did not differ among the groups. Production of 3H-dihydroxyphenylglycol (3H-DHPG), a purely intraneuronal metabolite of 3H-NE in clozapine-treated patients was normal, indicating that clozapine did not affect neuronal uptake of NE. Because plasma levels of DHPG and dihydroxyphenylacetic acid (DOPAC), deaminated metabolites of catecholamines, in clozapine-treated patients were normal, clozapine also did not seem to inhibit intraneuronal monoamine oxidase (MAO). High plasma NE levels in clozapine-treated patients, therefore, resulted from increased NE spillover rather than decreased reuptake, metabolism, or clearance.

Clozapine, the prototype for the new generation of atypical antipsychotics, has demonstrated efficacy in treating schizophrenia, particularly in patients with symptoms that are refractory to traditional antipsychotics. Unfortunately, clozapine is associated with agranulocytosis in a small but significant minority of patients. Reliable predictors of response, whether therapeutic or adverse, to clozapine would assist clinicians in using this drug more effectively.

Interindividual differences in the psychotomimetic response to the N-methyl-d-aspartate receptor antagonist ketamine are commonly observed. The apolipoprotein E (APOE) epsilon 4 allele has been associated with reduced severity of positive psychotic symptoms in schizophrenia. In this study, we sought to determine if the APOE epsilon 4 allele influences the psychotomimetic response to ketamine in schizophrenics. Eighteen patients genotyped at the APOE locus underwent a double-blind infusion of ketamine and of placebo. Ketamine-induced alterations in the brief psychiatric rating scale factors were compared between schizophrenics with and without the APOE epsilon 4 allele. APOE epsilon 4+ schizophrenics displayed significantly reduced ketamine-induced psychosis, as compared to epsilon 4-patients. These preliminary data indicate that the psychotomimetic response to ketamine may be genetically influenced and may provide additional evidence that APOE may modify expression of the positive symptoms in schizophrenia.

The regional cerebral metabolic rates of 19 male medication-withdrawn schizophrenic patients were determined by positron emission tomography (PET) while performing an auditory discrimination task (CPT). Regardless of the accuracy of their CPT performance, the schizophrenic patients had lower metabolic rates in their prefrontal cortex and higher rates in their posterior putamen compared to 41 healthy males. Abnormally low right anterior midprefrontal cortex metabolic rates predicted better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response to neuroleptics. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role in the expression of psychotic symptoms and the mediation of their response to antipsychotics.

The neurotransmitter serotonin has been implicated in the pathophysiology of psychosis. The serotonin transporter (5-HTT) plays a critical role in regulation of serotonergic function. A recently identified polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) produces significant differences in 5-HTT expression and function and was found to be associated with anxiety-related traits in healthy volunteers. We investigated whether 5-HTTLPR is associated with psychosis in neuroleptic-free schizophrenic or schizoaffective patients. Fifty patients with schizophrenia or schizoaffective disorder by DSM-III-R criteria were genotyped at 5-HTTLPR and underwent double-blind Brief Psychiatric Rating Scale (BPRS) ratings while neuroleptic-free for approximately 4 weeks. Patients with the 5-HTTLPR II genotype (n = 19) had significantly higher BPRS ratings for psychosis than patients with the Is (n = 25) or ss (n = 6) genotypes. Examination of individual items revealed a specific significant increase in intensity of hallucinations in patients with the 5-HTTLPR II genotpe. These data provide preliminary evidence for a role of serotonin in the pathophysiology of hallucinations and may represent the identification of an allelic variant that modifies the complex clinical presentation of schizophrenia.

Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA-dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean +/- SD) in specific 11C-raclopride binding from baseline for ketamine (11.2 +/- 8.9) was greater than for saline (1.9 +/- 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean +/- SD) in specific 11C-raclopride binding caused by amphetamine (15.5 +/- 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in 11C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed.

Expression of preproenkephalin, dynorphin and D2 dopamine receptor mRNAs was examined in selected regions of the forebrain of homozygous and heterozygous tottering mice, using in situ hybridization histochemistry. Homozygous tottering mice carry an autosomal recessive mutation causing them to exhibit petit mal-like epilepsy. Preproenkephalin mRNA levels were significantly higher in the lateral caudate and the core of the nucleus accumbens of homozygous tottering mice compared to wild-type controls. No differences were observed in the expression of dynorphin and D2 receptor mRNA distribution in brain regions examined in the mutant mice as compared to wild-type controls.

It is clear that cytokines exert a variety of modulatory actions on the central nervous system. As part of our work exploring the relationship between immune activation and psychosis, we measured cerebrospinal fluid (CSF) IL-1 alpha and IL-2 levels in 60 medicated schizophrenic patients and in 21 normal volunteers using a competitive enzyme immunoassay. The two groups did not differ significantly in their mean cytokine levels: 1.01 (0.149) ng/ml (patients) vs. 1.28 (0.150) ng/ml (controls) for IL-1 alpha and 0.970 (0.038) ng/ml (patients) vs. 1.25 (0.086) ng/ml (controls) for IL-2. There was a significant positive correlation between CSF IL-1 alpha and IL-2 levels for all subjects (r = 0.50, n = 44, p = 0.0001).

Positron emission tomography and single-photon emission computer tomography receptor-binding ligands can be used to measure changes in neurotransmitter levels. In particular, amphetamine-induced dopamine release has been assessed with [11C]raclopride by paired bolus injections and with [123I]iodobenzamide by using a single bolus plus infusion (B/I) study. Here, we measured the change in [11C]raclopride-specifìc binding in rhesus monkeys after i.v. administration of 0.4 mg/kg amphetamine by using both the bolus and B/I paradigms. Paired bolus studies (control and postamphetamine) were analyzed using compartment modeling and graphical analysis with a new plasma metabolite model to measure the total distribution volume (VT). Specific binding, calculated with three measures linearly proportional to the binding potential, demonstrated a 22–42% reduction in the postamphetamine study. VT values from B/I studies were determined by the tissue-to-plasma ratio at equilibrium, in addition to the bolus methods. There was good agreement between the control VT values between bolus and B/I studies. The amphetamine-induced change in specific binding in B/I studies was 19 ± 16%, measured directly from tissue radioactivity levels. This study demonstrates that stimulus-induced changes in specific binding can be measured with a single [11C]raclopride study using the B/I method.

Objective: Pediatric studies of cerebrospinal fluid (CSF) monoamine metabolites in childhood-onset schizophrenia may help to elucidate both pathophysiology and treatment response in early-onset psychosis. Method: CSF homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) and serum prolactin were measured during drug-free and antipsychotic medication conditions in 18 patients (mean age=14.2 years, SD=1.7) who had onset of schizophrenia by age 12 (mean age at onset=9.9 years, SD= 1.8). Relationships between changes in CSF monoamines and serum prolactin and clinical outcome were examined, and the degree of change in CSF monoamines in response to clozapine treatment was compared with that for 16 patients with later-onset schizophrenia. Results: Despite patients’ significant clinical improvement with treatment, CSF monoamine concentrations and ratios of HVA/5-HIAA and HVA/MHPG did not significantly change with 6 weeks of either haloperidol or clozapine treatment. Serum prolactin levels increased during haloperidol treatment. Clozapine had similar effects on CSF monoamines in patients with childhood- and later-onset schizophrenia. Conclusions: While these data are compatible with continuity between childhood- and later-onset schizophrenia, they also highlight the complexity of the biochemical events mediating clinical changes in schizophrenia. (Am J Psychiatry 1997; 154:69‐74)

Objective: The authors sought to determine if there were gender differences in neuroleptic response in male and female patients with schizophrenia who were matched for clinical and demographic variables and participated in a double-blind trial of traditional antipsychotic drugs. Methods: 24 males (m) and 20 females (f) with schizophrenia or schizoaffective disorder who did not differ in clinical characteristics (age of onset, course of illness, prior hospitalizations, premorbid functioning) participated in an extended drug-free period followed by a neuroleptic trial under double-blind, placebo-controlled conditions. Results: Males and females showed significant improvement in total, positive and negative BPRS symptoms during neuroleptic treatment. However, there were no significant differences in treatment response between sexes. No sex differences were found in baseline drug-free symptomatology, neuroleptic dose or dosage by weight. Conclusions: There were no significant sex differences in neuroleptic treatment response in male and female patients well-matched for clinical, treatment and demographic characteristics. Methodological issues which distinguish this study from prior studies reporting gender differences in neuroleptic response are examined.

Two reaction time (RT) paradigms were used to study clozapine's effects on sustained and selective attention compared to fluphenazine and placebo in 25 chronic schizophrenic patients. Sensory dominance was studied via simple and choice RTs to lights and tones, and on double-stimulus trials in which the two stimuli were presented simultaneously. Although 8 of the 25 patients could not perform the RT tasks when taking placebo, there were no effects of clozapine on simple or choice RT compared to placebo or fluphenazine. Subjects on all 3 treatments showed visual dominance: faster RT to lights than to tones on choice and double-stimulus trials. However, clozapine reduced this by means of a selective increase in RT to lights. Clozapine reduced failures to respond to the tone on double-stimulus trials. This was shown to be due to reductions in hallucinations. Clozapine does not generally improve attention, but it may increase the ability of schizophrenic persons to process nondominant or unattended stimuli possibly by increasing the efficiency of resource allocation. This may be partially mediated by a reduction in hallucinations.

Recent studies have identified immunologic abnormalities in some schizophrenic subjects. This experiment replicates previous findings that serum soluble interleukin-2 receptors (SIL-2Rs) are elevated in schizophrenic patients, and is the first study to describe this phenomenon in non-Caucasian patients. Despite differences between Korean and Caucasian schizophrenic patients in absolute serum SIL-2R levels, both groups were significantly elevated when compared with their respective ethnic control groups (477 +/- 171 U/ml versus 354 +/- 172 U/ml and 763 +/- 347 U/ml versus 567 +/- 231 U/ml, respectively). Neither age, gender, medication status, nor duration of illness correlated with SIL-2R levels. These findings are further evidence that immune activation is present, regardless of ethnic origin, in some schizophrenic patients.

Since the introduction of chlorpromazine in the 1950s, neuroleptic medications have been the mainstay of treatment of schizophrenia and other psychotic disorders. These medications do not always lead to complete remission of symptoms but they have allowed many patients to lead more productive and satisfying lives away from the restrictions of chronic hospitalisation. However, neuroleptics are associated with a number of adverse effects that can compromise their effectiveness. Extrapyramidal adverse effects include acute dystonic reactions, neuroleptic-induced Parkinsonism and akathisia. They can often be treated with neuroleptic dose reduction, addition of anticholinergic or beta-blocking agents, or medication change. Later-onset movement disorders such as tardive dyskinesia or dystonia require careful evaluation and may be treated with dose reduction or change of neuroleptic to an atypical agent. Potentially fatal reactions such as agranulocytosis and neuroleptic malignant syndrome can rarely occur and often require significant medical intervention. Clozapine offers some advantages over 'typical' neuroleptics but has a unique adverse effect profile which includes agranulocytosis.

Objective This study was designed to ascertain the degree and specificity of cognitive impairments in patients with schizophrenia and patients with affective disorders. Method Cognitive function was assessed with a neuropsychological test battery in consecutively admitted patients with schizophrenia (N = 57), unipolar depression (N = 29), and bipolar disorder (N = 16). Results The performance of the schizophrenic group was significantly below that of the groups with affective disorders on measures of attention and psychomotor speed, verbal and visual memory, and problem solving and abstraction. IQ was lower in the schizophrenic group and appeared to have deteriorated from a normal premorbid level that was not different from that of the affective disorder groups, as determined by the Wide Range Achievement Test--Revised reading test, a putative measure of premorbid intelligence. When IQ was controlled, differences between the groups in problem solving and visual memory remained. Psychiatric symptoms had a larger impact on test performance in the affective disorder groups than in the schizophrenic group. Conclusions These results suggest that patients with schizophrenia perform systematically worse on cognitive measures than patients with affective disorders, which is consistent with their generally poorer outcome. The results also indicate that schizophrenia and affective disorders are qualitatively distinguishable in neuropsychological terms, given differences in apparent intellectual deterioration, profiles of cognitive impairment, and associations between cognitive performance and psychopathology.

There is a confusing history of immune findings associated with schizophrenia. At least some of these discrepant results may be artifacts caused by heterogeneity. In an attempt to decrease heterogeneity, we studied three groups of monozygotic twins who were either discordant for schizophrenia, concordant and ill, or concordant and well. This comparison minimizes environmental and genetic variance, and heightens differences that are actually due to the disorder. Overall, schizophrenic subjects had higher levels of serum soluble interleukin-2 receptors (SIL-2Rs) than unaffected individuals (480.8, SD 238.6 U/ml vs 380.9, SD 170.6 U/ml; F = 5.256, df = 1.61, P = 0.02). When data from discordant and concordant twin groups were analysed separately, both the discordant ill twins (P = 0.06) and concordant ill twin pairs (P = 0.08) showed trends towards higher serum SIL-2R levels than their respective control groups. These data contribute to the growing body of evidence that immune activation is associated with some forms of schizophrenia.

Peripheral indicators of autonomic nervous system activity, including electrodermal activity and heart rate, were studied in 25 chronic schizophrenic patients given clinical trials of clozapine, a standard neuroleptic (fluphenazine), and placebo. The protocol included a rest period, presentation of nonsignal tones, and a reaction time task. Clozapine markedly attenuated electrodermal base levels and both phasic and tonic electrodermal responsivity compared to placebo, and somewhat less consistently compared to fluphenazine. Both electrodermal and vasoconstrictive orienting responses to tones were reduced. Elevated heart rate and reduced heart rate variability were also observed in patients taking clozapine. Many of these effects can be accounted for by clozapine's anticholinergic and antihistaminic properties. There was evidence that a smaller autonomic response to the mild stress of task performance and larger heart rate responses to nonsignal tones on the alternate treatments were predictive of a good clinical response to clozapine. These results suggest that when on alternate treatments good clozapine responders show more psychophysiological signs of pathology than clinical nonresponders.

To test the hypothesis that depressed and schizophrenic patients have a common pathophysiological mechanism for hypofunction of the prefrontal cortex (‘hypofrontality’), we measured regional cortical blood flow (rCBF) in ten depressed patients, ten patients with schizophrenia, and 20 age- and sex-matched normal controls. Blood flow was measured during three different cognitive conditions: a resting state, a simple number-matching sensorimotor control task, and the Wisconsin Card Sorting test (WCS). The schizophrenic patients had lower prefrontal rCBF during the WCS. There were no differences in global or regional flow between the depressed patients and the normal subjects during any testing condition. Analysis of rCBF lateralisation showed that during the WCS normal subjects had relatively more left parietal blood flow than depressed patients, who had more right parietal blood flow. Since the testing condition that has most consistently revealed hypofrontality in schizophrenia (i.e. the WCS) was not associated with abnormal rCBF in the depressed patients, these data suggest that the pathophysiological mechanisms underlying prefrontal hypofunction in depression and schizophrenia are different.

We compared the saccades made by 8 neuroleptic-treated and 7 drug-free schizophrenic inpatients with those made by 11 normal controls during two eye movement tasks. The first task was designed to elicit visually guided but not internally guided saccades. The second task was designed so that optimal performance required saccades be guided on the basis of an internal representation of target behavior. During the first task, schizophrenics made visually guided saccades that were as accurate as those made by control, but both drug-free and neuroleptic-treated schizophrenics made intrusive saccades at a significantly higher rate than control subjects. Most of these maladaptive saccades appeared to be premature attempts to anticipate target jump. During the second eye movement task, which for optimal performance required use of an internal representation to guide eye movements, most patients learned to anticipate target jump as well as controls. However, neuroleptic-treated patients made significantly smaller adaptive anticipatory saccades than either drug-free schizophrenic patients or normal subjects. These finding are discussed as they relate to the prefrontal cortex-basal ganglia circuits involved in the regulation of behavior by representational knowledge and the idea that the abnormal anticipatory saccades we observed represent a failure in the sensorimotor gating of information derived from internal representations.

Objective Benzodiazepines, either alone or added to neuroleptics, have been studied extensively as treatments for schizophrenia, but no consensus regarding their efficacy has been reached. The authors review the double-blind trials in the literature and relate the findings to the neurobiology of benzodiazepine actions. Method The clinical review included all double-blind studies through 1989 that could be identified by means of Index Medicus and computer-assisted searches and by the cross-referencing of articles. The findings from the 14 studies of benzodiazepines used alone and the 16 studies of adjunctive therapy are presented separately. Results The studies reviewed suggest that 1) response is highly variable, and about one-third to one-half of patients improve; 2) benzodiazepines are potentially most useful as adjuncts to neuroleptics in the acute management of psychotic agitation, although actual antipsychotic effects have also been observed in some patients; 3) relatively higher doses of benzodiazepines may be associated with better response; and 4) therapeutic effects, when seen, develop rapidly but diminish after several weeks in some patients. The authors explore the neurobiological bases of benzodiazepine action, which presumably underlie their efficacy in schizophrenia and may help explain the variability of response. Conclusions Future research on benzodiazepines in the treatment of schizophrenia should focus on features that predict response, the relation of dopamine or other neurotransmitter systems to therapeutic effects, the schizophrenic symptoms most amenable to benzodiazepine treatment, changes in neuroleptic dose during benzodiazepine augmentation, the role of benzodiazepines in maintenance therapy, and the optimal characteristics of benzodiazepine treatment.

Although previous studies have reported differences in computed tomography (CT scan attenuation values between patients with schizophrenia and controls, interpretation of these findings has been hindered by methodological shortcomings such as the failure to control for head size, scanner calibration differences, and other confounding variables. In the present study of CT attenuation values in multiple brain regions in 20 patients with chronic schizophrenia and an equal number of age- and sex-matched normal subjects we controlled for head size and normalized the attenuation values for each scan to an internal standard. No significant differences emerged between the patients with schizophrenia and the controls. However, in the controls only, the mean density of white matter in the left frontal area was significantly higher ( t = −2.83, p = 0.01) than that in the right. The results, although possibly suggestive of deviant lateralization in schizophrenia, raise questions about the sensitivity and validity of regional CT attenuation values in detecting subtle anatomic abnormalities in patients with this illness.

The short-term effects of fluphenazine on plasma HVA concentrations were compared with the effects of fluphenazine and concurrent administration of debrisoquin, a monoamine oxidase inhibitor which does not cross the blood brain barrier and is used to enhance the CNS contribution to circulating plasma HVA concentrations. Fluphenazine significantly increased plasma HVA with or without debrisoquin 24 hours following the initiation of treatment. Domperidone, a butyrophenone dopamine antagonist which acts only in the peripheral nervous system, failed to alter plasma HVA concentrations. These data suggest that the acute effects of neuroleptic drugs on plasma HVA concentrations are dependent upon interaction with CNS dopaminergic systems and provide additional support for the use of plasma HVA as a reflection of CNS dopamine system activity in clinical studies.

Plasma homovanillic acid (pHVA) levels were measured in 16 chronically ill patients with schizophrenia who also suffered from tardive dyskinesia, and in a group of 14 chronically ill patients with schizophrenia who did not have tardive dyskinesia. All patients were studied following an extensive drug-free period (mean = 32.9 months). Patients with orofacial dyskinesia had significantly lower levels of pHVA than did controls. In patients without tardive dyskinesia, pHVA levels were significantly correlated with both positive and negative symptomatology. In contrast, pHVA levels from patients with tardive dyskinesia bore neither a significant nor a nearly significant relationship to symptomatology. The implications of these findings for dopaminergic models of tardive dyskinesia are discussed.

Caffeine, 10 mg/kg, was administered to 13 schizophrenic patients in a double-blind placebo-controlled study of its behavioral effects. Some measures of psychopathology were significantly increased: Brief Psychiatric Rating Scale (BPRS) total, BPRS subscales thought disorder, unusual thought content, and euphoria-activation, and several individual BPRS items. Nurses' Bunney-Hamberg ratings of psychosis and mania, comparing the day before with the day after pharmacological challenge, increased significantly. Compared to placebo, caffeine also produced significant increases of diastolic blood pressure and cortisol. Thus, these findings indicate that caffeine increases arousal and has a psychotogenic effect when administered to schizophrenic patients. The possible roles of various neurotransmitters is discussed with special emphasis on caffeine's actions on dopaminergic and adenosinergic systems.

Corticosteroids reportedly decrease blood-brain barrier (BBB) permeability and/or IgG synthesis in patients with multiple sclerosis or brain tumors. However, these effects have not been studied in healthy humans. We investigated the effects of prednisone, 80 mg/day for five days, on the ratio of cerebrospinal fluid (CSF) albumin/serum albumin, a measure of blood-brain barrier (BBB) permeability, and on CSF and serum IgG levels in six healthy, normal volunteers. We found significant steroid-induced decreases in serum and CSF albumin levels and in serum IgG levels. However, we found only a nonsignificant decrease in BBB permeability and no significant change in CNS IgG synthesis. These findings, based on a small number of volunteers, suggest that it may be difficult to further decrease BBB permeability and CNS IgG synthesis in medically healthy subjects.

Objective:The purpose of this study was to examine the relationship between the personality trait involving personal detachment and dopamine D2 receptor specific binding in healthy subjects.Method:Eighteen adult subjects completed the Karolinska Scales of Personality and the Tridimensional Personality Questionnaire and participated in a study that used [11C]raclopride positron emission tomography (PET) to quantify striatal D2 receptor binding. Results:A significant relationship was found between D2 receptor specific binding and detachment scores on the Karolinska Scales of Personality but not between D2 receptor specific binding and attachment scores on the Tridimensional Personality Questionnaire. In an exploratory analysis, the authors found a significant relationship between binding and the sentimentality cluster on the Tridimensional Personality Questionnaire but on no other personality clusters scores on the Tridimensional Personality Questionnaire or Karolinska Scales of Personality.Conclusions:Thes...

Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in risperidone-treated patients and compared their data with those from patients treated with clozapine or placebo. NE levels in risperidone patients were significantly higher than in placebo patients, but lower than in clozapine patients. Neither drug, however, had significant effect on plasma levels of the main neuronal metabolite of NE, dihydroxyphenylglycol (DHPG), suggesting that adrenoceptors blockade alone would not explain the NE findings. The rate of release of endogenous NE into the bloodstream (spillover) was elevated in both risperidone and clozapine patients in a manner that paralleled their NE levels; the NE clearance in both groups did not differ from placebo. Following 3H-NE infusion in risperidone-treated individuals, production of 3H-DHPG was normal, as it was in the clozapine group, suggesting that risperidone does not impede neuronal uptake or intraneuronal metabolism of NE by monoamine oxidase. Our data suggest that both risperidone and clozapine elevate plasma NE levels via enhanced neurotransmitter spillover, with risperidone producing a smaller effect.

Effects of fluphenazine on electrodermal activity (EDA) and heart rate (HR) were studied in patients with schizophrenia and normal control subjects during rest periods, presentation of innocuous tones, and a reaction time (RT) task. Two types of analyses were used: (1) between-group analyses-patients taking placebo were compared with patients taking fluphenazine and with control subjects using only data from the first test session; and (2) within-subject analyses-the same patients were tested when taking fluphenazine and when taking placebo. Results showed higher resting EDA and HR and smaller increments to task performance in placebo patients than in control subjects. Fluphenazine attenuated EDA levels but not the tonic response. Fluphenazine attenuated the HR response but did not affect HR level. Placebo patients were electrodermally hyporesponsive to the RT stimuli but not to simple tones. Fluphenazine markedly attenuated responsivity to simple tones but it attenuated responsivity less for RT stimuli. Testing medicated patients may thus produce misleading results with respect to many, but not all, purported autonomic markers of diagnosis in schizophrenia studies.

Anabolic androgen steroid abuse is associated with multiple psychiatric symptoms and is a significant public health problem. The biological mechanisms underlying behavioral symptom development are poorly understood.We examined levels of monoamine metabolites, neurohormones, and neuropeptides in the cerebrospinal fluid (CSF) of 17 healthy men, at baseline and following 6 days of methyltestosterone (MT) administration (3 days of 40 mg/d, then 3 days of 240 mg/d). Subjects received MT or placebo in a fixed sequence, with neither subjects nor raters aware of the order. Potential relationships were examined between CSF measures, CSF MT levels, and behavioral changes measured on a visual analog scale.Following MT administration, levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly lower (mean +/- SD, 103.8 +/- 47 vs 122.0 +/- 50.7 pmol/mL; P.01), and 5-hydroxyindoleacetic acid (5-HIAA) levels were significantly higher (mean +/- SD, 104.7 +/- 31.3 vs 86.9 +/- 23.6 pmol/mL; P.01). No significant MT-related changes were observed in CSF levels of corticotropin, norepinephrine, cortisol, arginine vasopressin, prolactin, corticotropin-releasing hormone, beta-endorphin, and somatotropin release-inhibiting factor. Changes in CSF 5-HIAA significantly correlated with increases in "activation" symptoms (energy, sexual arousal, and diminished sleep) (r = 0.55; P =.02). No significant correlation was observed between changes in CSF and plasma MT, CSF MHPG, and behavioral symptoms.Short-term anabolic androgenic steroid use affects brain neurochemistry, increasing CSF 5-HIAA and decreasing MHPG. Changes in 5-HIAA levels caused by anabolic androgenic steroids are related to the behavioral changes we observed. In this small sample, we did not observe a significant relationship between behavioral measures and either dose of MT or CSF and plasma levels of MT.

Olanzapine is an atypical antipsychotic with potent antimuscarinic properties in vitro (K(i) = 2-25 nM). We studied in vivo muscarinic receptor occupancy by olanzapine at both low dose (5 mg/dy) and high dose (20 mg/dy) in several regions of cortex, striatum, thalamus and pons by analyzing [I-123]IQNB SPECT images of seven schizophrenia patients. Both low-dose and high-dose olanzapine studies revealed significantly lower [I-123]IQNB binding than that of drug-free schizophrenia patients (N = 12) in all regions except striatum. [I-123]IQNB binding was significantly lower at high-dose than low-dose in the same regions. Muscarinic occupancy by olanzapine ranged from 13% to 57% at 5 mg/dy and 26% to 79% at 20 mg/dy with an anatomical pattern indicating M(2) subtype selectivity. The [I-123]IQNB data indicate that olanzapine is a potent and subtype-selective muscarinic antagonist in vivo, perhaps explaining its low extrapyramidal side effect profile and low incidence of anticholinergic side effects.

Several lines of evidence indicate that a variety of metabolic stressors, including acute glucose deprivation are associated with dopamine release. Pharmacologic doses of the glucose analogue, 2-deoxyglucose (2DG) cause acute glucoprivation and are associated with enhanced dopamine turnover in preclinical studies. In this study, we utilized [11C]raclopride PET to examine 2DG-induced striatal dopamine release in healthy volunteers. Six healthy volunteers underwent PET scans involving assessment of 2DG-induced (40 mg/kg) decrements in striatal binding of the D(2)/D(3) receptor radioligand [11C]raclopride. Decreases in [11C]raclopride specific binding reflect 2DG-induced changes in synaptic dopamine. Specific binding significantly decreased following 2DG administration, reflecting enhanced synaptic dopamine concentrations (p =.02). The administration of 2DG is associated with significant striatal dopamine release in healthy volunteers. Implications of these data for investigations of the role of stress in psychiatric disorders are discussed.

The authors studied the relationship between performance on the Wisconsin Card Sorting Test and on the Trailmaking-B test and measures of smooth pursuit eye movements in 12 patients with chronic schizophrenia and 12 normal volunteers. They found that performance on the Wisconsin Card Sorting Test was significantly correlated with measures of smooth pursuit eye movements in schizophrenic patients but not in normal subjects. Trailmaking-B scores, however, were unrelated to smooth pursuit eye movements in either group. (AmJ Psychiatry1991; 148:1580-1582)

Objective: This study sought to determine whether thought disorder induced in healthy volunteers by the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine resembles the thought disorder found in patients with schizophrenia. Method: The Scale for the Assessment of Thought, Language, and Communication was used to assess thought disorder in healthy volunteers (N=10) who received subanesthetic doses of ketamine and in a group of clinically stable inpatients with schizophrenia (N=15) who did not receive ketamine. Results: Mean scores on the Scale for the Assessment of Thought, Language, and Communication for patients with schizophrenia and healthy volunteers receiving ketamine did not differ significantly. Moreover, three of the four highest rated test items in both groups were the same. Conclusions: These data suggest that ketamine-induced thought disorder in healthy volunteers is not dissimilar to the thought disorder in patients with schizophrenia and provide support for the involvement of the NMDA receptor in a cardinal symptom of schizophrenia. (Am J Psychiatry 1999; 156:1646‐1649) Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartic acid (NMDA) receptor is involved in the pathophysiology of schizophrenia. Postmortem studies have revealed a lower density of glutamatergic receptors in patients with schizophrenia, and one study of CSF reported lower levels of glutamate in patients with schizophrenia than in healthy comparison subjects (1‐3). The most compelling evidence is provided by the psychotomimetic effects of the NMDA antagonists phencyclidine (PCP) and ketamine. In patients with schizophrenia, the administration of PCP and ketamine exacerbates existing psychotic symptoms and may reactivate symptoms in remittance (4‐6). The administration of PCP or ketamine to healthy volunteers reproduces many of the symptoms of schizophrenia, including aspects of formal thought disorder (4, 7, 8). Because the effects of ketamine resemble many of the clinical features of schizophrenia, this ketamine-induced behavioral syndrome has been proposed as a model for schizophrenia. Nonetheless, few direct comparisons between the thought disorder of schizophrenia and the thought disorder induced by NMDA antagonists have been conducted.

The regional cerebral glucose metabolic rates of clozapine-treated and fluphenazine-treated women with schizophrenia and normal controls were obtained by positron emission tomography (PET) using [18F]-2-fluoro-2-deoxy-D-glucose (FDG) as the tracer. The regional metabolic patterns were compared to each other and to the changes previously observed in men. In women, as in men, both clozapine- and fluphenazine-treatment were associated with lower metabolism in the superior prefrontal cortex and higher metabolism in the medial temporal lobe. In both men and women, clozapine treatment led to a greater lowering of inferior prefrontal cortex activity than fluphenazine, which was statistically significant in the larger male cohort. Fluphenazine led to higher metabolic rates in the lateral temporal lobe than clozapine did, but the differences between the two neuroleptics were not statistically significant in either group. The greatest differences in the female as compared to the male responses to fluphenazine and clozapine were in the cingulate and striatum. As compared to controls, the cingulate metabolic rates of women were reduced by 9.1% and 11.4% on clozapine and fluphenazine, respectively; whereas, men have a statistically nonsignificant reduction of 0.1% with clozapine and a 3.2% increase with fluphenazine. In men, fluphenazine was associated with a much greater elevation in basal ganglia metabolic rates than was clozapine, 23.5 % as compared to 3.75%; whereas, in women, basal ganglia metabolic rates are nearly equally increased by fluphenazine (21.6%) and clozapine (15.1%).

In vivo studies of dopamine D2 receptor occupancy with atypical antipsychotics have suggested good clinical efficacy at occupancy rates less than those observed with typical neuroleptics, and few extrapyramidal side effects (EPS), possibly even at high levels of D2 occupancy. We used [123I]IBZM-SPECT to investigate striatal D2 receptor occupancy in 10 schizophrenic patients who were treated with both a low (5 mg) and a high dose (20 mg) of the novel antipsychotic olanzapine without concomitant medications. The mean D2 occupancy at 5 mg was 59.8% (range 33-81%); the mean D2 occupancy at 20 mg was 82.8% (range 56-97%). Although the D2 occupancy rates on 5 and 20 mg olanzapine were significantly different (P0.001), there were no significant differences in clinical ratings for psychiatric symptoms or extrapyramidal side effects between the two doses of olanzapine. These data suggest that: (1) olanzapine doses below those used routinely occupy D2 receptors at levels approaching those associated with therapeutic response; (2) higher doses produce relatively high levels of D2 occupancy rates; and (3) EPS are mild even at relatively high levels of D2 occupancy.

Clozapine, risperidone, and other new “atypical” antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed.