[Historical approach to reserpine discovery and its introduction in psychiatry]. / Aproximación histórica al descubrimiento de la reserpina y su introducción en la clínica psiquiátrica.

Reserpine, an alkaloid of the Rauwolfia serpentina plant isolated during the middle of the 20th Century, represented a highly important clinical advance in the treatment of schizophrenia whose pharmacological tools were limited to chlorpromazine that was introduced in the clinical area two years before. Both agents would come into the history as the drugs that made possible the beginning of the psychopharmacological era. In the present article, a revision is made of the complicated process leading to the isolation and synthesis of reserpine, by the Swiss pharmaceutical company Ciba (Schlittler and Müller) and how its pharmacological properties (Bein) were discovered and studied, in the animals laboratory, mainly, the "tranquillizers". The introduction of this antipsychotic in psychiatry, which was initiated in 1954 (half a century ago), and the results obtained in the first clinical studies, as well as the role played by researchers such as Kline, Delay, Noce, Hollister, Altschule, etc. are then described. In addition, and from a historical perspective, the discovery of the adverse effects of this drug, especially those of extrapyramidal nature (dyskinesia and akathisia), are studied, concluding with the reasons that produced its rapid clinical decline, among which the genesis of depressive pictures (phenomenon presently questioned) may be emphasized. Finally, the conclusion reached was that, although the clinical relevance of reserpine was not as evident and long lasting as chlorpromazine, its initial contribution to the treatment of schizophrenic patients was of maximum importance.

El papel de la medicina herbal ayurvédica en el descubrimiento de las propiedades neurolepticas de la reserpina: a propósito de la Rauwolfia serpentina y los orígenes de la era antipsicótica / The role of the ayurvedic herbal medicine in the discovering of neuroleptic properties of reserpine: Rauwolfia serpentina and the origins of antipsychotic era

En el presente trabajo se revisa el papel de la planta Rauwolfia serpentina en el origen de la denominada "era psicofarmacológica". Para ello, se ha sumarizado su empleo en la tradicional medicina ayurvédica, fundamentalmente en los trastornos mentales. En el clásico tratado hindú Charaka Samhita ya se hablaba de una forma de psicosis denominada Ounmaad, uno de cuyos remedios terapéuticos era la "planta de raíz de serpiente". La medicina científica se ocupó del estudio, durante la primera mitad del siglo XX, de las actividades farmacológicas de esta planta, destacando las propiedades sedantes e hipotensivas. Finalmente, se analiza el proceso de aislamiento de los alcaloides de la raíz de Rauwolfia, iniciado en la India, y que concluyó con el descubrimiento de la reserpina en los laboratorios suizos de Ciba. Con la reserpina, el arsenal farmacológico para el tratamiento de la esquizofrenia, sustentado únicamente en la clorpromazina, se vio sustancialmente implementado; permitiendo un gran avance en el manejo de los trastornos psiquiátricos (AU)

Medication management of stimulants in pediatric practice settings: a national perspective.

Using a nationally representative sample of office-based physicians, the management practices of pediatricians, psychiatrists, and family practice physicians were investigated. The major aims were to determine (1) what types of services these physicians were providing to children who received stimulants, (2) what factors predicted receipt of stimulants, and (3) whether these practices were concordant or discordant with professional consensus on diagnosis and treatment of attention-deficit hyperactivity disorders (ADHD). Prescribing and management practice data from the 1995 National Ambulatory Medical Care Survey (NAMCS) were analyzed for children ages 0 to 17 years who were seen for psychiatric problems and received stimulant medication. Results indicated that 2 million visits by children were made in 1995 to psychiatrists, pediatricians, or family practitioners in which psychotropic medications were prescribed. In pediatric visits where stimulant medication was prescribed, mental health counseling was provided 47.3% of the time and psychotherapy 21.6%. Follow-up arrangements were made in 79.1% of the visits. Psychiatrists were significantly more likely to provide psychotherapy and to specify follow-up visits than were pediatricians, but less likely to provide other health counseling. Controlling for demographic and physician effects, the factors with the most significant effect on the probability of receiving stimulants were geographic region (living in the South), race (being white), receiving mental health counseling, not receiving psychotherapy, and having health insurance. Less than 50% of pediatric visits for psychiatric reasons involving stimulant medications included any form of psychosocial intervention. In 21% of these visits, no recommendations were made for follow-up care. These practices diverge from National Institutes of Health (NIH) consensus panel recommendations and association-issued practice parameters.

Risperidone in the treatment of choreiform movements and aggressiveness in a child with "PANDAS".

The acronym 'PANDAS' (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) is used to describe neuropsychiatric symptoms putatively resulting from autoimmune responses to streptococcal infection in vulnerable children. A case of 'PANDAS' is presented to increase physician awareness of this disorder and to document effectiveness of risperidone in chorea and treatment-resistant disruptive behavior associated with this syndrome. To our knowledge, this is the first case report on risperidone in pediatric chorea, although studies on effectiveness of this agent in Tourette's disorders have been previously published.

Mood stabilizers in children and adolescents.

OBJECTIVE: The efficacy of mood stabilizers in children and adolescents has not been studied adequately. This article will review existing studies and highlight some important issues in designing future studies on these agents. METHOD: Electronic databases including Medline, Psycholnfo, and CRISP were searched for data in children receiving compounds that have mood-stabilizing properties in adults. RESULTS: Some open clinical data and an extremely modest amount of controlled research data suggest lithium, carbamazepine, and valproate may be effective mood stabilizers in children and adolescents. There are no controlled data on other potential mood stabilizers in children. CONCLUSIONS: The disorders that may be responsive to mood stabilizers are among the most morbid in child psychiatry. More studies are needed to clarify the efficacy of these compounds in children and adolescents and to provide a rational basis for choosing among them.

Psychoactive medication prescribing practices for U.S. children: gaps between research and clinical practice.

OBJECTIVE: To determine national pediatric prescribing practices for psychotropic agents and to examine these practices in view of the available evidence concerning their safety and efficacy in this age group. METHOD: Prescribing data from 2 national databases based on surveys of office-based medical practices were determined and reviewed vis-à-vis available safety and efficacy evidence. RESULTS: Data indicate that levels of psychotropic prescribing in children and adolescents are greatest for stimulants, resulting in nearly 2 million office visits and 6 million drug "mentions" in 1995. Selective serotonin reuptake inhibitors were the second most prescribed psychotropic agents, while anticonvulsant mood stabilizers (prescribed for a psychiatric reason), tricyclic antidepressants, central adrenergic agonists, antipsychotics, benzodiazepines, and lithium were also prescribed for a substantial number of office visits. Comparison of prescribing frequencies with available safety and efficacy data indicates significant gaps in knowledge for commonly used agents. CONCLUSIONS: Most psychotropic agents require further sustained study to ensure appropriate health care expenditures and vouchsafe children's safety. Recommendations for researchers, parents, federal agencies, and industry are offered as a means to accelerate the pace of research progress.

Neuropsychiatric aspects of pediatric thyrotoxicosis.

The neurobehavioural and neuropsychiatric changes associated with thyrotoxicosis are multiple and varied. This association is well recognised although the true incidence of neuropsychiatric symptoms in thyrotoxicosis is not known. Review of available literature suggests that frank psychiatric symptoms in thyrotoxicosis may be in the order of 10%. In pediatric thyrotoxicosis the neuropsychiatric symptoms may be pronounced and may antedate the medical diagnosis by six months to one year. One of the classic presentation is deterioration in school performance. Frequently noticed cognitive and behavioural abnormalities in pediatric thyrotoxicosis are hyperactivity, irritability or anxious dysphoria, and problems of attention. Successful treatment of thyrotoxicosis usually leads to resolution of the major mental disturbances associated with it and delayed treatment possibly results in enduring neuropsychiatric problems. Awareness of neuropsychiatric symptomatology can help in early detection and appropriate management of children with thyrotoxicosis.

Frontal lobe proton magnetic-resonance spectroscopy in Graves' disease: a pilot study.

Patients with hyperthyroidism may show impaired performance on several neuropsychological tests that require complex visual discrimination, conceptualization, mental flexibility or organization. These neurocognitive impairments appear to be consistent with prefrontal lobe dysfunction. This pilot study was undertaken to characterize the metabolite profile in the right prefrontal cortex in six patients with untreated Graves' disease by using in vivo proton magnetic-resonance spectroscopy (1H-MRS). For comparison, 1H-MRS was also carried out in seven healthy controls. The choline/creatine (Cho/Cr) and N-acetyl aspartate/creatine (Naa/Cr) ratios were determined. Cho/Cr ratios of the hyperthyroid patients were significantly lower than that of controls (means +/- SD = 0.61 +/- 0.09 vs. 0.90 +/- 0.18, p = .05). The two groups did not differ in their Naa/Cr ratios. Follow-up data after antithyroid treatment were available in three patients: Cho/Cr ratios were higher after treatment (euthyroidism) than before treatment (1.06 vs. 0.55; 0.82 vs. 0.54; 1.15 vs. 0.76). Tentatively, these preliminary data are most consistent with reversible reductions in the concentrations of choline-containing compounds (especially glycerophosphocholine and phosphocholine) in the prefrontal area during hyperthyroidism. However, these findings await confirmation by a definitive study with a larger sample size. A possible explanation of the findings is an altered brain cholinergic-adrenergic balance in hyperthyroidism.

Postpartum psychosis and postpartum thyroiditis.

The term postpartum psychosis refers to a group of severe and heterogeneous disorders with psychotic symptoms that occur most frequently in the context of a mood disorder during the postpartum period. We report a case of 'postpartum psychosis' possibly associated with postpartum thyroiditis in a 29 year-old woman. The appearance of psychotic symptoms was chronologically related to the onset of postpartum thyroiditis and resolution of psychosis synchronized with the achievement of biochemical euthyroidism. The patient had typical symptoms of 'classic postpartum psychosis' (a historical term not included in DSM-IV, but used frequently by many physicians to describe diagnostic and therapeutic challenges posed by puerperal psychoses). Three months postpartum, the patient began to believe that she was pregnant with the Christ child, although she was not pregnant. Her delusions resolved around the 'pregnancy' and harm to her 'unborn' child. She also believed that her child (Jesus) was going to be killed. Other key symptoms included hallucinations, mixed mood symptoms, agitation and transient disorientation. Her DSM-IV diagnosis on admission was major depression with psychotic features and her discharge diagnosis (most likely diagnosis) was psychotic disorder due to thyrotoxicosis caused by postpartum thyroiditis. The differential diagnosis of co-occurring psychosis and postpartum thyroiditis can be examined relative to four possibilities: (1) psychosis due to thyrotoxicosis caused by postpartum thyroiditis; (2) a coincidence (no association between psychosis and postpartum thyroiditis); (3) precipitation of psychotic symptoms and disorientation related to a postpartum thyroiditis in a woman with a pre-existing mood disorder; or (4) both psychosis and thyroiditis caused by a pre-existing defect in autoimmunity. The authors stress the importance of early diagnosis and prompt treatment of postpartum psychosis. They discuss the indications for thyroid screening in postpartum psychoses. Further research is needed to clarify the nosology and mechanisms of severe postpartum disorders and to elucidate treatment-relevant and etiologically-distinct subsets of postpartum psychosis.

Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms.

OBJECTIVE: To document a case of serotonin syndrome associated with venlafaxine and fluoxetine that did not involve a monoamine oxidase inhibitor, and to examine the multiple factors, including pharmacodynamic and pharmacokinetic interactions, that likely caused this adverse drug reaction (ADR). CASE SUMMARY: A 39-year-old white woman with depression and panic attacks was being treated with fluoxetine, trazodone, clonazepam, and cimetidine. After fluoxetine and clonazepam were abruptly discontinued, venlafaxine and lorazepam were started. Within 24 hours, she developed diaphoresis, tremors, slurred speech, myoclonus, restlessness, impaired thinking, and diarrhea. This constellation meets Sternbach's criteria for serotonin syndrome. DISCUSSION: The possible contributors to this ADR are discussed, including a single drug effect (e.g., an idiosyncratic reaction to venlafaxine), a pharmacokinetic interaction, a pharmacodynamic interaction, a combined pharmacokinetic-pharmacodynamic interaction, and the patient' s panic disorder. CONCLUSIONS: As more serotonergic drugs are developed and used for psychiatric disorders, frequently in combination or close temporal proximity, clinicians must be aware of and consider the factors that may increase the risk of patients experiencing serotonin syndrome.

Resistance to thyroid hormone: implications for neurodevelopmental research on the effects of thyroid hormone disruptors.

Thyroid hormones are essential for normal behavioral, intellectual, and neurological development. Congenital hypothyroidism, if not treated, can result in irreversible mental retardation, whereas thyroid diseases with more moderate impairment of thyroid function, such as resistance to thyroid hormone, cause less severe intellectual and behavioral abnormalities, including attention deficit hyperactivity disorder. There is increasing evidence that exposure to certain synthetic compounds, including dioxins and polychlorinated biphenyls (PCBs), during the perinatal period can also impair learning, memory, and attentional processes in offspring. Animal and human studies suggest that exposure to these environmental toxicants impair normal thyroid function. Although the precise mechanisms of action of the adverse effects these toxicants have on neurodevelopment have not yet been elucidated, it is possible that they are partially or predominantly mediated by alterations in hormone binding to the thyroid hormone receptor. The convergence of studies that examine the neurodevelopmental consequences of moderate impairment of thyroid function, such as is found in resistance to thyroid hormone, with those studies that demonstrate the adverse behavioral and cognitive effects of perinatal exposure to dioxins and PCBs serves to generate new hypotheses to test in a research setting. Such studies may provide new insights into the basic pathogenesis of developmental neurotoxicity following exposure to thyroid-disrupting synthetic compounds.

Trazodone is only slightly faster than fluoxetine in relieving insomnia in adolescents with depressive disorders.

This retrospective chart review examined the relative effectiveness of fluoxetine and trazodone in relieving insomnia associated with depressive disorders in adolescents (aged 13-17 years). We reviewed the hospital charts of consecutively admitted adolescents with a depressive disorder and insomnia, who received one of three treatments: fluoxetine (20 +/- 2.2 mg), trazodone (71 +/- 32 mg), or a fluoxetine-trazodone combination (fluoxetine 29 +/- 2.2 mg, trazodone 68 +/- 29 mg). Each treatment was examined in 20 patients. Insomnia was defined as a change in sleep patterns characterized by decreased total sleep time that was sufficient to cause clinical concern, and insomnia resolution was defined as sleep starting by midnight and lasting 6 hours. Mean time to resolution of insomnia was significantly faster in adolescents treated with trazodone rather than fluoxetine (2.5 vs. 5.1 days, p < 0.05). Trazodone seemed to save only about 3 days and insomnia resolved in all subjects by the 11th day of antidepressant treatment. Median time to insomnia resolution was 2 days (range 1-5 days) in the trazodone group and 4 days (range 1-11 days) in the fluoxetine group. This difference between trazodone and fluoxetine, although statistically significant, was generally not clinically significant in the management of insomnia associated with depressive disorders in adolescents. The resolution of insomnia was not faster for treatment with a combination of fluoxetine and trazodone in comparison to fluoxetine monotherapy. Insomnia resolution was slightly later in older children. These clinical findings await confirmation by a controlled study. Both drugs seemed effective in ameliorating sleep symptoms in this sample, although it is likely that they produced these changes by different mechanisms.

A possible clonidine-trazodone-dextroamphetamine interaction in a 12-year-old boy.

A 12-year-old boy on a dextroamphetamine-clonidine-trazodone treatment regimen had a recurrence of insomnia, and his bedtime trazodone dose was doubled from 50 mg to 100 mg. Within 45 mins after taking the first 100-mg trazodone dose on an empty stomach, the patient had a syncopal episode associated with hypotension, bradycardia, and sedation. The drug reaction could have resulted from either trazodone or clonidine, but it is more likely to have resulted from a pharmacodynamic clonidine-trazodone interaction, presumably aggravated by rapid absorption (on an empty stomach) of a recently increased dose of trazodone. It is conceivable but less likely that the psychostimulant was a clinically significant factor. However, a drug interaction between clonidine and D-amphetamine does not need to be postulated to explain this child's syncopal reaction. The authors advise that (1) if trazodone and clonidine are used concurrently, the doses of both agents should be changed slowly, (2) blood pressure and pulse should be carefully monitored at baseline and then periodically during treatment, and (3) administration of trazodone on an empty stomach, and especially dose increases on an empty stomach, should be avoided. Physicians should remain aware that trazodone has the potential to produce hypotension and sedation, especially when combined with other agents (such as clonidine) that might produce the same adverse effects.