Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine?

Alcohol and other drugs of abuse are commonly used by persons with schizophrenia and contribute to the overall morbidity of the disorder. Standard, or typical, antipsychotic drugs do not limit such substance use and may even render it more likely. However, preliminary data from our group and others suggest that the atypical antipsychotic clozapine may decrease substance use in this population. While recognizing the likelihood that substance use decreases negative symptoms (as well as extrapyramidal symptoms) in persons with schizophrenia, we hypothesize that the biological basis of substance use relates to a "reward-deficiency syndrome" secondary to dysfunctional dopamine-mediated mesocorticolimbic neurons in these individuals. We further suggest that clozapine's beneficial effect in patients with comorbid schizophrenia and substance use disorders may relate to its presumed ability to ameliorate the deficits in both the mesocortical and mesolimbic dopaminergic neuronal projections through its various actions on dopaminergic, serotonergic, and particularly noradrenergic neurons.

Hypothalamic-pituitary-adrenal axis effects on plasma homovanillic acid in man.

BACKGROUND: Effects of the hypothalamic-pituitary-adrenal (HPA) axis on central dopaminergic systems have been proposed to underlie the development of psychotic symptoms in depression. This study examined HPA axis hormone effects on plasma levels of homovanillic acid (HVA), the dopamine metabolite, in healthy volunteers, using a placebo-controlled, double-blind, random-assignment, crossover design. On the basis of preliminary studies, we hypothesized that HPA axis hormones would produce delayed effects on plasma HVA levels measured in the afternoon. METHODS: Ten healthy subjects underwent a standard protocol on four occasions and each time received ovine corticotropin-releasing hormone, synthetic adrenocorticotropic hormone (ACTH), cortisol, or placebo. Plasma HVA was measured at 9 AM and 4 PM on Day 1, immediately prior to administration of the test substance at 7 PM, then at 30-60-min intervals until 11 PM. Plasma HVA levels were subsequently obtained at 9 AM and 4 PM on Days 2 and 3. RESULTS: As predicted, there were significant differences between test substances in delayed effects on afternoon HVA levels measured on Days 2 and 3, with cortisol and ACTH producing greater increases in HVA than placebo. Acute effects of HPA axis hormones on HVA were not found, while differences between test substances in delayed effects on morning HVA levels approached significance. CONCLUSIONS: HPA axis hormones exert delayed effects on plasma HVA levels in healthy humans.

Late feedback effects of hypothalamic-pituitary-adrenal axis hormones in healthy subjects.

We tested the hypothesis that hypothalamic-pituitary-adrenal (HPA) axis hormones exert prolonged negative feedback on corticotropin (ACTH) secretion. Ten healthy subjects underwent a standard protocol 4 x and each time received i.v., under double blind conditions and in random order, corticotropin-releasing hormone (CRH) 1 microgram/kg, co-syntropin (ACTH1-24) 0.25 mg, cortisol (hydrocortisone) 15 mg, or placebo. Subjects had a venipuncture for cortisol and ACTH levels at 0900h on Day 1, then had i.v. insertion and cortisol and ACTH levels measured at 1600 and 1855h. The test substance was given at 1900h and cortisol and ACTH levels were monitored until 2300h, when the i.v.'s were discontinued. Subjects then had venipunctures for cortisol and ACTH levels at 0900 and 1600h on Day 2 and 3. Hormones had the expected acute effects. Hormones did not differ from placebo in effects on cortisol levels measured over Days 2 and 3. There were significant differences between test substances in effects on afternoon ACTH levels on Days 2 and 3, with ACTH levels increasing significantly less from baseline to Day 2 and 3 after CRH administration than after placebo, and tending to increase less from baseline to Day 3 after ACTH administration than after placebo. Examination of Day 2 and 3 morning ACTH levels showed a significant interaction between the test substances and time (Day 2 vs. 3), and interpretation of this interaction is not straightforward. We conclude that CRH and possibly ACTH exert late inhibitory effects on ACTH secretion measured in the afternoon of the 2 days following hormone administration.

Signal transduction by platelet adenylate cyclase: alterations in depressed patients may reflect impairment in the coordinated integration of cellular signals (coincidence detection).

BACKGROUND: Adenylate cyclase (AC) responds to distinct but coincident signals from the agonist-stimulated G-protein Gs and the inhibitory G-protein Gi by generating a greater output signal-to-noise ratio--i.e., agonist-stimulated to basal ratio (fold-stimulation)--through coincidence detection than that generated by a single input (Gs) alone. Such coincidence detection by murine brain AC was found to be enhanced during chronic antidepressant treatment with imipramine. METHODS: We examined and compared the basal, agonist-stimulated, and guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) or AlF4 ion postreceptor-stimulated AC activities in mononuclear leukocytes and platelets from the same blood specimens obtained from depressed patients (n = 27) and control subjects (n = 19). RESULTS: In all subjects, the differences (delta GTP gamma S or delta AlF4) between postreceptor measures of AC in mononuclear leukocytes (where AC is regulated by Gs but not by Gi) and platelets (where AC is regulated by both Gs and Gi) were highly significant. In controls, the relationships between delta GTP gamma S or delta AlF4 and basal, agonist-stimulated, and the fold-stimulation of agonist-stimulated platelet AC resembled the regulation of AC by Gi in model-membrane systems. Comparable relationships between delta GTP gamma S or delta AlF4 and basal, agonist-stimulated, and the fold-stimulation of agonist-stimulated platelet AC activities were not observed in depressed patients. CONCLUSIONS: Our results suggest that in controls, platelet AC enzyme activity is determined (in part) by the coordinated integration of signals from Gs and Gi through coincidence detection, while such coincidence detection by platelet AC may be impaired in patients with depressive disorders.

Cortisol feedback effects on plasma corticotropin levels in healthy subjects.

An abnormality of rapid cortisol feedback on activity of the hypothalamic-pituitary-adrenal axis has been reported in depression. However, there is controversy regarding the existence of rapid cortisol feedback on corticotropin (ACTH) secretion in humans. We investigated the effects of cortisol on ACTH levels in healthy subjects using a placebo-controlled, double blind, random assignment, cross-over design. Ten medication-free volunteers with no psychiatric history and no active medical problems underwent a standard protocol on two occasions separated by at least 2 weeks. Each time, subjects were admitted to a General Clinical Research Center and had infusion of 15 mg cortisol (hydrocortisone sodium succinate) over 120 min or placebo. Serum levels of cortisol and plasma ACTH levels were determined at baseline and over the 4 h after the start of the infusion. Over the two GCRC admissions subjects received both cortisol and placebo infusions, and the order of the two infusions was randomized. Compared to placebo, cortisol infusion produced a significant decrease in plasma ACTH levels beginning within 60 min from the start of the infusion. We conclude that cortisol infusion produces early inhibition of ACTH secretion in normal humans.

Focal cerebral perfusion defects demonstrated by 99mTc-hexamethylpropyleneamine oxime SPECT in elderly depressed patients.

High resolution single photon emission computed tomography (SPECT) was used to evaluate regional cerebral blood flow (rCBF) in 14 acutely depressed elderly patients and 29 normal subjects. SPECT images of the two groups were randomized and blindly read. Foci of decreased radionuclide uptake were assessed by number and location. The total number of rCBF defects per whole brain study was significantly greater in the depressed patients than in the normal subjects. A significantly greater number of rCBF defects was found most strikingly in the lateral frontal and less prominently in the lateral and medial temporal brain regions of the depressed patients.

Diurnal variation of plasma cortisol and homovanillic acid in healthy subjects.

We investigated the relationship between plasma levels of cortisol, the dopamine metabolite homovanillic acid (HVA) and norepinephrine in healthy human subjects. Plasma cortisol and HVA levels were measured at 0800h, and in an integrated sampling procedure involving samples every 15 min between 1300 and 1600h. Plasma norepinephrine was measured at 0800 and 1300h. Cortisol, HVA and norepinephrine indices did not show significant correlations with each other. Both cortisol and HVA showed significant decreases over time. Longitudinal Random Effects (LRE) models were used to test whether individual cortisol and HVA curves over time were correlated; significant correlations were not found with this procedure. While significant correlations between cortisol and catecholamine indices have been reported in depressed patients, our results do not suggest such correlations in healthy subjects.

Norepinephrine metabolism and psychoactive drugs in the endogenous depressions. 1968.

After intraventricular injection of norepinephrine-H3, the concentration of norepinephrine, of normetanephrine and of the deaminated catechols in rat brains was determined, following action of imipramine, desmethylimipramine, chlorpromazine, lithium chloride or cocaine. Following administration of imipramine, desmethylimipramine, and chlorpromazine, norepinephrine concentration decreased significantly at first, had distinctly increased 4.5 hours after imipramine and desmethylimipramine but was normal once again after chlorpromazine. Normetanephrine concentration increased after imipramine and desmethylimipramine but was unchanged after chlorpromazine. Under the effect of these drugs, the deaminated catechols showed no changes compared with control values. Cocaine resembled the antidepressants, but the amount of deaminated compounds was reduced. Lithium chloride, on the other hand, increased the concentration of deaminated catechols under certain conditions, reduced normetanephrine concentration but did not influence norepinephrine concentration. In addition to the animal experiments, the following data of six patients with an "endogenous" depression were recorded over a period of several weeks: the clinical findings by means of the Hamilton Depression Rating Scale, and the excretion of normetanephrine and of vanillylmandelic acid (VMA) in the urine before, during and after treatment with imipramine. The therapy led to a significant reduction of VMA; however, this reduction cannot be correlated with an improvement in the clinical findings. On the other hand, excretion of normetanephrine is apparently not dependent on the administration of imipramine but seems to reflect the clinical state, since improvement of the depression was regularly combined with an increased excretion of normetanephrine.

Should clozapine be a first-line treatment for schizophrenia? The rationale for a double-blind clinical trial in first-episode patients.

Recent studies suggest that clozapine is more effective than typical neuroleptics for patients with treatment-resistant schizophrenia. Although other investigations suggest that clozapine may also be at least as effective, and probably more so, than typical neuroleptics for individuals with acute psychosis, the toxicity of this drug has caused its use to be restricted to patients who have demonstrated resistance to previous treatment. The hypothesis behind this article, however, is that clozapine may not only be more effective than typical neuroleptics for individuals with "first-episode" schizophrenia but may also lead to a better long-term course in such patients. This hypothesis is based on the clinical literature concerning clinical and biological response to typical and atypical neuroleptic drugs, as well as on preliminary findings from studies of clinical, neuroendocrine, and biochemical effects that occur during treatment with haloperidol but not with clozapine. When examined in light of Wyatt's recent proposal that each period of symptom exacerbation may lay the groundwork for further symptoms and for increasing syndrome severity, the data suggest that clozapine, despite its disturbing side-effect profile, should be studied in controlled double-blind clinical trials during patients' first episode of schizophrenia. If such investigations show that clozapine is more effective than typical neuroleptics for patients with first-episode schizophrenia and results in a better long-term course, then its benefits and risk as a routine first-line treatment for schizophrenia can be considered. The findings of these studies may also lead us to the regular clinical use of new agents that are less toxic than clozapine but have similar clinical and biological profiles.

Platelet monoamine oxidase activity and deficit syndrome schizophrenia.

Measures of affective flattening that combine self-reported emotional experience with observed affect may identify deficit syndrome patients better than ratings based on observed affect alone. In this study, we examined 23 clinically stable but chronically ill schizophrenic patients, 15 of whom were found to have a deficit syndrome. After exclusion of patients with self-reported depressed mood from the deficit syndrome group, the remaining patients with a deficit syndrome not accompanied by self-reported depressed mood showed a strikingly homogeneous distribution of platelet monoamine oxidase activity. Results suggest that inclusion of self-reported emotional experience in clinical definitions of the deficit syndrome will increase the specificity of diagnosis.

Acute and delayed effects of corticotropin-releasing hormone on dopamine activity in man.

Interactions between the hypothalamic-pituitary-adrenal (HPA) axis and central dopamine systems have been hypothesized to play a role in the pathophysiology of psychosis, but the normal physiology of HPA axis-dopamine interactions has not been fully defined. We report results from two uncontrolled pilot studies which explored the effects of ovine corticotropin-releasing hormone (CRH) on dopamine activity in healthy human subjects. Administration of CRH did not produce changes in plasma levels of homovanillic acid (HVA), the major dopamine metabolite, over the subsequent 3.5 hours. However, when the effects of CRH were followed over a longer period in a small subgroup, we found that CRH administration produced a two-fold rise in plasma HVA levels 20 hours later, without affecting plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine. Thus, the findings of these pilot studies suggest that CRH may exert delayed but not acute effects on dopamine activity in man.

Mind and mood in modern art, II: Depressive disorders, spirituality, and early deaths in the abstract expressionist artists of the New York School.

This article documents the high prevalence of mood disorders in a group of 15 of the mid-twentieth-century Abstract Expressionist artists of the New York School. These artists, using the technique of psychic automatism (based on free association) in order to reveal unconscious material, created a psychologically and spiritually significant art that addressed the mythic themes of creation, birth, life, and death. Over 50% of the 15 artists in this group had some form of psychopathology, predominantly mood disorders and preoccupation with death, often compounded by alcohol abuse. At least 40% sought treatment and 20% were hospitalized for psychiatric problems. Two committed suicide; two died in single-vehicle accidents while driving; and two others had fathers who killed themselves. Many of these artists died early deaths, and close to 50% of the group (seven of 15) were dead before the age of 60. The material presented in this article suggests the following formulation and hypothesis. Depression inevitably leads to a turning inward and to the painful reexamination of the purpose of living and the possibility of dying. Thus, by bringing the artist into direct and lonely confrontation with the ultimate existential question, whether to live or to die, depression may have put these artists in touch with the inexplicable mystery that lies at the heart of the "tragic and timeless" art that the Abstract Expressionists aspired to produce.

Urinary MHPG and clinical symptoms in patients with unipolar depression.

The relationship between levels of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) and symptom scores on the Hamilton Rating Scale for Depression was examined in 31 patients with unipolar depression. Patients with either low MHPG or high MHPG showed significant sleep disturbance in the form of early morning awakening. Patients with mid-range or high MHPG showed decreased work and activities. Endogenomorphy factor scores represented a blend of these findings.

Hypothalamic-pituitary-adrenal axis activity and 1-year outcome in depression.

The relationships of longitudinal biological measures to longer-term outcome in depressed patients have not been well explored. This study was designed to investigate whether in a sample of depressed patients: (a) symptomatic and functional outcome at 1 year was significantly different in psychotic major depressed (PMD) patients as compared with nonpsychotic major depressed (NPMD) patients and (b) high urinary or plasma cortisol levels at baseline or 1 year were associated with poorer outcomes at 1 year. Forty-two depressed patients (9 psychotic, 33 nonpsychotic) were evaluated at baseline and at 1 year using a battery of clinical ratings and measures of cortisol. A group of normal, healthy control subjects were similarly evaluated at baseline. At 1-year follow-up, PMD patients did not differ from NPMD patients in their Hamilton Depression Rating Scale (HDRS) and Brief Psychiatric Rating Scale scores (BPRS), but PMD patients demonstrated significantly poorer social and occupational functioning. Significant correlations were observed (n = 18) between higher levels of urinary and plasma cortisol at 1 year and poorer social and occupational functioning at 1 year, independent of the degree of residual depression. In contrast, baseline measures of urinary and plasma cortisol did not predict social and occupational functioning at 1 year.

Haloperidol response and plasma catecholamines and their metabolites.

Eleven acutely psychotic patients with schizophrenia or schizoaffective disorder underwent a 5-7 day drug-washout period (with lorazepam allowed) prior to participating in a 6-week controlled dose haloperidol trial. Patients were evaluated longitudinally with clinical ratings and with plasma measures of the catecholamines dopamine (pDA) and norepinephrine (pNE) and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG). All patients exhibited clinical improvement with haloperidol; the decrease in their Brief Psychiatric Rating Scale (BPRS) scores ranged from 32 to 89%. Measures of pHVA increased within the first week of treatment and returned to baseline by week 5. The pattern of change of pDA resembled that of pHVA. The pattern of change of pNE and pMHPG revealed a decrease over the course of treatment. The early increase and the subsequent decrease in pHVA were strongly correlated with improvement in positive symptoms on the BPRS. These data are consistent with previous reports on the change in pHVA and pMHPG during clinical response to haloperidol. The data on change of pDA and pNE further describe the nature of the biochemical response to this drug.

Clozapine response and plasma catecholamines and their metabolites.

The atypical neuroleptic clozapine has an unusual profile of clinical effects and a distinctive spectrum of pharmacological actions. Plasma measures of catecholamines and their metabolites have been used in the past to study the action of typical neuroleptics. We obtained longitudinal assessments of plasma measures of dopamine (pDA), norepinephrine (pNE), and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG), in eight treatment-resistant or treatment-intolerant schizophrenic patients who were treated with clozapine for 12 weeks following a prolonged drug-washout period. Our findings from the study of these eight patients suggest the following: Plasma levels of HVA and possibly NE derived from the neuroleptic-free baseline period may predict response to clozapine; plasma levels of HVA and MHPG decrease during the initial weeks of treatment in responders but not in nonresponders; and plasma levels of DA and NE increase in both responders and nonresponders to clozapine.

Changes in norepinephrine output following light therapy for fall/winter seasonal depression.

Recurrent fall/winter depressions that remit during spring and summer have been called Seasonal Affective Disorders (SAD) (Wehr and Rosenthal 1989). The pathophysiology of SAD, its relationship to nonseasonal affective disorders, and the mechanism of action of light therapy, which is effective in treating SAD, remain to be elucidated (Depue et al 1989; Jacobsen et al 1987; James et al 1986; Joseph-Vanderpool et al 1991; Skwerer et al 1988, Terman et al 1989). Norepinephrine (NE) may play a role in the mechanisms of action of many antidepressant treatments (Schildkraut 1965) that alter NE metabolism (Schildkraut et al 1964 and 1965) and decrease the urinary output of NE and its metabolites, i.e., "whole-body NE turnover" (WBNET) (Golden et al 1988; Potter et al 1988). The present study explored whether light therapy also reduces the urinary output of NE and its metabolites.

Learned helplessness and urinary MHPG levels in unipolar depression.

OBJECTIVE: Studies of the learned helplessness paradigm in laboratory animals show increased central noradrenergic activity following exposure to uncontrollable stressors. In clinical studies, depressed patients as a group report higher perceptions of helplessness and powerlessness. The authors examined the relationship between perceptions of powerlessness and noradrenergic activity in depressed patients. METHOD: Twenty drug-free patients (12 women and 8 men) meeting DSM-III criteria for major depressive disorder were given the Kobasa Hardiness Questionnaire, which contains subscales measuring feelings of powerlessness, security, and alientation. Concurrently, 24-hour urine samples were collected for measurement of urinary MHPG. RESULTS: Significant correlations were found between MHPG levels and total hardiness scores as well as between MHPG levels and total powerlessness scores but not between MHPG levels and total security or total alientation scores. CONCLUSIONS: These results suggest that depressed patients with high urinary output of MHPG are more likely to show the cognitive features of learned helplessness.

Abnormal flash visual evoked response in melancholia: a replication study.

Grand mean flash visual evoked responses (FVER) were measured in two new groups of depressed patients with melancholia to replicate findings of an abnormal FVER in a previously reported pilot study (Vasile et al 1989). These different, independently collected groups of melancholic patients demonstrated a statistically significant negative deviation of the FVER 224-300 msec poststimulus maximal in the midline centroparietal region when compared with appropriate normative age-matched control groups (n = 56) in each group). We utilized the identical computer-based quantified neurophysiological technique with mapping to analyze the data in all three melancholic patient groups--the pilot group (n = 9) with mean age 73.1 years, an older replication group (n = 14) with mean age 75.5 years, and a younger replication group (n = 15) with mean age 63.8 years. We also studied a group of depressed patients without melancholia (n = 11) with mean age 65.2 years, and found a similar, but less pronounced, alteration of the FVER. Lastly, we studied a group of nondepressed neuropsychiatric patients (n = 10) with mean age 61.9 years and found no abnormality of the FVER. Our data suggest that a gradient of FVER abnormality exists in depressed patients, most prominent, but not limited to elderly melancholic patients.