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Biomedical subjects

C J McDougle

Publications and source records attributed to C J McDougle.

At least 19 recordsLinked to original sources
PubMed2001

The pathophysiology and treatment of autism.

This article critically reviews research done in the past 2 years concerning the pathophysiology and treatment of autism. Recent research in genetics, neuroimaging, neurochemistry, and pharmacologic treatment has advanced the body of knowledge about the pathophysiology of autism. Relatively new imaging technologies (eg, positron emission tomography) are increasingly being applied to the study of subjects with autism and have produced promising results that await replication. Neurochemical and challenge studies continue to suggest a role for 5-HT dysregulation in autism. Additional research is needed to determine the role of neuroendocrine and autoimmune factors in autism. Significant gains have been made in determining which pharmacologic treatments are efficacious in autism. Additional research is needed on agents that might ameliorate the core and associated symptoms of autism.

Autistic Disorder↗
PubMed2001

A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders.

OBJECTIVE: The aim of this study was to conduct a naturalistic, open-label examination of the efficacy and tolerability of mirtazapine (a medication with both serotonergic and noradrenergic properties) in the treatment of associated symptoms of autism and other pervasive developmental disorders (PDDs). METHODS: Twenty-six subjects (5 females, 21 males; ages 3.8 to 23.5 years; mean age 10.1 +/- 4.8 years) with PDDs (20 with autistic disorder, 1 with Asperger's disorder, 1 with Rett's disorder, and 4 with PDDs not otherwise specified were treated with open-label mirtazapine (dose range, 7.5-45 mg daily; mean 30.3 +/- 12.6 mg daily). Twenty had comorbid mental retardation, and 17 were taking concomitant psychotropic medications. At endpoint, subjects' primary caregivers were interviewed using the Clinical Global Impressions (CGI) scale, the Aberrant Behavior Checklist, and a side-effect checklist. RESULTS: Twenty-five of 26 subjects completed at least 4 weeks of treatment (mean 150 +/- 103 days). Nine of 26 subjects (34.6%) were judged responders ("much improved" or "very much improved" on the CGI) based on improvement in a variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. Mirtazapine did not improve core symptoms of social or communication impairment. Adverse effects were minimal and included increased appetite, irritability, and transient sedation. CONCLUSIONS: Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder and other PDDs.

Adolescent↗
PubMed2001

Induction of indoleamine 2,3-dioxygenase in vivo by IFN-con1.

Indoleamine 2,3-dioxygenase (IDO) activity as determined by increases in serum kynurenine was measured in a group of hepatitis C patients treated with consensus interferon (IFN-con1). Kynurenine levels increased significantly within 2 days of initiation of treatment but returned to normal values by week 4 after treatment. Although IDO is normally induced by IFN-gamma, no such IFN was detected by ELISA or biologic assays. Thus, consensus IFN induces low levels of IDO in vivo without an IFN-gamma intermediate.

Enzyme Induction↗
PubMed2001

Pharmacotherapeutic management of autism.

There are no medications that are specifically marketed for the treatment of autism. There does exist, however, an extensive body of literature describing both open-label and controlled studies of medications in the treatment of both children and adults with autism. Some of the better-studied medications (including haloperidol and risperidone) are often efficacious in treating associated symptoms of autism but can also cause unacceptable adverse effects. Early studies of serotonin re-uptake inhibitors appear promising but may not be indicated for all age groups. Small, controlled studies of methylphenidate and clonidine indicate a possible role for these medications in the treatment of hyperactivity in autism. No medications have been proven to be efficacious in the treatment of the core social or communication impairment seen in autism. Current pharmacological management is best aimed at target symptoms that have been demonstrated to respond to medication in treatment studies.

Adrenergic alpha-Agonists↗
PubMed2001

Trichotillomania. Presentation, etiology, diagnosis and therapy.

Trichotillomania (TTM) is an impulse disorder, in which patients chronically pull hair from the scalp and/or other sites. Very early onset of hair pulling in children under the age of 6 may be more benign and self-limiting than the more common syndrome of late childhood onset hair pulling. While far more women and adolescent girls appear for treatment, survey studies suggest chronic hair pulling also occurs in males. Diagnosis may be complicated by patient and family denial or ignorance of the hair pulling; accurate scalp examination and biopsy can be critical. Classic scalp biopsies for TTM feature trichomalacia, pigment clumps, peribulbar hemorrhage and hair canal pigment casts, and lack lymphocytic infiltrates seen in alopecia areata. Treatment is difficult: the tricyclic antidepressant clomipramine is the most promising agent, although many patients find it difficult to tolerate at adequate dosages, and treatment response may not be maintained over the long term. More benign medications have not demonstrated efficacy in controlled studies. Augmentation with topical preparations or psychotropic medications may be helpful for patients experiencing limited efficacy or relapse. Specialized psychotherapy, known as habit reversal training, is highly recommended; however, the treatment is intensive and highly specialized. Skilled therapists are difficult to locate.

Adolescent↗
PubMed2001

Tolerability profile of atypical antipsychotics in children and adolescents.

Antipsychotics are frequently used in the treatment of a variety of neuropsychiatric conditions in children and adolescents. Atypical antipsychotics have come to the forefront in child psychiatry due largely to their tolerability profiles as well as their efficacy. Potential treatment options include clozapine, risperidone, olanzapine, quetiapine and ziprasidone. A number of studies investigating the use of clozapine have been published in children; however, owing to the frequent monitoring required for agranulocytosis, the use of clozapine may be restricted to patients with treatment-refractory disease. With accumulating data on the development of glucose intolerance in adults receiving clozapine, closer monitoring of bodyweight and fasting blood glucose is imperative. Clozapine also has an increased seizure risk, therefore a baseline electroencephalogram should be performed, as well as continued vigilance for this adverse effect. Risperidone is an atypical antipsychotic that is generally well tolerated and numerous studies have been published investigating this drug in children. Unlike clozapine, its receptor interaction profile lends itself toward increased risk of extrapyramidal symptoms (EPS) and hyperprolactinaemia. Bodyweight gain is a common adverse effect, although somewhat less than that reported with olanzapine. Baseline liver function studies prior to initiation of this medication are recommended. Risperidone-induced mania has been reported in adults and, therefore, increased caution should be used when deciding to treat children and adolescents with risperidone, particularly in those with a predisposition toward mania. Olanzapine, like risperidone, has also been associated with onset of mania in adults. Olanzapine has a receptor profile that results in significant risk for bodyweight gain and sedation. Furthermore, this drug has been linked to the development of glucose intolerance; thus, it is important to monitor bodyweight and fasting blood glucose on a frequent basis. Less information is known about quetiapine in children and adolescents. Reports about its efficacy and tolerability vary. Quetiapine appears to have increased risk for sedation and bodyweight gain, albeit less than that of olanzapine. The compound appears to be less likely to induce EPS. Finally, ziprasidone has recently been approved for use in the adult population. This compound, in terms of its receptor profile, has more in common with risperidone. This suggests a potential for increased risk of EPS and hyperprolactinaemia. It also has an increased risk of QTc prolongation; thus, a baseline electrocardiogram is suggested, particularly in those patients with a history of cardiovascular illness. Lack of evidence for bodyweight gain with ziprasidone is a considerable advantage.

Adolescent↗
PubMed2000

A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.

BACKGROUND: To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response. This report describes the first controlled study of risperidone addition in patients with OCD refractory to treatment with SRI alone. METHODS: Seventy adult patients with a primary DSM-IV diagnosis of OCD received 12 weeks of treatment with an SRI. Thirty-six patients were refractory to the SRI and were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition. Behavioral ratings, including the Yale-Brown Obsessive Compulsive Scale, were obtained at baseline and throughout the trial. Placebo-treated patients subsequently received an identical open-label trial of risperidone addition. RESULTS: For study completers, 9 (50%) of 18 risperidone-treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005). Seven (50%) of 14 patients who received open-label risperidone addition responded. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. There was no difference in response between OCD patients with and without comorbid diagnoses of chronic tic disorder or schizotypal personalty disorder. Other than mild, transient sedation, risperidone was well tolerated. CONCLUSION: These results suggest that OCD patients with and without comorbid chronic tic disorders or schizotypal personality disorder may respond to the addition of low-dose risperidone to ongoing SRI therapy.

Adult↗
PubMed2000

Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. Research Units on Pediatric Psychopharmacology.

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.

Antipsychotic Agents↗
PubMed2000

Repetitive thoughts and behavior in pervasive developmental disorders: treatment with serotonin reuptake inhibitors.

Repetitive thoughts and behavior are considered integral and core components of autistic disorder. Results from recent studies suggest that the types of repetitive thoughts and behavior of adults with autism and those with obsessive-compulsive disorder (OCD) may be different. Serotonin reuptake inhibitors (SRIs), the primary drug treatment for patients with OCD, may reduce the repetitive phenomena of some autistic patients. Two controlled studies of the nonselective SRI clomipramine have shown the drug to be more efficacious than the relatively selective norepinephrine reuptake inhibitor desipramine and placebo in children with autism. One controlled study of the selective SRI fluvoxamine found it to be significantly better than placebo for reducing repetitive phenomena and aggression in adults with autistic disorder. Additional research is needed.

Adolescent↗
PubMed2000

Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Background and rationale for an initial controlled study of risperidone.

This article has reviewed the background and rationale for the choice of risperidone as the first drug to be studied by the RUPP Autism Network. Risperidone has potent effects on 5-HT and DA neuronal systems, both of which have been implicated in the pathophysiology of autism. Unlike the typical antipsychotics, haloperidol and pimozide, which have been shown to be effective for reducing many of the maladaptive behaviors associated with autism, risperidone's 5-HT2A/DA D2 ratio of receptor blockade appears to produce a lower risk of acute and chronic extrapyramidal side effects, as well as enhanced efficacy for the "negative" symptoms of autism. Indirect clinical and preclinical evidence supports the use of risperidone to treat impaired social behavior, interfering repetitive phenomena, and aggression, targets of pharmacotherapy for many patients with autism. Numerous published open-label trials in children and adolescents with autism and related PDDs and one double-blind, placebo-controlled study in adults suggest that risperidone has promise for the treatment of children and adolescents with autism. Because most of these studies have been short-term, open-label trials in small samples, however, a large-scale controlled study of risperidone in children and adolescents with autism is needed to confirm these results. Finally, because it is likely that children who demonstrate short-term benefit from risperidone will remain on the medication indefinitely, the longer-term effectiveness and safety of risperidone in this population also needs to be determined. The design of this study and the assessments used are described separately.

Adolescent↗
PubMed1999

Effects of catecholamine depletion with AMPT (alpha-methyl-para-tyrosine) in obsessive-compulsive disorder.

BACKGROUND: Several lines of evidence suggest that brain dopamine function may contribute to some obsessive-compulsive (OC) phenomena. The effects of catecholamine depletion were examined in drug-free patients with obsessive-compulsive disorder (OCD). METHODS: The tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT) and diphenhydramine hydrochloride (placebo) were administered for three consecutive days, one week apart, to 6 drug-free adult OCD patients without a personal or family history of chronic tics, in a double-blind, randomized design. The effects of AMPT and placebo on OC, depression, anxiety and global clinical symptoms were assessed. RESULTS: AMPT produced no clinically or statistically significant change in any behavioral ratings, including OC symptom severity, compared with placebo. CONCLUSIONS: Acute reduction of catecholamine levels does not seem to affect OC symptoms in drug-free patients with OCD. Studies of catecholamine depletion with AMPT in patients with comorbid OCD and chronic tics may be of considerable neurobiological and clinical interest.

Adult↗
PubMed1999

Possible role of neuropeptides in obsessive compulsive disorder.

The most consistent finding in clinical research of obsessive compulsive disorder (OCD) is the significant treatment advantage of potent serotonin uptake inhibitors (SUIs) over other classes of antidepressant and antianxiety drugs. Clinical neurobiological studies of OCD, however, have yielded limited and inconsistent evidence for significant fundamental abnormalities in monoamine systems including serotonin, norepinephrine and dopamine. Furthermore, one-third to one-half of OCD patients do not experience a clinically meaningful improvement with SUI treatment. Investigation beyond the monoamine systems may be necessary in order to more fully understand the pathophysiology of obsessive-compulsive symptoms and develop improved treatments. Evidence from preclinical studies suggests that neuropeptides may have important influences on memory acquisition, maintenance and retrieval; grooming, maternal, sexual and aggressive behavior; fixed action patterns; and stereotyped behavior; these phenomena may relate to some features of OCD. In addition, extensive interactions have been identified in the brain between neuropeptidergic and monoaminergic systems, including co-localization among specific populations of neurons. The purpose of this review is to present the current knowledge of the role of neuropeptides in the clinical neurobiology of children, adolescents and adults with OCD focusing primarily on results from pharmacological challenge and cerebrospinal fluid studies. Where evidence exists, developmentally regulated differences in neuropeptide function between children and adolescents versus adults with OCD will be emphasized; these data are intended to underscore the potential importance of establishing the age of symptom onset (childhood versus adult) in individual patients with OCD participating in clinical neurobiological investigations. Likewise, where information is available, differences in measures of neuropeptides between patients with non-tic-related OCD versus tic-related OCD will be highlighted; these data will demonstrate the critical value of diagnostic precision, as these two particular subtypes of OCD may have different neurochemical underpinnings.

Adolescent↗
PubMed1999

Risperidone in the treatment of two very young children with autism.

This report describes the use of risperidone in the treatment of two very young children with autistic disorder, a 29-month-old boy and a 23-month-old boy, respectively. These children presented with severe and persistent symptoms of aggression and irritability that had not responded to previous treatment. In both cases, risperidone significantly reduced aggression and improved social relatedness. One patient's treatment with risperidone was complicated by persistent tachycardia and QTc interval prolongation that was dose-related. Consideration should be given to the appropriate use of medication in the treatment of very young children with autism when other interventions do not prove helpful.

Antipsychotic Agents↗
PubMed1999

Risperidone addition in serotonin reuptake inhibitor-resistant trichotillomania: three cases.

Open-label addition of a low-dose typical (pimozide) neuroleptic was shown to be beneficial in some patients with serotonin reuptake inhibitor (SRI)-refractory trichotillomania (TTM). Risperidone's potentially more benign acute and long-term side effect profile makes it a candidate for investigation in the treatment of TTM. We report our experience with the systematic addition of open-label risperidone 0.5 to 3 mg/day in three patients with SRI-refractory TTM. All three patients had a robust decrease in hair pulling as measured by clinician-rated instruments. These results suggest that risperidone addition to ongoing treatment with SRIs may be an effective treatment strategy for patients with SRI-refractory TTM.

Adult↗