Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients.

Plasma-free homovanillic acid, a major metabolite of dopamine, was measured in chronically ill schizophrenic patients both before and during treatment with the antipsychotic phenothiazine, fluphenazine. Neuroleptic treatment was associated with a significant time-dependent decrease in plasma homovanillic acid from pretreatment values, which were significantly elevated when compared with those of age- and sex-matched healthy control subjects. Further, both the absolute concentrations as well as the neuroleptic-induced reductions in plasma homovanillic acid determined over 5 weeks of neuroleptic treatment were statistically significantly correlated with ratings of psychosis and improvement in psychosis, respectively. These findings suggest that the delayed effects of neuroleptic agents on presynaptic dopamine activity may more closely parallel their therapeutic actions than do their immediate effects in blocking postsynaptic dopamine receptors and that a decrease in dopamine "turnover" may be responsible for their antipsychotic effects.

Pharmacogenomics of psychiatric disorders.

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.

Primary affective disorder, clinical state change, and MHPG excretion: a longitudinal study.

Urinary 3-methoxy-4-hydroxyphenethylene glycol (MHPG) excretion, which is thought to reflect CNS norepinephrine metabolism, has been shown to be significantly decreased in some depressed patients. Although there is consensus that urinary MHPG excretion varies directly with mood in rapidly cycling bipolar patients, there is little information on longer term state changes, such as those that accompany recovery from depression. Ten female patients with diagnoses of primary affective disorder were studied initially during an inpatient hospitalization and restudied at least ten months after discharge. Five healthy female comparison subjects were also studied over a similar interval of time. During the baseline period, the patient sample excreted less MHPG than did the comparison group. Improvement in clinical state from a seriously depressed baseline was associated with a significant increase in MHPG excretion, while the patients with recurrences of depression showed no change and continued to excrete less MHPG than the comparison subjects. These results suggest that urinary MHPG excretion may represent an index of psychobiological state in depressive patients.

CSF somatostatin and abnormal response to dexamethasone administration in schizophrenic and depressed patients.

Low levels of cerebrospinal fluid (CSF) somatostatin and abnormal response to dexamethasone are two neuroendocrine disturbances reported to appear in depression and other neuropsychiatric disorders. We measured the levels of CSF somatostatin in patients with schizophrenia (n = 44) and depression (n = 19). In view of in vitro and animal evidence of the ability of somatostatin to inhibit stimulated corticotropin secretion, we also administered the dexamethasone suppression test to a subgroup of the patients with schizophrenia (n = 16) and the total depressed group. Lower levels of CSF somatostatin were found in dexamethasone nonsuppressors regardless of diagnosis and were negatively correlated with maximum postdexamethasone cortisol level in the total and depressed patient groups. These data suggest a functional relationship between hypothalamic-pituitary-adrenal axis hyperactivity and reduced CSF somatostatin level.

Platelet tritiated imipramine binding and serotonin uptake in depressed patients and controls. Relationship to plasma cortisol levels before and after dexamethasone administration.

We measured platelet tritiated imipramine binding and serotonin uptake in 51 depressed patients and 43 normal controls. Although there were no significant differences in platelet 3H-imipramine binding or serotonin uptake when the total group of depressed patients was compared with controls, depressed women (n = 32) had a significantly lower maximal density of 3H-imipramine binding sites (beta max) than control women (n = 25). Moreover, among the total group of depressed patients, there were significant negative correlations between the beta max values and plasma cortisol levels at 4 PM (n = 41) and 11 PM (n = 41) following dexamethasone administration. These negative correlations between beta max and cortisol levels were strongest among melancholic patients both at 4 PM before dexamethasone administration (n = 14) and at 11 PM after dexamethasone administration (n = 15). These data suggest that the reported decrease in beta max found among depressed patients may be related to and is perhaps secondary to the hypercortisolemia of depression.

National Institute of Mental Health longitudinal study of chronic schizophrenia. Prognosis and predictors of outcome.

We performed a longitudinal study of chronic schizophrenic patients who were hospitalized for research purposes at the National Institute of Mental Health (NIMH) Intramural Program in the 1970s and early 1980s. We assessed present course, outcome and predictor data from the initial cohort of 58 young chronic schizophrenic patients who were followed up for 2 to 12 years following their NIMH index hospitalization. At follow-up, the sample showed substantial functional impairment and levels of symptoms with only about 20% of the sample demonstrating a good outcome. In addition, strong intercorrelation was noted among the symptom and functioning indexes at follow-up. Moreover, neuropsychologic tests of frontal cortical functioning were significantly correlated with outcome levels of negative symptoms and social functioning but not with levels of positive symptoms. During the period from the index hospitalization to the follow-up assessment, 78% of the sample suffered a relapse, 38% attempted suicide and 24% had episodes of major affective illness. Furthermore, levels of positive and negative symptoms ascertained when patients received optimal neuroleptic treatment during the index hospitalization significantly predicted outcome levels of symptoms and functioning and time spent hospitalized during the follow-up period. In contrast, levels of index positive and negative symptoms ascertained during the drug-free state did not predict outcome symptoms or functioning. These data suggest that treatment response is a critical predictor variable. We examined the implication of these data for the course of illness in schizophrenics.

Are there two types of unipolar depression?

Personality traits and clinical characteristics in psychiatric outpatients with affective disorder were examined. Two groups of unipolar patients, divided on the basis of treatment response to tricyclic antidepressants, were compared to a bipolar group. While the unipolar-T (tricyclic responder) group showed premorbid personality traits of chronic anxiety and obsessiveness, neither the bipolar nor unipolar-L (tricyclic nonresponder, lithium carbonate responder) groups showed such findings. In fact, the unipolar-L and bipolar groups were similar not only with regard to personality variables, but also in terms of both drug response and certain family history features. These findings cast doubt on the homogeneity of unipolar depression and suggest the possibility of a subtype of unipolar depression with psychobiologic and personality features resembling bipolar disorder.

Plasma norepinephrine level in affective disorders. Relationship to melancholia.

The plasma norepinephrine (NE) level was measured in 45 depressed patients and in 41 normal control subjects. Patients who met DSM-III criteria for a major depressive episode with melancholia (MDE-MEL; N = 16), and those with MDE but with melancholia in a previous episode (MDE-PMEL; N = 8), had significantly higher levels of plasma NE than normal control subjects while lying and standing and a greater change in the levels; whereas, patients with MDE alone (N = 10) and patients with dysthymic disorder (N = 11) had levels of NE comparable with control levels. Bipolar patients (N = 7), all with current melancholia or a history of it, had significantly lower levels of NE while lying down or standing than depressed unipolar patients with similar histories of melancholia. Among unipolar patients with melancholia, nonsuppressors on the dexamethasone suppression test had significantly higher lying-down NE values than did suppressors, suggesting that dysregulation of both the hypothalamic-pituitary-adrenal axis and the peripheral sympathetic nervous system occur together in this subgroup of depressed patients.

Quantitative neuroanatomy in schizophrenia. A controlled magnetic resonance imaging study.

Twenty-four patients with schizophrenia and 14 normal control subjects underwent magnetic resonance imaging scans using a 0.5-tesla scanner and 600-ms inversion recovery technique. A midsagittal section and twelve 1-cm coronal sections beginning at the frontal pole were obtained, and linear, area, and signal intensity measurements were made on nine brain regions. Volume estimates were made by summing consecutive sections for four of the following regions: the precallosal frontal lobes, temporal lobes, lateral ventricles, amygdala-hippocampal complexes, and cerebral hemispheres. The area of the third ventricle in its most anterior coronal slice was increased by 73% in schizophrenic subjects (0.83 +/- 0.08 cm2) in comparison with controls (0.48 +/- 0.04 cm2). Lateral ventricular volume was increased by 62% in schizophrenic subjects (24.7 +/- 2.6 mL) in comparison with controls (15.2 +/- 1.4 mL). The lateral ventricular enlargement in schizophrenic subjects was more pronounced posteriorly than anteriorly, especially at the level of the anterior thalamus and the colliculi. There were no other significant differences between schizophrenic and control groups in any other spatial or signal intensity measures. There was no brain region the size of which correlated with ventricular size. These data corroborate third and lateral ventriculomegaly in schizophrenia using magnetic resonance imaging but fail to further localize the structural abnormality.

Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression.

Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients.

High intercorrelations among urinary outputs of norepinephrine and its major metabolites. A replication in depressed patients and controls.

We examined the intercorrelations among urinary outputs of norepinephrine (NE) and its three major metabolites in unipolar depressed patients (n = 28) and normal controls (n = 24). Among the depressed patients, levels of NE correlated with normetanephrine (NM), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA), and VMA correlated with NM and MHPG. In the total group of depressed and control subjects (n = 52), the sum of NE and its major metabolites correlated with urinary outputs of NE, NM, MHPG, and VMA. These highly significant correlations among urinary outputs of NE and its major metabolites replicate a previous report of strong correlations among these same four urinary substances in a smaller group of depressed patients.

Urinary 3-methoxy-4-hydroxyphenylglycol and major affective disorders. A replication and new findings.

We studied group and subgroup differences in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with major affective disorder (66 depressed, 13 manic) and normal volunteers (27 subjects). Bipolar I depressed patients excreted less MHPG than unipolar depressed patients, manic patients, or normal volunteers. The mean (+/- SEM) MHPG excretion rate was 1.44 +/- 0.10 mg/day in 19 depressed bipolar I patients, 1.79 +/- 0.11 mg/day in 28 unipolar depressed patients, 2.11 +/- 0.19 mg/day in 13 manic patients, and 1.85 +/- 0.12 mg/day in 27 normal volunteers. Other sources of variance that affected urinary MHPG levels did not explain subgroup or state differences. There was only a trend for a low pretreatment MHPG level to be associated with positive response to imipramine hydrochloride or desipramine hydrochloride in the 19 patients treated with these drugs. The application of this biological test value for prediction of differential response to antidepressant drugs would therefore seem premature.

Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine.

OBJECTIVE: To test the hypothesis that interindividual differences in response to clozapine therapy might be attributable to the D4 dopamine receptor (DRD4) alleles they carry. Different alleles of the D4 dopamine receptor, coded by the DRD4 gene, differ in the affinity with which they bind the atypical antipsychotic drug clozapine in vitro. This may have physiologic implications. Clinical response to clozapine therapy varies among patients. The observation that, in vitro, clozapine binds the protein products of different DRD4 alleles with differing affinity characteristics suggested this hypothesis. METHOD: The region of the DRD4 gene that encodes the putative third cytoplasmic loop of the D4 receptor contains a 48-base pair sequence repeated a variable number of times. With use of polymerase chain reaction amplification, we assessed this variable number of tandem repeats polymorphism in a series of schizophrenic and schizoaffective subjects who had been treated with clozapine, and related genotype with treatment response, to test the hypothesis that DRD4 alleles lead to varying response to clozapine. RESULTS: Allelic variation at the DRD4 locus does not predict clinical response to clozapine relative to either fluphenazine hydrochloride or placebo in subjects with treatment-refractory schizophrenia or schizoaffective disorder. CONCLUSIONS: DRD4 alleles do not predict therapeutic response to clozapine in schizophrenic and schizoaffective patients. There are implications from these data for the pathophysiology of schizophrenia and the mechanism of clozapine's therapeutic effect are discussed.

Cerebrospinal fluid monoamine and monoamine metabolite levels and the dexamethasone suppression test in depression. Relationship to life events.

The cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 23 patients meeting DSM-III criteria for major depressive episode, 15 of whom also met criteria for melancholia. Life events during the six-month period before the onset of depression were recorded using Paykel's method. There was no difference in Hamilton depression ratings between patients with life events and those without. However, depressed patients who did not have a life event in the six months before the onset of depression had significantly lower levels of the dopamine metabolite homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid than those with life events. The incidence of nonsuppression on the dexamethasone suppression test was also greater in patients with a major depressive episode who did not have an undesirable life event than in those who did. Thus, the presence or absence of life events led to a separation into biologically distinct groups.

Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine.

Twenty-one patients with schizophrenia who met criteria for neuroleptic treatment resistance or intolerance participated in a crossover, placebo-controlled, double-blind comparison of long-term typical neuroleptic and clozapine treatment. Clozapine significantly reduced total as well as positive and negative symptoms in comparison with both fluphenazine and placebo. Of the 21 patients, eight (38%) showed clozapine superiority on the basis of prospective response criteria. High levels of extrapyramidal side effects during fluphenazine treatment and later onset of illness were clinical predictors of clozapine superiority. Clozapine and fluphenazine equally reduced plasma homovanillic acid levels in comparison with placebo, although fluphenazine but not clozapine increased plasma prolactin level. A striking biologic difference between clozapine and fluphenazine was clozapine's enhancement of indexes of noradrenergic activity. Superior clozapine response was predicted by low ratios of cerebrospinal fluid homovanillic acid to 5-hydroxyindoleacetic acid, consistent with the notion that balance between dopaminergic and serotoninergic systems is important for clozapine's mechanism of action.

A quantitative analysis of smooth pursuit eye tracking in monozygotic twins discordant for schizophrenia.

BACKGROUND: Previous studies of discordant monozygotic (MZ) twins have suggested that abnormal smooth pursuit eye tracking is an indicator of genetic liability for schizophrenia. We attempted to replicate this in a different sample of twins. METHODS: Probands from 12 sets of MZ twins discordant for schizophrenia who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and their co-twins without psychiatric diagnosis (except 2 with a history of substance abuse) and 12 sets of normal control MZ twins. Psychiatric diagnosis was based on Structured Clinical Interview; monozygosity was based on analysis of 19 red blood cell antigens. Smooth pursuit eye movement gain (equal to the ratio of eye-target velocity) and numbers, amplitudes, and subtypes of saccadic eye movements were compared. Measures were derived from computer analysis of digitized infrared oculographic recordings of constant velocity (16.67 degrees per second) smooth pursuit eye tracking. RESULTS: Quantitative measures of eye tracking for the affected twin were inferior to those of the unaffected co-twin, with affected twins showing significant decreases in gain and significant increases in numbers and amplitudes of total and intrusive saccades. Moreover, whereas means for the group of affected twins differed significantly from those of normal controls on measures of gain and total saccades, means for the group of unaffected co-twins were well within the normal range. CONCLUSIONS: These data are consistent with the hypothesis that abnormal eye tracking is associated with the expression of illness, or phenotype, in schizophrenia, at least in this twin sample. The data raise questions regarding the use of eye tracking measurement for identifying putative gene carriers among at-risk relatives in genetic linkage studies of schizophrenia.

The brain metabolic patterns of clozapine- and fluphenazine-treated patients with schizophrenia during a continuous performance task.

BACKGROUND: The comparison of the effects of 2 classes of neuroleptic drugs on regional brain functional activities may reveal common mechanisms of antipsychotic drug efficacy. METHODS: The regional cerebral glucose metabolic rates of patients with schizophrenia who were and were not receiving neuroleptic drugs and normal control subjects were obtained by positron emission tomography using fludeoxyglucose F 18 as the tracer. RESULTS: Compared with normal controls and patients not receiving medication, fluphenazine hydrochloride- and clozapine-treated patients had lower global gray matter absolute metabolic rates throughout the cortex. When normalized regional glucose metabolic rates were examined, both medications lowered rates in the superior prefrontal cortex and increased rates in the limbic cortex. Fluphenazine, but not clozapine, increased metabolic rates in the subcortical and lateral temporal lobes, whereas clozapine, but not fluphenazine, decreased inferior prefrontal cortex activity. CONCLUSIONS: These changes are consistent with the idea that neuroleptic drugs lead to "compensation" and "adaptation" rather than "normalization" of the functional activities of brain structures in schizophrenia. The overall similarity of their global and regional metabolic effects suggests that both classes of antipsychotic drugs share some common mechanisms of action. One possibility is that of inducing a shift in the balance of cortical to limbic cortex activity. Differential effects in the inferior prefrontal cortex and the basal ganglia might underlie differences in the therapeutic efficacy and side effect profile of clozapine and fluphenazine.

Atrophy limited to the third ventricle in chronic schizophrenic patients. Report of a controlled series.

Computed tomographic scans of 30 chronic schizophrenic patients and 26 matched medical controls were blindly assessed for ventricular brain ratio, cortical atrophy, third-ventricle diameter, and cerebellar atrophy. Schizophrenic patients had significantly larger third ventricles than the medical controls. There was no difference in the other brain morphologic variables. Phenomenology, drug response, CSF levels of 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, and a wide variety of clinical variables did not correlate with any measure of brain morphology. Clinicopathologic correlates of brain morphology may be limited to those patients with significant atrophy.

High-dose naloxone infusions in normals. Dose-dependent behavioral, hormonal, and physiological responses.

Hypotheses of involvement of the endogenous opioid system (EOS) in the regulation of human behavior suggest that functional blockade of the EOS should have behavioral consequences. Clinical administration of the opiate receptor antagonist naloxone hydrochloride, however, has had little or inconsistent behavioral effects in normals. This may be attributable to the use of doses insufficient to yield a complete EOS blockade. To assess this explanation, normals were administered increasing doses of naloxone hydrochloride (0.3 to 4 mg/kg) in a single-blind design. Significant dose-dependent behavioral, hormonal, and physiological effects were found. With increasing doses of naloxone, volunteers demonstrated increasingly dysphoric affects, a deterioration of performance on memory testing, increasing systolic BP and respiratory rate, and increasing plasma cortisol and growth hormone levels. These results are consistent with the expected effects of increasing EOS blockade, and thus suggest that lower doses of naloxone used in previous clinical studies may not have been sufficient to produce a complete EOS blockade. Specifically, they suggest involvement of the EOS in the tonic regulation of normal human mood, memory, BP, respirations, and plasma growth hormone and cortisol levels.

Selective and nonselective monoamine oxidase inhibitors: behavioral disturbances during their administration to depressed patients.

The occurrence of behavioral disturbances during four-week treatment of depressed patients with the nonselective monoamine oxidase (MAO) inhibitor, phenelzine sulfate (N = 14), the selective MAO-type A inhibitor, clorgyline (N = 12), and the partially selective MAO-type B inhibitor, pargyline hydrochloride (N = 13), was studied. Behavioral disturbances were encountered during treatment with each of the MAO-inhibiting drugs, with an overall incidence of 15% (six of 39 patients). All but one episode met criteria for mania or hypomania. Patients with bipolar illness experienced significantly greater incidences of behavioral disturbances in comparison with patients with unipolar illness (35.3% v 4.5%, respectively). The earliest latency to onset of a behavioral disturbances was 18 days, whereas the mean latencies were 22 to 26 days. Episodes of hypomania were observed after discontinuation of drug treatment in individual patients with unipolar and bipolar illness. Repeated MAO-inhibitor treatment, as part of a crossover study of clorgyline and pargyline, produced an increased severity of behavioral disturbances and a significantly shortened latency to onset.