Clonidine treatment of schizophrenia: Can we predict treatment response?

doi:10.1016/0165-1781(89)90145-5

Psychiatry Research

Volume 27, Issue 3, March 1989, Pages 297-311

https://doi.org/10.1016/0165-1781(89)90145-5 Get rights and content

Abstract

Four out of 13 drug-free relapsed schizophrenic patients improved with double-blind clonidine treatment. All responders were paranoid schizophrenic patients. Pretreatment growth hormone (GH) response to the clonidine challenge test (CCT) correlated significantly with clonidine treatment improvement in psychosis, anxiety, and negative symptom ratings. Spontaneous GH peaks following placebo correlated significantly with the behavioral change with clonidine treatment. Our data suggest that patients with normal or high α₂- receptor activity and “normal” cerebrospinal fluid (CSF) norepinephrine (NE) are likely to respond to clonidine treatment. Patients with either high or low CSF NE levels did not respond to clonidine treatment. CSF NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) decreased significantly with clonidine treatment. Changes in CSF NE and MHPG did not correlate significantly with improvement in psychosis, but they correlated with changes in other behaviors.

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Citation Excerpt :
In summary, the above clinical studies suggest that clonidine and related drugs may produce therapeutic effects in the treatment of some cases of schizophrenia. Double blind treatment with clonidine in relapsed PWS produced improvement in four of 13 patients, all of whom exhibited paranoid schizophrenia (van Kammen et al., 1989). Drug challenge that compared drug-free PWS with healthy controls found that clonidine produced a greater than normal growth hormone response in paranoid patients (Brambilla et al., 1994).
A number of hypotheses have been put forth regarding the etiology of schizophrenia, including the dopamine hypothesis, NMDA receptor hypofunction hypothesis, and others. A lesser known theory is that elevated noradrenergic signaling plays a causative role in the disease. This paper briefly re-examines the merits of this hypothesis, including as it relates to some recently published studies. Several lines of evidence are investigated, including: endogenous level studies of norepinephrine (NE); modulation of the disease by noradrenergic drugs; association of the disease with bipolar disorder and hypertension, since these latter two conditions may involve elevated NE transmission; and effects of psychological stress on the disease, since stress can produce elevated release of NE. For many of these lines of evidence, their relationship with prepulse inhibition of startle is examined. A number of these studies support the hypothesis, and several suggest that elevated NE signaling plays a particularly prominent role in the paranoid subtype of schizophrenia. If the hypothesis is correct for some persons, conventional pharmaceutical treatment options, such as use of atypical antipsychotics (which may themselves modulate noradrenergic signaling), may be improved if selective NE transmission modulating agents are added to or even substituted for these conventional drugs.
The role of norepinephrine in the pathophysiology of cognitive disorders: Potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease
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The role of noradrenergic neurotransmission in normal cognitive functions has been extensively investigated, however, the involvement of noradrenergic functions in the cognitive impairment associated with schizophrenia and Alzheimer’s disease has not been as intensively considered. The limited ability of atypical antipsychotics to treat the cognitive impairment of schizophrenia, and cholinomimetics to treat the cognitive impairment of Alzheimer’s disease, may be related to the influence of a multiplicity of neurotransmitter abnormalities including noradrenergic dysfunction, which these treatments do not address. The evidence of noradrenergic dysfunction occurring concomitantly with dopamine dysfunction in schizophrenia and acetylcholine dysfunction in Alzheimer’s disease supports therapeutic approaches using noradrenergic drugs in combination with neuroleptics and cholinesterase inhibitors, respectively, to enhance the treatment of cognitive impairment. Given the results of animal and human studies, it appears that α-2A agonists may be the optimal choice for this purpose.
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There is recognition that the cognitive symptoms of schizophrenia have the most substantial impact on illness outcome. Domains of cognition reported to be significantly affected include serial learning, executive function, vigilance, and distractibility, to name a few. Dopamine activity at D1 receptors mediates many cognitive processes subserved by the prefrontal cortex (PFC), particularly working memory. The number of D1 receptors in the PFC is decreased in schizophrenics and is unaffected by chronic administration of typical neuroleptics. Therefore, medications that increase dopamine in the PFC, such as atypical neuroleptics, or that directly activate the D1 receptor may prove useful in the remediation of prefrontal-dependent cognitive deficits in schizophrenia. Decreased levels of cortical norepinephrine (NE) are associated with impaired learning and working memory in animal models, and can be reversed by drugs that restore NE activity. More specifically, α-2 adrenergic receptor agonists have been particularly effective in improving delayed response performance in young monkeys with localized 6-hydroxydopamine lesions in the PFC. Furthermore, human postmortem studies have demonstrated decreased NE in the frontal cortex of demented schizophrenic patients. Therefore, α-2 receptor agonists hold promise as drugs to improve cognitive performance on tasks dependent upon PFC function in schizophrenics. Finally, the finding that cortical choline acetyl transferase activity correlates with Clinical Dementia Rating scores in schizophrenic patients and that cholinomimetic drugs enhance cognition in healthy subjects suggests that cholinergic drugs may also treat cognitive symptoms in schizophrenia. Two potential types of cholinomimetics for use in schizophrenics are the acetylcholinesterase inhibitors and M1/M4 muscarinic agonists, both of which increase cortical cholinergic activity.
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The study attempted to identify pretreatment characteristics of chronic schizophrenic patients that would predict remission in psychosis and amount of clinical improvement after treatment with haloperidol. Thirty-five acutely relapsed schizophrenic patients were entered into a blind 6-week treatment protocol. Pretreatment measures were assessed for prediction of both remission status (dichotomous) and for correlations with change in psychopathology (continuous). Later age of onset and higher plasma homovanillic acid values were significant predictors of remission status (model 1), However, higher cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol, as well as indices of normal neurodevelopment, predicted larger changes in psychopathology. The results indicate that the definition of drug response determines the predictive variables. Dopaminergic activity seems to relate to the ability to reach remission, while noradrenergic activity relates to symptom intensity and reduction. In addition to catecholamine activity, neurodevelopmental changes determine response to haloperidol.
A study of enzymes involved in catecholamine metabolism in parents of patients with schizophrenia
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The concentrations of serum homovanillic acid (HVA), norepinephrine (NE), tyrosine (Tyr), phenylalanine (Phe) and tryptophan (Trp), and the activities of serum dopamine-β-hydroxylase (DBH), platelet monoamine oxidase (MAO), and erythrocyte catechol-O-methyl transferase (COMT) were measured in 68 healthy parents who had schizophrenic offspring. The results show a significant correlation between the parents of schizophrenic patients in serum HVA (r=0.38, n=34, p < 0.05), NE (r=0.40, n=33, p < 0.02), Phe (r=0.44, n=34, p < 0.01). Tyr (r=0.43, n=34, p< 0.02) and DBH activity (r=0.51, r=30, p < 0.005), but do not show a significant correlation in erythrocyte COMT (r=0.01, n=27), platelet MAO (r=0.04, n=23) or serum Trp (r=0.10, n=34). There were no significant correlations in these measurements between randomly matched parents. The present study suggests that both parental sides of schizophrenic patients are likely to have similar alleles associated with the catecholamine pathway, and their ill offspring may possess a double dose of the schizophrenogenic alleles.
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Reviewing Brief Psychiatric Rating Scale (BPRS) research indicates that combining items to form larger ‘symptom factors’ (e.g., depression, psychosis) has become the standard methodology. Unfortunately, a single symptom factor may be defined by different combinations of different BPRS items in different studies. To examine the potential impact of these differences, a number of different BPRS definitions of positive and negative symptoms in schizophrenia were culled from previous research. To compare these definitions, one hundred schizophrenics were interviewed with regard to current and recent symptomatology and rated on the BPRS, the Schedule for the Assessment of Negative Symptoms (SANS), and the Schedule for the Assessment of Positive Symptoms (SAPS). The four BPRS negative symptom definitions all correlated highly with one another and with the SANS. There were no differences in the amount that these different definitions of negative symptoms correlated with the SANS. Also, the nine definitions of positive symptoms all correlated highly with one another and with the SAPS. However, there were significant differences in how they correlated with the SAPS. Because of these differences, possible standard definitions for negative and positive symptoms of schizophrenia are proposed for future use of the BPRS in research.

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Clonidine treatment of schizophrenia: Can we predict treatment response?

Abstract

Psychiatry Research

Brain Research

Psychiatry Research

Psychiatry Research

Psychiatry Research

Psychiatry Research

Analytical Biochemistry

Life Sciences

Biochemical and neuroendocrine studies in schizophrenics: Attempts to characterize the illness biochemically

Experimental stress situations and the state of autonomic arousal in schizophrenic and depressive patients

International Pharmacopsychiatry

DSM-III: Diagnostic and Statistical Manual of Mental Disorders

Locus coeruleus activity in vitro: Intrinsic regulation by a calcium-dependent potassium conductance but not alpha2-adreno-receptors

Journal of Neurosciences

Negative symptoms in schizophrenia: Definition and reliability

Archives of General Psychiatry

Partial improvement in negative schizophrenic symptoms after amphetamine

Psychopharmacologia

Noradrenergic and dopaminergic interactions in escape behavior: Analysis of uncontrollable stress effects

Psychopharmacology

Decrease in dopamine and its metabolites and noradrenaline in cerebrospinal fluid of schizophrenic patients after withdrawal of long-term neuroleptic treatment

Psychopharmacologia

Monoamine metabolites in cerebrospinal fluid during treatment with clonidine or alprenolol

European Journal of Clinical Pharmacology

Brain norepinephrine and dopamine in schizophrenia

Science

Postmortem central catecholamines and antemortem cognitive function in elderly schizophrenics and controls

Neuropsychobiology

Effect of clonidine on dopaminergic activity in the substantia nigra

Methods for reliable longitudinal observation of behavior

Archives of General Psychiatry

Flexible system for the diagnosis of schizophrenia: Report from the WHO International Pilot Study of Schizophrenia

Science

Growth hormone and other response to clonidine in patients with endogenous depression

British Journal of Psychiatry

Platelet alpha2 adrenoceptors at the onset of schizophrenia

Monoamine mechanisms in chronic schizophrenia: Post-mortem neurochemical findings

British Journal of Psychiatry

Plasma noradrenaline and clinical psychopathology in schizophrenia

Neuropsychobiology

Stages of onset of schizophrenic psychosis

American Journal of Psychiatry

Monoaminergic control of episodic growth hormone secretion in the rat: Effects of reserpine, α-methyl-p-tyrosine, p-chlorphenylalanine, and haloperidol

Endocrinology

Evidence for a growth hormone releasing factor mediating alpha-adrenergic influence on growth hormone secretion in the rat

Neuroeneocrinology

Activation of alpha2-adrenoceptors enhances haloperidol-induced suppression of operant behavior

Journal of Neural Transmission

Norephinephrine in chronic paranoid schizophrenia: Above-normal levels in limbic forebrain

Science

Clonidine treatment of schizophrenia: Double-blind comparison to placebo and neuroleptic drugs

Acta Psychiatrica Scandinavica

Noradrenergic overactivity in chronic schizophrenia: Evidence based on cerebrospinal fluid noradrenaline and cyclic nucleotide concentrations

British Journal of Psychiatry

NOSIE-30: A treatment-sensitive ward behavior scale

Psychological Reports

Locus coeruleus activity in vitro: Intrinsic regulation by a calcium-dependent potassium conductance but not alpha₂-adreno-receptors

Platelet alpha₂ adrenoceptors at the onset of schizophrenia

Activation of alpha₂-adrenoceptors enhances haloperidol-induced suppression of operant behavior