New Advances in the Psychopharmacological Treatment of OCD
Daniel A. Geller, M.D.
It is fascinating that Obsessive Compulsive Disorder (OCD), once considered a cornerstone in psychodynamic and psychoanalytic theory, has evolved into a prototypical neuropsychiatric biological disorder. The efficacy and specificity of serotonergic antidepressants in the treatment of OCD, and evidence of abnormalities in serotonin binding capacity and of decreases in platelet serotonin concentration during clomipramine treatment in pediatric OCD subjects contribute to the hypothesis derived from adult studies that central serotonin pathways are implicated in the pathophysiology of this disorder. Neuroimaging including functional neuroimaging studies have also implicated the basal ganglia, caudate nucleus and frontal cortex in the genesis of OCD symptoms. In addition, clinical and family studies provide strong evidence for a genetic etiology in at least some patients with OCD. The available family studies have found OCD to be a highly familial disorder in children and adolescents.
It is also fascinating to note that once considered relatively rare, OCD is now believed to be one of the most common of all psychiatric disorders affecting both children and adults. Since the observation was first made in Europe that the drug clomipramine, long ignored in the USA, seemed to have anti obsessional properties, new drug treatments for OCD have continued to emerge, and the disorder has been increasingly recognized by mental health professionals. Thus, the availability of new and effective medications combined with the shift in thinking about the etiology and pathophysiology of OCD has led to a radical change in the way that the disorder is treated at the turn of the century when compared to the treatment that Freud's famous "Rat Man" case implied at the turn of the last century.
Treatment approaches include both medication and non medication treatments (see the last paragraph). Drug studies in pediatric subjects have all found serotonergic medications to be effective in both the short term and medium term treatment of children and adolescents with OCD. Although most studies were acute treatment trials lasting no longer than 10 weeks, several longer term studies (>12 months) found efficacy maintained over time. Prospective controlled trials with both placebo and non serotonergic drugs also indicated specificity of response for the serotonergic reuptake inhibitors (SRIs). Four studies evaluated clomipramine (a non selective SRI), five fluoxetine, two fluvoxamine and one sertraline (selective SRIs or SSRIs) with reported response rates ranging from 50% to 75% and amount of symptom abatement ranging from 25% to 57% using the Children's version of the Yale Brown Obsessive Compulsive Scale (CY BOCS). In addition, both preadolescent and adolescent OCD subjects respond equally well to treatment with similar reductions in symptoms.
These studies document that the need for aggressive dosing in pediatric OCD is shared with the adult disorder. For example, clomipramine at 3 5 mg/kg/day was used in the NIMH cohort. In a retrospective series of children and adolescents treated for OCD with fluoxetine, doses averaged 1.0 mg/kg/day or 35 mg/day in children (< 12 years) and 64 mg/day in adolescents (> 12 years). Dosing for sertraline and fluvoxamine are somewhat higher at 1 3 mg/kg/day. Industry sponsored trials of both sertraline and fluvoxamine used flexible dose regimes of 50 to 200 mg/day in children. The mean dose of sertraline was 178 mg/day across all subjects indicating that both robust dosing was needed and that the medication was well tolerated. Pretreatment CY BOCS scores fell from 23 to a post treatment score of 17, a fairly typical reduction on this instrument. Dosing requirements for fluvoxamine were similar and both agents are generally well tolerated. At the end of 1999, only sertraline and fluvoxamine have FDA labeling for the treatment of pediatric OCD. Furthermore, the safety of sertraline has been established by an independent review of multi center EKG data collected serially over the active treatment phase.
Although paroxetine in pediatric OCD is now being systematically studied in placebo controlled trials, clear guidelines for dosing in this age group («16 years) are not yet available. The first such trial (1998) used flexible doses of paroxetine of 10 60 mg/day and the current trial 10 50 mg/day so that 0.5 1.0 mg/kg/day appears to be equivalent to the other SSRI dose ranges noted above. An industry sponsored placebo controlled double blind trial of fluoxetine has just been completed in children and adolescents and analyses are awaited but are expected to confirm clinical findings of efficacy and safety so that FDA labeling is expected for both fluoxetine as well as paroxetine in the next couple of years.
Pharmacokinetic data is more limited in this age group since these studies are more difficult to undertake in children, due to the need for frequent blood sampling. Three of the SSRIs have been investigated in this way; sertraline, paroxetine and fluoxetine. Each shows pharmacokinetic profiles consistent with that seen in adults although the half life tends to be slightly shorter in younger subjects due to more rapid metabolism and a higher relative hepatic blood flow. This increased clearance is not clinically significant and does not alter the dosing schedules, i.e. fluoxetine and sertraline are still administered once a day and fluvoxamine twice a day when doses are above 100/mg day total.
Placebo responses in studies range from 10% to 27%. The recently completed industry-sponsored controlled trial of fluvoxamine in 120 juvenile subjects showed similar efficacy but a higher placebo response rate than other studies. A paroxetine placebo controlled withdrawal trial also showed a high placebo response rate that did not discriminate from the active treatment group. Although no predictors of response were statistically significant, Leonard et al. found that younger age at discontinuation of serotonergic medication predicted later relapse. Serum levels do not correlate with clinical response.
In the most comprehensive study to date of clominapramine in pediatric OCD, adverse effects were common and included anticholinergic symptoms (e.g. dry mouth), 63%; tremor, 33%; dizziness, 41%; and sedation, 46%, making it difficult to tolerate for some patients even in the context of a robust clinical response. Adverse effects are also common although generally better tolerated in youth treated with the SSRIs. For example, reported adverse effects for fluoxetine included insomnia, 16%; somnolence, 11%; weight change and appetite disturbance, 8%; dry mouth and headache, 5%; and myoclonus, increased tics, bruising, and nervousness, 3%. One of the most common adverse effects with fluoxetine and other SSRIs (as well as clomipramine) is behavioral activation/ agitation which may occur in up to a quarter of treated subjects and may be sever enough to warrant a diagnosis of organically induced mania or hypomania. Whether children with this adverse effect are predisposed to the development of bipolar disorder, which is then unmasked by the SSRI, remains unknown.
To date, controlled trials of augmentation in treatment-resistant adult OCD have shown only haloperidol (inpatients with a chronic tic disorder or possibly psychotic symptoms) and clonazepam to be helpful. One case study suggests that clonazepam may also be a useful adjunct in the treatment of pediatric cases. Although the addition of neuroleptics has not been systematically studied in children, such a trial may be indicated in those patients with comorbid Tourette's Disorder (TD) or psychotic symptoms. The newer so called atypical neuroleptics such as risperidone, olanzepine and quetiapine have not been systematically studied in children and adolescents for the treatment of any disorder at this time though evidence is mounting that they are effective mood stabilizers. There are open label reports that these agents may be useful as augmentation treatment for adults with OCD who have concurrent tic disorders or more schizotypal presentations. However, these drugs are not at all selective and include among their actions antagonist activity at the 5HT2 site, which is post synaptic. Theory predicts that this action could exacerbate obsessional symptoms and this has been reported clinically in some cases so that caution is needed in using the atypical neuroleptics for the treatment of children and adolescents with OCD, despite their attractiveness due to fewer serious adverse effects. They may still be indicated in cases with comorbid Tourette's syndrome and significant mood instability and of course in psychotic symptoms.
A more common and perhaps safer combine pharmacotherapeutic approach for the CCD juvenile with a chronic tic disorder or Attention-Deficit/Hyperactivity Disorder is clomipramine plus an SSRI. While attention to blood levels is mandatory due to hepatic inhibition of clomipramine by certain SSRIs and consequent increased blood levels, this combination may be extremely useful in certain patients. In addition, because the secondary amine tricyclic antidepressants have recently been demonstrated to be useful in both tic disorders and ADHD, the noradrenergic tricyclic metabolite of clomipramine (desmethylclomipramine) may have a unique role in the treatment of these comorbid patients.
The use of clomipramine mandates a thoughtful evaluation of the pediatric patient's general medical condition, and cardiac status in particular. Baseline evaluation should include a systems review and questions about personal or family history of heart disease. If in doubt, a general pediatric examination including auscultation of the heart and measurement of pulse and blood pressure is indicated. A history of nonfebrile seizures should also be noted but is not an absolute contraindication to clomipramine. A baseline (i.e., pretreatment) electrocardiogram (EKG) should be requested. Indices of interest are heart rate and rhythm, and cardiac cycle intervals such as PR, QRS and QTc. Since all tricyclics are Type I antiarrhythmic agents they may slow electrical conduction in the heart. While statistically significant changes in conduction intervals and heart rate may occur, these are rarely of clinical significance. However, in view of the current debate in pediatric psychopharmacology circles regarding the safety of desipramine, the prudent practitioner will evaluate and document these cardiac parameters. These issues have been reviewed by Biederman and FDA guidelines. They have identified unacceptable electrocardiographic indices for not using, or not increasing, clomipramine which are: 1) PR interval >200 ms; 2) QRS interval >30% increased over baseline or >120 ms; 3) blood pressure >140 systolic or 90 diastolic; and 4) heart rate >130 bpm at rest. Finally a prolonged QTc (corrected QT interval, 450 ms) is associated with increased risk of ventricular tachyarrhythmias and is relative contraindication for clomipramine use (or further increase). Despite these concerns, clomipramine remains an important drug in the armamentarium of antiobsessional medications.
In summary, the treatment of CCD has changed dramatically over the last twenty years. The younger the child the more one would first attempt a non pharmacological treatment such as cognitive-behavioral treatment and such is the recommendation of the American Academy of Child and Adolescent Psychiatry in its "Expert Guidelines for the Treatment of OCD." However, the ability of children to tolerate this form of treatment varies and depends on the presence of other disorders (disruptive behavior disorder or depression), degree of insight, and the intactness of the family unit. At this time the outlook is very positive for the great majority of children with this disorder.