Mazindol and cocaine addiction in schizophrenia.
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Adult↗
Biomedical subjects
J H Krystal
Publications and source records attributed to J H Krystal.
Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine.
The effects of oral administration of the alpha 2 adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful alpha 2 antagonist in humans.
Adrenergic alpha-Antagonists↗
Baclofen-assisted detoxification from opiates. A pilot study.
In an open label pilot study, five opiate-dependent patients underwent baclofen-assisted opiate detoxification after abrupt discontinuation of methadone. Patients received baclofen in oral doses up to 80 mg/day, and all patients subjectively reported some reduction in discomfort. However, 3 of 5 (60%) patients could not complete detoxification with baclofen, primarily because of insufficient suppression of vomiting, myalgias, and headache. These patients successfully completed their detoxification with clonidine. These findings suggest that, in the dose range studied, baclofen is of limited use as a primary treatment for opiate dependence, although adjunctive roles for this medication in detoxification should be explored.
Adult↗
Controlled trial of alprazolam supplementation during imipramine treatment of panic disorder.
To investigate whether alprazolam (ALP) coprescription early in the imipramine (IMI) treatment of panic disorder would improve overall treatment response to IMI alone, 48 panic disorder patients were randomly assigned to receive either IMI plus placebo or IMI plus ALP for 4-6 weeks, followed by 2 weeks of IMI plus placebo-ALP taper and 2 more weeks of IMI alone. Although patients in the IMI plus ALP group improved more quickly, significantly more patients in the IMI plus ALP group could not follow the taper schedule. The results suggest that studies employing other benzodiazepines or other ALP dosage or taper schedules would be required to demonstrate any benefit for the IMI plus early benzodiazepine cotreatment strategy over IMI alone in the routine pharmacologic management of panic disorder.
Adolescent↗
Effects of age and alcoholism on the prevalence of panic disorder.
Findings are reported evaluating the effects of aging and alcoholism histories on the 6-month prevalence rates of panic disorder. The data were collected in 5 communities as part of the Epidemiologic Catchment Area (ECA) study: New Haven, CT; Baltimore, MD; St. Louis, MO; Durham, NC; and Los Angeles, CA. Reanalysis of ECA data provided additional support for a decline in the prevalence of panic disorder among elderly people. In addition, the presence of a history of alcohol abuse or dependence was associated with significantly elevated panic disorder rates in younger individuals, but an earlier decline in panic disorder prevalence with age, regardless of gender. These findings offer preliminary support for neurodevelopmental hypotheses for the onset and outgrowing of panic disorder. They also highlight the impact of alcoholism on the course of panic disorder.
Adolescent↗
Noradrenergic neuronal dysregulation in panic disorder: the effects of intravenous yohimbine and clonidine in panic disorder patients.
In order to evaluate possible abnormal noradrenergic neuronal functional regulation in patients with panic disorder, the behavioral, biochemical and cardiovascular effects of intravenous yohimbine (0.4 mg/kg) and clonidine (2 micrograms/kg) were determined in 15 healthy subjects and 38 patients with panic disorder. A subgroup of 24 panic disorder patients were observed to experience yohimbine-induced panic attacks and had larger yohimbine-induced increases in plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) than healthy subjects and other panic disorder patients. A blunted growth hormone response to clonidine and a significant clonidine-induced decrease in plasma MHPG was also observed in this subgroup of panic disorder patients. These data replicate and extend previous investigations, which are consistent with a large body of preclinical and human data relating increased noradrenergic neuronal function to human anxiety and fear states.
Adult↗
Prolonged postictal encephalopathy in two patients with clozapine-induced seizures.
Two patients with prolonged postictal encephalopathy lasting 63 and 72 hours, respectively, following seizures with clozapine are reported. Clozapine alters the EEG in a majority of patients treated, with seizure frequency as high as 5-10% in doses above 600 mg/d. Prolonged postictal encephalopathy following a clozapine-induced seizure has not been previously reported but may be an important side effect of this medication. Pharmacologic and clinical issues are discussed.
Adult↗
Chronic 3,4-methylenedioxymethamphetamine (MDMA) use: effects on mood and neuropsychological function?
3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in animals. There is now preliminary evidence in humans of 5-HT deficits associated with extensive use of MDMA. In order to begin to describe the cognitive and mood effects of chronic MDMA use, nine individuals with extensive MDMA use histories were studied. Despite the absence of memory deficits on clinical examination, a pattern of mild-to-moderate impairment was observed on both the Initial and Delayed Paragraph Tests of the Wechsler Memory Scale; eight of the subjects had at least mild impairment on at least one test in the neuropsychological battery. Despite previously reported suggestive evidence of 5-HT deficit in this group, none reported depressed mood or met clinical criteria for an affective disorder at the time of testing. These preliminary findings raise concern about possible detrimental effects of MDMA use on neuropsychological function for future systematic study and they highlight important issues regarding the effects of 5-HT deficits on cognitive function and mood regulation.
3,4-Methylenedioxyamphetamine↗
Valproate management of psychosis in a patient with carbamazepine-induced hyponatremia.
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Carbamazepine↗
Excitatory amino acids and morphine withdrawal: differential effects of central and peripheral kynurenic acid administration.
The non-selective excitatory amino acid antagonist kynurenic acid, which does not readily cross the blood-brain barrier, dose-dependently attenuated the behavioral signs of naltrexone-precipitated withdrawal in morphine-dependent rats following both intraventricular and subcutaneous administration. However, intraventricular and subcutaneous administration of kynurenic acid had different effects on individual withdrawal behaviors. Moreover, single unit recordings in anesthetized animals showed that intraventricular, but not subcutaneous, kynurenic acid administration attenuated the withdrawal-induced increased firing of locus coeruleus neurons. These studies indicate that: (1) both central and peripheral excitatory amino acid receptors may play an important role in opiate withdrawal; and (2) excitatory amino acid antagonist treatments might be developed to reduce opiate abstinence symptoms in man.
Amino Acids↗
Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects.
Ten healthy male subjects were administered i.v. meta-chlorophenylpiperazine (MCPP) (0.1 mg/kg) after oral ritanserin (5-10 mg), a putative 5HT1c/5HT2 (serotonin) antagonist, or placebo. Behavioral responses, cardiovascular effects, and neuroendocrine responses (cortisol, growth hormone, and prolactin) were measured serially for 4 hours after MCPP infusion. Premedication with ritanserin attenuated the MCPP-induced increases in self-rated anxiety and prolactin, and completely antagonized MCPP cortisol elevations. In contrast, ritanserin did not significantly alter growth hormone response to MCPP. These findings suggest a role for 5-HT1c/5-HT2 receptors in the endocrine and behavioral responses to the mixed serotonin agonist MCPP in humans.
Adult↗
Behavioral, biochemical, and cardiovascular responses to the benzodiazepine receptor antagonist flumazenil in panic disorder.
To evaluate the possibility that abnormal regulation of benzodiazepine receptor (BZR) function may relate to the pathophysiology of anxiety disorders, two doses of the BZR antagonist flumazenil (Ro 15-1788) and placebo were administered to panic disorder patients in a double-blind, randomized, crossover design. All 11 patients received flumazenil (600 mg). Ten of the 11 also received flumazenil (200 mg), and 8 of the 11 were given matching placebo capsules orally on separate test days. Neither dose of flumazenil showed significant anxiolytic effects or significantly altered heart rate, blood pressure, or levels of plasma cortisol or 3-methoxy-4-hydroxyphenylglycol in comparison to placebo. On 200 mg days, anxiety ratings on a visual analog scale significantly increased compared to placebo at 30 min and then returned to baseline levels. Panic attacks occurred on placebo, 200 mg, and 600 mg days in 0/8, 4/10, and 0/11, respectively. Failure to observe anxiolytic effects suggests that flumazenil at these doses does not antagonize a tonic increased interaction of BZRs with an endogenous BZR inverse agonist in panic patients.
Adult↗
SPECT regional cerebral blood flow and neuropsychological testing in non-demented HIV-positive drug abusers: preliminary results.
1. Non-demented HIV seropositive and seronegative methadone maintained patients and healthy volunteers (n = 10 each) participated. 2. All subjects underwent SPECT regional cerebral blood flow scanning following injection of Tc-99m HMPAO. All patients underwent neuropsychologic (NP) testing. 3. The left striatum/whole brain blood flow ratio was elevated in the HIV positive group compared to the healthy subjects. Two HIV positive patients had clearly abnormal striatal ratios. Both groups were impaired on NP testing; HIV+ patients were somewhat more impaired on tests of sustained attention and verbal memory. 4. SPECT scanning with Tc-99 HMPAO may identify a subgroup of HIV positive patients with evidence of CNS involvement prior to onset of dementia symptoms.
AIDS Dementia Complex↗
Clinical phenomenology and neurobiology of cocaine abstinence: a prospective inpatient study.
OBJECTIVE: This study was undertaken to document symptoms and changes in dopaminergic function emerging after abrupt cessation of cocaine use. METHOD: After admission, 22 patients with DSM-III-R cocaine dependence were observed drug free for 3 weeks. The patient-rated Ribicoff Abstinence Rating Scale, Symptom Rating Scale, Physical Symptom Scale, Patient Rated Anxiety Scale, Beck Depression Inventory, and visual analogue scales for 16 subjective states were completed daily, and nurses rated 13 patients with the global anxiety and depression items of the Short Clinical Rating Scale. Serial blood samples were obtained three times weekly, and the patients' levels of prolactin, growth hormone (GH), and homovanillic acid (HVA) were measured. Their prolactin and GH values were compared with those of matched normal subjects. RESULTS: A total of 62 subjective symptom variables were evaluated. At baseline, the symptom ratings were mildly elevated. At 3 weeks there were significant decreases from baseline in 28 variables and nearly significant decreases in six additional variables. Nurse-rated anxiety and depression also changed, but in a more variable pattern. There was a small but significant increase from baseline over time in plasma prolactin, but there were no significant changes in GH or HVA. The patients' prolactin and GH values did not differ from those of the normal subjects. CONCLUSIONS: These findings suggest that symptoms after inpatient cessation of uncomplicated cocaine addiction are relatively mild and decrease linearly over the first month. Evidence of dysregulated central dopamine function was limited. The findings do not support routine use of pharmacological agents in the inpatient management of such patients.
Adult↗
Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression.
Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported on the effects of rapid dietary TRP depletion in psychiatric patients; this study extends those reports and summarizes the effects of rapid TRP depletion on mood in depressed patients. One hundred and fifteen depressed (according to DSM-III-R) patients (69 drug free and symptomatic; 46 in clinical remission after antidepressant treatment) received tryptophan depletion testing in a double-blind, placebo-controlled, crossover fashion. Of 69 symptomatic, drug-free, depressed patients, 30 percent were unchanged the day of the tryptophan-free drink (TFD), but became clinically less depressed the day after the TFD. Although 80 percent of monoamine oxidase inhibitor- or fluvoxamine-treated patients experienced a depressive relapse during TRP depletion testing, only 18 percent of desipramine-treated patients relapsed. Brain 5-HT function may be intimately involved in the modulation of some affective states and in the mechanism of action of some antidepressant medications.
Antidepressive Agents↗
Visual stimulation increases technetium-99m-HMPAO distribution in human visual cortex.
The ability of changes in the distribution of technetium-99m-hexamethylpropylene amine oxime (99mTc-HMPAO) to reflect physiologic changes in regional cerebral blood flow (rCBF) was evaluated using photic stimulation, a procedure known to increase rCBF in the striate cortex. Seven healthy subjects were injected with 740 MBq 99mTc-HMPAO on two separate days. On one day, the injection was performed following closure of the eyes and patching for 5 min. On the other day, subjects were exposed to a stroboscopic light to produce photic simulation. Images of distribution of 99mTc-HMPAO were obtained using a Strichman 810X single-photon emission computed tomogram (SPECT) brain scanner. Comparison of images obtained during light occluded versus stimulation conditions revealed a significant increase in distribution of radiopharmaceutical in visual cortex relative to whole brain (peak increase corrected for radiopharmaceutical backdiffusion 36.7% +/- 6.6%). HMPAO appears to provide a useful method for detecting relative rCBF increases with SPECT.
Adult↗
Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder. Comparison of fluvoxamine and desipramine.
To evaluate whether serotonin reuptake inhibition is critical to the treatment of obsessive-compulsive disorder, 40 outpatients with a principal diagnosis of obsessive-compulsive disorder were randomized in a double-blind fashion to 8 weeks of treatment with either the serotonin reuptake inhibitor fluvoxamine maleate (n = 21) or the norepinephrine reuptake inhibitor desipramine hydrochloride (n = 19). Fluvoxamine was significantly better than desipramine in reducing the severity of obsessive-compulsive symptoms, as measured by the Yale-Brown Obsessive Compulsive Scale and by the global response rate ("responder" equaling "much improved"). Eleven of 21 patients were responders with fluvoxamine compared with 2 of 19 patients with desipramine. Fluvoxamine, but not desipramine, was also effective in reducing the severity of "secondary" depression. Fluvoxamine-induced improvement in symptoms of obsessive-compulsive disorder was not correlated with the severity of baseline depressive symptoms. This study provides additional evidence that the acute serotonin reuptake properties of a drug are predictive of its anti-obsessive-compulsive efficacy. It is hypothesized that the mechanism of action of serotonin reuptake inhibitors in obsessive-compulsive disorder may be related to chronic treatment-induced adaptive changes in presynaptic serotonin receptor function (eg, autoreceptor desensitization) and/or indirect influences on dopaminergic function (eg, in the basal ganglia).
Adult↗
Clinical studies of 5-HT function using i.v. L-tryptophan.
1. Preclinical studies reveal that long-term treatment with antidepressant drugs induces significant changes in serotonergic (5-HT) receptor sensitivity. Similarly, clinical studies suggest that brain 5-HT function is abnormal in depression. Of the available methodologies for conducting such clinical studies, the pharmacological challenge strategy has proven particularly useful. 2. I.v. L-TRP has emerged as the most frequently used challenge agent in diagnostic and neuropsychopharmacological studies of 5-HT function. I.v. L-TRP increases serum prolactin (PRL) in humans, probably via 5-HT mechanisms. Under carefully standardized conditions, this PRL response to L-TRP appears to be a reasonably sensitive and valid measure of net 5-HT function. 3. The PRL response to L-TRP is blunted in depressed patients compared with healthy controls. Blunting has not been observed in panic disorder, obsessive compulsive disorder, or schizophrenia, although preliminary findings suggest it may occur in bulimia. 4. The PRL response to L-TRP is enhanced by certain classes of thymoleptic drugs (TCAs, MAOIs, 5-HT reuptake inhibitors, lithium) in a differentially time-dependent fashion. So-called "atypical" antidepressants (trazodone, mianserin) and benzodiazepines have no effect. Such findings are generally consistent with preclinical electrophysiological findings. 5. These clinical studies of the PRL response to L-TRP, in conjunction with emerging evidence that experimentally reduced plasma TRP can reverse the therapeutic effects of some antidepressants, suggest that antidepressant drug action may be more accurately conceptualized as 5-HT dependent rather than 5-HT enhancing. The availability of more selective 5-HT-active drugs promises to further clarify 5-HT mechanisms of neuropsychiatric disease and drug action at the clinical level.
Animals↗