Serotonin in obsessions, compulsions, and the control of aggressive impulses.
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Aggression↗
Biomedical subjects
D L Murphy
Publications and source records attributed to D L Murphy.
Obsessive-compulsive disorder: treatment with serotonin-selective uptake inhibitors, azapirones, and other agents.
Obsessive-compulsive disorder (OCD) has recently been recognized as a relatively common disorder, affecting one in 40 individuals in the United States. OCD has also been demonstrated to be at least partially drug-responsive, although fewer than 20 adequate, fully controlled treatment trials in OCD patients have been reported, all in the last decade. The partially selective serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitor clomipramine has been the most studied drug and uniformly has been found to be of some benefit in patients with OCD. Several recent controlled trials with other, more highly selective 5-HT uptake inhibitors have also shown these drugs to be more effective than placebo. More recently, preliminary data from several studies have questioned whether buspirone, an azapirone with prominent 5-HT-related anxiolytic and possible antidepressant properties, may have direct therapeutic effects in OCD patients or may be a useful adjunct when used in combination with the selective 5-HT uptake inhibitor fluoxetine. These studies are reviewed briefly and evaluated in the context of investigations that used other drugs with serotonergic actions either alone or in combination with selective 5-HT uptake inhibitors in OCD patients.
Anti-Anxiety Agents↗
A comparative examination of a role for serotonin in obsessive compulsive disorder, panic disorder, and anxiety.
Recent clinical and laboratory studies have suggested that changes in brain serotonin (5-HT) function may contribute to anxiety symptoms and anxiety-type behaviors. Among the anxiety disorders, perhaps the most compelling evidence implicating 5-HT exists for obsessive compulsive disorder (OCD). In controlled trials, patients with OCD were markedly more responsive to treatment with 5-HT-selective uptake inhibitors such as clomipramine, fluvoxamine, or fluoxetine than to norepinephrine-selective or nonselective uptake inhibitors or to other psychoactive drugs. Studies with 5-HT agonists and antagonists also support a role for 5-HT in OCD. In this review, pharmacologic studies involving 5-HT-selective therapeutic and anxiogenic agents and non-5-HT-selective anxiogenic agents in patients with OCD are compared and contrasted with similar studies in patients with anxiety and panic disorder.
Anxiety Disorders↗
A clomipramine dosage reduction study in the course of long-term treatment of obsessive-compulsive disorder patients.
Ten patients with DSM-III-R obsessive-compulsive disorder (OCD) who were being treated chronically with clomipramine (270 +/- 20 mg/day) were studied to determine the minimum dose of clomipramine needed to maintain therapeutic benefit. These 10 patients were among the 17 of 18 patients recently reported to develop a return of OC symptoms following discontinuation of clomipramine under double-blind, placebo-controlled conditions. Each patient was rated twice--open and double-blind--at both initial and minimum doses of clomipramine, using the following three OC measures: the Yale-Brown Obsessive Compulsive Scale (YBOCS), the National Institute of Mental Health-Obsessive Compulsive Scale (NIMH-OC), and the National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH Global OC Scale). Gradual, open dosage reduction resulted in a mean dosage of 165 +/- 19 mg/day, a reduction of 105 mg/day (approximately 40%, t = 5.55, p less than .001). This decrease in dose was accompanied by no significant change in the three OC measures, as determined by paired t-test. These results suggest that even though OCD patients were not able to discontinue medication completely, they were able to do well at lower doses than those used initially in treatment of the disorder.
Adult↗
Obsessive-compulsive disorder and its treatment with serotonin-selective agents.
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Antidepressive Agents, Tricyclic↗
Reduced plasma dehydroepiandrosterone concentrations in Alzheimer's disease.
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Age Factors↗
A preliminary study of the effects of intravenous m-chlorophenylpiperazine, a serotonin agonist, in elderly subjects.
m-Chlorophenylpiperazine (m-CPP), a serotonin receptor agonist, is currently being investigated as a probe of serotonergic responsivity in various neuropsychiatric disorders. The safety of m-CPP in elderly populations and its potential usefulness in exploring possible serotonergic dysfunction in Alzheimer's disease and normal aging were assessed by examining the behavioral, neuroendocrine, and physiological effects of this agent in 15 elderly subjects (mean age 69 +/- 2 years): 9 Alzheimer patients and 6 healthy normal volunteers. Intravenous m-CPP (0.08 mg/kg) was well tolerated in all subjects and produced no serious adverse effects. The behavioral effects were modest; in particular, minimal anxiety was observed, a finding that contrasted to results from an earlier study reporting that intravenous m-CPP at a slightly higher dose induced marked anxiety and panic attacks in younger subjects. m-CPP produced significant increases in plasma cortisol and prolactin, and significant changes in blood pressure and temperature in these elderly subjects. The results of this preliminary study suggest that intravenous m-CPP is safe and well-tolerated in elderly subjects. Future studies at higher doses can now proceed to study more definitively the question of possible age- and disorder-related reductions in central nervous system (CNS) serotonergic responsivity.
Aged↗
Clomipramine in obsessive-compulsive disorder. Further evidence for a serotonergic mechanism of action.
Data from several previous studies link clomipramine's potent serotonergic effects to its clinical efficacy in reducing the symptoms of obsessive-compulsive disorder (OCD). To investigate this relationship further, we administered the serotonin (5-HT) receptor antagonist, metergoline, and placebo to ten patients with OCD in a crossover study carried out under double-blind, random-assignment conditions. In a previous study of untreated patients with OCD, we found no differences in the behavioral response to single-dose administration of metergoline or placebo. In the present study, patients with OCD receiving clomipramine hydrochloride on a long-term basis (with an average 40% lessening in OC symptoms) responded to a four-day period of administration of metergoline with significantly greater self- and observer-rated anxiety compared with the four-day placebo period. Obsessive-compulsive symptoms also tended to be greater during the metergoline phase, with significant drug-time interactions for both OC symptoms and anxiety peaking on day 4 of the metergoline phase. As anticipated, metergoline lowered plasma prolactin concentrations (providing evidence of physiologically significant 5-HT antagonism) but did not alter plasma clomipramine concentrations. These data further support the hypothesis that clomipramine's therapeutic behavioral effects in OCD are mediated via serotonergic mechanisms.
Adult↗
Fenfluramine and dextroamphetamine treatment of childhood hyperactivity. Clinical and biochemical findings.
Twenty boys (mean age, 9 +/- 2 years) with attention deficit disorder with hyperactivity received three weeks each of dextroamphetamine sulfate (0.5 mg/kg/d), fenfluramine hydrochloride (0.6 mg/kg/d increased to 2.0 mg/kg/d), and placebo in a double-blind, random-order, crossover design. Half the boys also met criteria for conduct disorder. Dextroamphetamine produced immediate and marked improvement in disruptive, overactive behaviors. Fenfluramine had no effect on any behavioral measure at either the low or high dosage. Both drugs decreased levels of urinary norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid. Fenfluramine, however, also produced a significant decrease in plasma MHPG levels and a larger decrease in urinary norepinephrine levels. It reduced urinary epinephrine levels as well, an effect opposite to that of dextroamphetamine. These findings suggest that different mechanisms of action are involved in the ability of the two drugs to reduce levels of MHPG and vanillylmandelic acid. Fenfluramine increased plasma prolactin levels and decreased platelet serotonin levels. Despite the structural similarity of the two drugs, some common overall effects on catecholamine metabolism, and similar effects on weight, fenfluramine had none of the motor activity or therapeutic effects of dextroamphetamine.
Attention Deficit Disorder with Hyperactivity↗
Hyperresponsivity to the serotonin agonist m-chlorophenylpiperazine in Alzheimer's disease. A controlled study.
The serotonin agonist m-chlorophenylpiperazine (mCPP) was administered intravenously to 12 patients with Alzheimer's disease and ten age-matched controls. It produced distinct behavioral effects in both treatment groups; however, significantly greater responsivity to mCPP was found in patients with Alzheimer's disease than in controls in measures of psychomotor activation, restlessness, and perceptual abnormalities. Significant and similar increases in plasma prolactin and cortisol levels were found in both patients with Alzheimer's disease and controls following the administration of mCPP vs placebo. Furthermore, blood pressure and pulse changes following mCPP were not significantly different between the groups. Elderly controls, however, did show a significantly greater temperature response following mCPP than did patients with Alzheimer's disease. The overall cognitive effects of mCPP were minimal; however, mCPP produced significantly greater worsening in recent memory and knowledge memory in patients with Alzheimer's disease than in controls. These findings could not be explained by pharmacokinetic differences across populations, because plasma concentrations of mCPP were similar in patients with Alzheimer's disease and controls. The increased behavioral responsivity but unchanged neuroendocrine or other physiologic responsivity to mCPP may be related to damaged brain serotonin neurons or other neuronal systems that interact with serotonin neurons that have been found in postmortem and biopsy studies of patients with Alzheimer's disease.
Aged↗
Long-term lithium treatment in rats attenuates m-chlorophenylpiperazine-induced decreases in food intake but not locomotor activity.
Administration of various doses of m-chlorophenylpiperazine (m-CPP, a 5-HT agonist) to rats produced dose-related decreases in food intake and locomotor activity. Long-term (21-25 days) but not short-term (3-7 days) lithium treatment attenuated m-CPP-induced decreases in food intake. However, neither short-term nor long-term lithium treatment had any significant effect on m-CPP-induced decreases in locomotor activity. These findings suggest development of functional subsensitivity of 5-HT1B receptors mediating decreases in food intake and provide further evidence that m-CPP's effects on food intake are mediated by different mechanisms from those regulating locomotor activity.
Animals↗
Hyperthermia induced by m-CPP in the rat and its modification by antidepressant treatments.
Administration of the serotonin agonist m-chlorophenylpiperazine to rats produced a dose-related hyperthermia. Pretreatment with the serotonin receptor antagonist metergoline totally abolished this response, whereas similar treatment with haloperidol, phenoxybenzamine, naloxone, clonidine, pindolol, propranolol, methiotepin, and ritanserin was ineffective. In studies investigating the modification of the response by antidepressant treatments both acute (3 day) and chronic (22 day) administration of the MAO inhibitor clorgyline, as well as the tricyclics clomipramine and imipramine, attenuated the hyperthermic response to m-CPP. These findings are discussed with regard to the specificity of m-CPP-induced hyperthermia and its subsequent modification by antidepressant treatments, in order to evaluate this model's use as a probe for assessment of the serotonergic system.
2-Methyl-4-chlorophenoxyacetic Acid↗
Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers.
The serotonin agonist m-chlorophenylpiperazine (m-CPP) had greater anxiogenic and other mood and cognitive effects when administered intravenously (0.1 mg/kg) rather than orally (0.5 mg/kg) to healthy subjects. Nonetheless, similar elevations in peak plasma cortisol and prolactin concentrations were obtained with the two dosage regimens, and temperature elevations were greater after oral m-CPP. Plateau phase plasma concentrations of m-CPP at the times of the maximum neuroendocrine responses to intravenous and oral m-CPP were similar. Since all rodent and nonhuman primate studies have used parenterally administered m-CPP, and previous clinical investigations using intravenous rather than oral m-CPP have yielded somewhat discrepant results, our normative data should be useful for comparing results across different human studies and across species.
Administration, Oral↗
Acute effects of high-dose thyrotropin releasing hormone infusions in Alzheimer's disease.
Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimer's Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.
Aged↗
Clinical, psychophysiological, and neurological characteristics of volunteers with impaired smooth pursuit eye movements.
Two hundred eighty-five volunteers from a community college were screened on campus for accuracy of their smooth pursuit eye movements (SPEM) by electrooculograph (EOG). Those volunteers with the least and the most accurate SPEM were recalled to the laboratory for a comprehensive evaluation of clinical and demographic characteristics, family history, neurological status, and psychophysiological and biological measures, including SPEM [repeat EOG test and infrared (IR) test], an electroencephalogram, auditory and visual evoked potentials, reaction time (RT), the continuous performance task (CPT), platelet monoamine oxidase (MAO), plasma amine oxidase, and dopamine-beta-hydroxylase (DBH). Low-accuracy SPEM was associated with social isolation, inadequate rapport, eccentricity, and a variety of related schizotypal or schizophrenia-like characteristics, but not with generalized psychopathology or other demographic/medical/clinical history variables. Low-accuracy SPEM also was associated with neurological and psychophysiological abnormalities frequently observed in schizophrenic patients. These results suggest that impaired SPEM may reflect an underlying central nervous system dysfunction that is specifically associated with clinical and biological characteristics related to schizophrenia, even in the absence of overt schizophrenia.
Adult↗
Intravenous physostigmine increases cerebrospinal fluid neuropeptide-Y.
The ability to measure directly central nervous system (CNS) neurotransmitter changes after an acute pharmacological challenge would be a useful clinical tool in psychiatric research. As one approach to this possibility, we attempted to measure cerebrospinal fluid (CSF) neuropeptide changes produced by an intravenous infusion of the indirect cholinergic agonist physostigmine. Six rhesus monkeys, with indwelling CSF catheters, had serial CSF samples removed before and after a 15 micrograms/kg physostigmine infusion. Five of six monkeys studied showed at least a 50% increase in CSF neuropeptide-Y (NPY) levels. Normal human subjects (n = 27) had CSF sampled before and 15, 30, and 45 min after an acute intravenous infusion of physostigmine (either 0, 5, or 15 micrograms/kg). An Analysis of Variance revealed a significant (p = 0.04) dose-time interaction, suggesting that physostigmine increased CSF NPY at the 15 micrograms/kg dose. CSF levels of seven other neuropeptides remained unchanged. These results suggest that the pharmacological challenge paradigm can be adapted to CSF neuropeptides, providing new measures of CNS stimulus-induced response beyond the peripheral plasma determinations usually employed.
Animals↗
Long-term imipramine treatment potentiates m-chlorophenylpiperazine-induced changes in prolactin but not corticosterone or growth hormone levels in rats.
Intravenous administration of m-chlorophenylpiperazine (m-CPP, a selective 5-HT agonist) to rats produced increases in plasma prolactin and corticosterone and a decrease in plasma growth hormone concentrations. Long-term but not short-term imipramine treatment potentiated m-CPP's effect on plasma prolactin, but not its effects on corticosterone or growth hormone. Short-term or long-term imipramine treatment did not produce significant changes in baseline levels of prolactin, corticosterone or growth hormone. These findings are compatible with development of functional supersensitivity of 5-HT receptors mediating prolactin release. Lack of potentiation of m-CPP's effects on corticosterone and growth hormone following long-term imipramine treatment suggests either differential regulation of these hormones by serotonergic and possibly other mechanisms, or different 5-HT receptor subtypes mediating the release of these hormones. Alternatively, adaptive changes in other aminergic neurotransmitter mechanisms such as the noradrenergic system may account for the differential effect of long-term imipramine treatment on m-CPP-induced neuroendocrine changes.
Animals↗
Differential effect of clomipramine treatment on m-chlorophenylpiperazine-induced increases in plasma prolactin and corticosterone in rats.
Intravenous administration of m-chlorophenylpiperazine (m-CPP, a serotonin agonist) to rats increased plasma prolactin and corticosterone concentrations. Long-term (21-day) and short-term (3-day) treatment with the tricyclic antidepressant, clomipramine, did not have any significant effect on baseline levels of either prolactin or corticosterone. Long-term but not short-term clomipramine treatment significantly potentiated m-CPP's effect on plasma prolactin. On the other hand, both long-term and short-term clomipramine treatment significantly attenuated m-CPP's effect on plasma corticosterone. These findings are consistent with other animal and clinical studies demonstrating a differential effect of antidepressant treatment on two different serotonin-mediated neuroendocrine functions.
2-Methyl-4-chlorophenoxyacetic Acid↗