Inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates nocturnal melatonin secretion in humans.

The catecholamine dopamine (D) is involved in the regulation of LH and PRL secretion, whereas a dysregulated noradrenergic system may contribute significantly to symptoms encountered in affective disorders. This explains the attraction of using alpha-methyl-para-tyrosine (AMPT) in neuroendocrine and psychiatric research, as it inhibits both neurotransmitters. PRL has been used as a marker of the effectiveness of AMPT in blocking D function, but no good marker for the effectiveness of AMPT in blocking norepinephrine (NE) is available. The purpose of this study was to determine whether melatonin (M) might serve as such a marker, as its production and secretion are regulated by NE. Seven subjects were given either AMPT or promethazine, which does not alter M secretion, in a randomized, double blind fashion, and 24-h M secretion was studied. Two-way analysis of variance revealed a significant difference in M secretion (F = 13.2; df = 17,102; P = 0.0013), with the following time points being different: 22, 23, 24, 1, 2, 3, 4, 5, and 6 h. Also, 24-h urinary 6-sulfatoxymelatonin excretion correlated highly with 24-h M secretion, expressed as the area under the curve in the AMPT experiment (r = 0.93; P = 0.002), which indicates that AMPT does not alter the metabolism of M. These results demonstrate for the first time that AMPT significantly attenuates nocturnal M secretion. It is concluded that M is a good marker for characterizing the effectiveness of AMPT in inhibiting sympathetic NE activity.

Narcolepsy associated with other central nervous system disorders.

The authors identified patients with the coexistence of narcolepsy and another CNS disorder seen between 1975 and 1998 at their institution. Eighteen patients were identified, nine with narcolepsy commencing within 1 year before or after the other disorder. Seven patients (39%) had hypothalamic-pituitary syndromes. When they occur together, narcolepsy and other CNS disorders frequently emerge at about the same time, suggesting a causative relationship. Hypothalamic-pituitary pathology was the most common association.

Examining serotonin function: a modified technique for rapid tryptophan depletion.

Tryptophan (TRP) depletion was used to study serotonin because the ratio of TRP to large neutral amino acids (TRP/LNAA) determines the quantity of TRP that enters the brain. Because TRP is not universally available, a modified technique of TRP depletion was developed where a 1/4 strength preparation of an amino acid mixture (AAM) replaces TRP as the placebo. Seven healthy subjects could not differentiate between the preparations in this double-blind, placebo-controlled study. Urinary 6-hydroxymelatonin sulfate (6-MS) was monitored as a biochemical marker of serotonin. The TRP/LNAA ratio (GG = 0.001) and 6-MS secretion (GG = 0.024) were decreased, but placebo TRP levels (GG = 0.062) were not altered significantly. This modified technique facilitates the use of TRP depletion in clinical research.

Psychiatric implications of surgical treatment of epilepsy.

Clinicians must consider the psychiatric issues relevant to patients undergoing neurosurgical procedures for epilepsy. Obtaining the patient's psychiatric history can facilitate stabilizing the patient's condition before operative intervention. Preoperatively, depressive and anxiety disorders are the most common psychiatric conditions diagnosed in candidates for surgical treatment of epilepsy. Although psychotic disorders occur infrequently, they demand attention because symptoms may interfere with patient compliance with follow-up care. Patients with chronic psychotic symptoms who have ongoing seizures postoperatively and bilateral seizure foci are at higher risk for a poor outcome and postoperative psychosis. When psychiatric disorders are present, surgical management is not contraindicated, but preoperative psychiatric intervention may be warranted. Most patients have a favorable outcome with the elimination of seizures, which simplifies the subsequent treatment of a psychiatric disorder.

Childhood-onset schizophrenia associated with parkinsonism in a patient with a microdeletion of chromosome 22.

The deletion of a gene or genes on chromosome 22q11 is responsible for the velocardiofacial syndrome (VCFS), which is associated with cardiac anomalies, short stature, palate abnormalities, learning disabilities, and developmental delay. Herein we describe a 30-year-old man with VCFS in whom a chronic psychotic disorder originated during childhood. A 10% rate of psychotic disorders has been reported in association with this genetic syndrome. In our patient, the clinical manifestation was complicated by extrapyramidal symptoms that predated the onset of psychotic symptoms. To our knowledge, extrapyramidal symptoms have not previously been reported in a patient with VCFS. The diagnosis of VCFS was confirmed with the fluorescence in situ hybridization probe for VCFS. The role of the atypical antipsychotic drug clozapine is discussed with respect to treating this patient who has severe psychotic symptoms coexisting with extrapyramidal symptoms and seizures. In light of the observation that patients with VCFS have an unexpectedly high rate of psychotic disorders, issues concerning the genetics of schizophrenia are intriguing.

Narcolepsy: new understanding of irresistible sleep.

Recently, low levels of a newly identified neuropeptide, hypocretin 1, were described in the cerebrospinal fluid of patients with narcolepsy. This neurochemical finding furthers our understanding of this enigmatic sleep disorder typically characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Narcolepsy appears to be fundamentally related to abnormally regulated rapid eye movement sleep. The diagnosis of this disorder remains challenging because of multiple other conditions that can cause daytime sleepiness and the difficulties in recognizing cataplexy based on patient report. The role of hypocretins in narcolepsy is unclear but intriguing because the cell bodies are restricted to the lateral hypothalamus, a brain region long associated with sleep regulation, with neuronal widespread projections to areas including the locus ceruleus, ventral tegmental area, amygdala, and dorsal raphe. Hypocretins potentially modulate the activity of monoamines and acetylcholine, and therefore their absence leads to the multiple symptoms of narcolepsy. This article reviews the current understanding of the diagnosis and treatment of narcolepsy and discusses the possible implications of the hypocretin discovery.

Psychogenic nonepileptic seizures.

Psychogenic nonepileptic seizures (NES) are commonly encountered in clinical practice, and they may pose difficult diagnostic problems. For appropriate evaluation and treatment of NES, a multidisciplinary team approach is needed; typically, a neurologist with expertise in epilepsy, a psychologist or psychiatrist, and a support staff should be involved. Psychogenic NES have no single initial clinical manifestation, and various etiologic factors may contribute to their development. Of importance, psychogenic NES are "real" seizures that may be as disabling as epileptic seizures. Most often, they occur on a subconscious level, and the patient may have no control over their occurrence. Precipitation or termination of a habitual seizure during video-electroencephalographic monitoring has often been used to distinguish NES from epileptic seizures, but the results can sometimes be misleading. Numerous additional diagnostic techniques can be used to assist in making the diagnosis. Treatment is based on the type of psychiatric disorder present. Favorable prognostic factors include being female and having an independent lifestyle, normal electroencephalographic findings, higher intelligence, and no prior psychotherapy.

Delirium in elderly patients: evaluation and management.

OBJECTIVE: To review the evaluation and management of delirium in elderly patients for primary-care providers. DESIGN: We summarize the clinical features, course, pathophysiologic aspects, predisposing factors, causes, and differential diagnosis of delirium and discuss approaches to affected patients and various management strategies. RESULTS: Delirium, an altered mental state, occurs more frequently in elderly than in younger patients. The pathophysiologic changes associated with aging and the higher occurrence of multiple medical problems and need for medications contribute to the higher frequency of delirium in elderly patients. Evaluation should begin with a consideration of the most common causes, such as a change in or addition to prescribed medications, a withdrawal from alcohol or other sedative-hypnotic drugs, an infection, or a sudden change in neurologic, cardiac, pulmonary, or metabolic state. Finally, management of delirium is threefold: (1) identifying and treating underlying causes, (2) nonpharmacologic interventions, and (3) pharmacologic therapies to manage symptoms of delirium. CONCLUSION: Elderly patients frequently experience delirium. Delirious symptoms can produce devastating consequences if they are not recognized and appropriately treated.

Patient satisfaction with electroconvulsive therapy.

OBJECTIVE: To determine whether patients who have electroconvulsive therapy (ECT) are satisfied with their treatment and demonstrate more favorable attitudes about ECT compared with controls. PATIENTS AND METHODS: We developed a 44-item survey measuring ECT treatment satisfaction and attitudes. The survey was administered to 24 psychiatric inpatients near the end of ECT treatment and 2 weeks later. A modified survey was administered to 24 outpatient controls who had never received ECT and who were recruited from a psychiatry clinic waiting room. RESULTS: Patients who received ECT had positive attitudes about it. For example, 21 (91%) of 24 patient respondents endorsed the statement, "I am glad that I received ECT." Attitude score was significantly higher for the ECT group compared with controls. A higher degree of satisfaction was associated with a higher level of education and younger age. CONCLUSIONS: Patients who received ECT were satisfied with their treatment and had more favorable attitudes about it than patients who did not receive this treatment.

Treating fibromyalgia with a brief interdisciplinary program: initial outcomes and predictors of response.

OBJECTIVES: To evaluate the efficacy of a brief, intense treatment program for fibromyalgia and to determine which patient characteristics are associated with a better treatment response. PATIENTS AND METHODS: Two self-report measures, the Fibromyalgia Impact Questionnaire (FIQ) and the Multidimensional Pain Inventory (MPI), were administered before patients completed treatment and 1 month after participating in the program. The main outcome measure was the difference in FIQ score and MPI scale before and after program participation. RESULTS: Of 139 patients who met the American College of Rheumatology criteria for fibromyalgia, 100 chose to participate in the 1 1/2-day Fibromyalgia Treatment Program at the Mayo Clinic, Rochester, Minn. Of these 100 patients, 74 completed the follow-up surveys. Patients were less affected by fibromyalgia after participation in the treatment program. This was demonstrated by a posttreatment improvement in the total FIQ score (P<.001), the MPI pain severity score (P<.001), and the MPI interference score (P=.01). The 1 patient characteristic found to be significantly associated (P<.001) with a better response to treatment was a high pretreatment level of impairment from fibromyalgia, as measured by the pretreatment FIQ score. CONCLUSIONS: A brief interdisciplinary program for treating fibromyalgia reduced some associated symptoms. Patients more severely affected by fibromyalgia may benefit most from this approach. Clinicians may apply these findings to develop beneficial and convenient treatment programs for patients with fibromyalgia.

Major depression in medically ill patients.

Major depression is one of the most common psychiatric problems complicating the treatment and prognosis of patients with active medical illness. Recognizing and treating major depressive conditions in this population can often be challenging, even for the most seasoned clinicians. This article reviews the medical and neurologic conditions that have been associated with the high prevalence rates of major depression. Highlights of the evaluation process that help confirm this suspected diagnosis are addressed, and management issues are discussed. Brief reviews of supportive psychotherapeutic tools that the clinician may find helpful are included, as well as current advances in pharmacologic interventions.

The impact of gender on alpha-methyl-para-tyrosine mediated changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion.

Prolactin (PRL) and melatonin (ML) secretion are mediated by dopamine (DA) and norepinephrine (NE), respectively. Alpha-methyl-para-tyrosine (AMPT) inhibits the production of CNS catecholamines (CA). The purpose of the study is to determine: (1) if AMPT inhibition of ML has the same gender-dependent effect as on PRL secretion; (2) if there is a post AMPT-induced NE depletion mood change in men and/or women. In a randomized, double-blind cross-over fashion, five healthy young males and five females were either given five doses of AMPT 1 g (active) or promethazine 50 mg (placebo) over a 28 h period, separated by 4-6 weeks. The PRL and ML concentrations were collected at regular intervals via an indwelling venous catheter and concurrently, two 12 h urinary 6-hydroxymelatonin sulfate (6-MS) measurements were made. Mood and anxiety states of subjects at baseline and post drug were assessed with appropriate rating scales at regular intervals. Light exposure beginning at dusk and lasting until dawn was controlled to no more than 200 lux during all phases of the study. The PRL secretion showed a significant interaction of drug x time (p = .0001) in women and a non-significant trend (p = .056) in men. No difference in PRL secretion was found between the two genders in the placebo condition, whereas the PRL secretion was significantly higher in the AMPT condition in women when compared to men (df 17,119, F = 1.9, p = .021). Total 24 h urinary 6-MS secretion highly correlated with ML secretion expressed as area under the curve (AUC) during both active and placebo experiments (r = 0.8, p < .01) and (r = 0.86, p < or = .01), respectively. The ANOVA reveals a significant interaction of drug x time for 6-SM excretion. There was no gender difference in AMPT suppression of 6-MS excretion. No mood changes were detected in men or women. We conclude that urinary 6-MS is a reliable indirect measure of the degree of AMPT-induced decrease in CNS NE activity as part of overall AMPT-induced reduction of central catecholamine activities. The pre and post AMPT-induced changes in 6-MS are not gender dependent, dissimilar to the AMPT-induced changes in PRL secretion. Therefore, 6-MS, in addition to PRL, should be measured when applying the AMPT paradigm in future research.

Electroconvulsive therapy and cardiovascular complications in patients taking trazodone for insomnia.

BACKGROUND: Trazodone has been used widely to treat insomnia in depressed patients. When used in combination with electroconvulsive therapy (ECT), trazodone has been suspected to cause cardiovascular side effects. METHOD: A retrospective study was done of 100 patients who received ECT with concurrent trazodone. One patient was excluded because permission to review the patient's records had not been given. The remaining 99 patients were matched with control ECT patients. RESULTS: No statistically significant between-group differences were identified in cardiovascular side effects, although a trend toward more orthostatic hypotension was observed in patients taking trazodone. CONCLUSION: Administering low-dose trazodone for insomnia in conjunction with ECT does not appear to increase cardiovascular complications. The true incidence of adverse cardiac events was not higher than 3.66% at a 95% confidence level.

The effect of presynaptic catecholamine depletion on 6-hydroxymelatonin sulfate: a double blind study of alpha-methyl-para-tyrosine.

Because it is a competitive inhibitor of tyrosine hydroxylase, alpha-methyl-para-tyrosine (AMPT) is used to study psychiatric disorders. Melatonin serves as a biological marker of catecholamine function since its secretion is regulated by noradrenergic neurons via beta-adrenergic receptors in the pineal gland. Ten healthy volunteers were administered AMPT in a double-blind placebo controlled study. When subjects received AMPT, nocturnal 6-hydroxymelatonin sulfate (6-SM) decreased significantly as compared with promethazine (night 1 P=0.002; and night 2 P=0.001). Urinary MHPG also decreased on both study days (DF1,9 F=9.82, GG=0.0121). Nocturnal 6-SM excretion and melatonin secretion correlated highly (r=0.91, P=0.0007). Behavioral ratings did not reveal a difference in symptomatology and did not correlate with changes in 6-SM or MHPG. This study demonstrates in healthy controls that 6-SM reliably reflects presynaptic catecholamine depletion induced by AMPT without the emergence of behavioral symptoms.

Prolonged inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates the circadian rhythm of human TSH secretion.

OBJECTIVE: Originating from the pituitary gland, TSH secretion is regulated predominantly by thyroid-releasing hormone (TRH) neurons located in the hypothalamus. Norepinephrine and dopamine have important effects in modulation of TSH secretion. An inhibitor of catecholamine synthesis, alpha-methyl-para-tyrosine (AMPT) has been used in several studies of the regulation of human TSH secretion. The short-term effects (<8 hours) of low doses of AMPT include stimulation of pituitary TSH secretion by selective lowering of brain dopamine levels. After prolonged administration of AMPT (>24 hours), theoretically both dopamine and norepinephrine levels are lowered significantly in the brain, although this has not been reported previously. METHODS: Nine subjects (five women and four men) received a total of five 1-g doses of AMPT or five 50-mg doses of promethazine (active placebo) over 28 hours in a randomized, double-blind, placebo-controlled crossover design in which the active and control tests were separated by 4-6 weeks. Blood samples were obtained over 24 hours (18 time points) on day 2 of each condition. RESULTS: Changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion indirectly showed the effects of AMPT on dopamine and norepinephrine. The typical circadian rhythm of TSH secretion was blunted by AMPT throughout the night; at ten time points, the difference between the two groups was statistically significant (P <.01). The long-term effects of repeated doses of AMPT were inhibition of TSH secretion and significant attenuation of the circadian rhythm of TSH. Additionally, AMPT induced low norepinephrine levels, which counteracted the stimulatory effect of low dopamine levels on TSH. CONCLUSION: Through its inhibitory effect on TRH, norepinephrine appeared to be involved in the regulation of TSH.

Delusions of disfigurement in a woman with acne rosacea.

A 36-year-old woman with newly diagnosed acne rosacea is presented. Her skin changes were noticeable only under closest scrutiny, but she quit her job, became despondent about her acne, and developed suicidal ideation. The diagnosis and treatment of this patient allow a broader discussion of the somatically focused patient whose ideation reaches delusional intensity.

Hypokalemia leading to torsades de pointes. Munchausen's disorder or bulimia nervosa?

A 45-year-old woman traveled over 1000 miles from a major metropolitan area to obtain another opinion for medically refractory diarrhea. She had an extremely complicated medical history with no outside records or family members accompanying her to give collateral history. She had multiple previous diagnostic evaluations including 13 surgical procedures and many therapeutic trials of various medications. She acknowledged a preoccupation with weight and appearance, described previous attempts to diet, and repetitively denied purging, including laxative abuse. During her hospitalization she had two episodes of torsades de pointes requiring cardiac defibrillation. Laboratory testing revealed hypokalemia at the time of these events, and a toxicology screen was positive for bisacodyl, confirming laxative abuse. When confronted by a combined team of cardiology, gastroenterology, and psychiatry specialist, she admitted her laxative abuse and surrendered her supply of Dulcolax tablets. The discussion addresses the procedures employed to detect her surreptitious medication use, the near lethal cardiac complications, and the appropriate psychiatric diagnosis.

The effects of antidepressants on sleep: a review.

Sleep disturbances are a frequent complication of depressive disorders and their treatment. Familiarity with the interaction among sleep, depression, and antidepressant medications may assist the clinician in selecting agents to suit the needs of individual patients. The authors review the current knowledge of changes in sleep architecture associated with particular antidepressant agents and with depressive illness, as well as the theoretical relevance of such changes to the antidepressant effect. Articles for review were found through a Medline search on the terms "polysomnography," "sleep," "antidepressants," and "insomnia" in English-language papers published from 1966 through March 2000. Additional articles were found in the reference lists of relevant papers.