Obsessive-compulsive Disorders/Antipsychotics in Youth

From the 14th Annual Psychopharmacology Update,
presented by the University of Nevada School of Medicine and the Nevada Psychiatric Society

Educational Objectives

The goal of this program is to improve the treatment of obsessive-compulsive and impulse-control disorders and dif­ferentiate the use of atypical antipsychotics in youth from their use in adults. After hearing and assimilating this pro­gram, the clinician will be better able to:

1.   Discuss the American Psychiatric Association’s guidelines on the treatment of obsessive-compulsive disorder (OCD).

2.   Develop strategies for the treatment of OCD and impulse-control disorders.

3.   Manage the side effects of medications used to treat OCD and impulse-control disorders.

4.   Compare responses to and outcomes of treatment with atypical antipsychotic medications in adolescents vs adults.

5.   Select appropriate first- or second-generation antipsychotic medications for treatment of  adolescents.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Koran is on the Speakers’ Bureau for Forest Pharmaceuticals. Dr. Schulz is a consultant to, on the Speakers’ Bureau of, and receives grant/research sup­port from Abbott, AstraZeneca, and Eli Lilly. Both speakers discussed the off-label use of medications. The planning commit­tee reported nothing to disclose.

Acknowledgments

Drs. Koran and Schulz were recorded at the 14th Annual Psychopharmacology Update, held February 12-14, 2009, in Las Ve­gas, NV, and sponsored by the University of Nevada School of Medicine and the Nevada Psychiatric Association. The Audio-Digest foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Treating Obsessive-compulsive and Impulse-control Disorders

Lorrin M. Koran, MD, Professor of Psychiatry, Emeritus, Stanford University School of Medicine, Palo Alto, CA

Obsessive-compulsive disorder (OCD): American Psychiatric Association (APA) practice guidelines available at www.psychiatryonline.com 

Initial treatment: cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitor (SSRI), or combination of CBT and SSRI; patient has 50-50 chance of responding to CBT or to any SSRI; clomipramine (Anafranil), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft) approved by Food and Drug Administration (FDA) for treatment of OCD; speaker discourages using clomipramine as first-line treatment be­cause of side effects

SSRIs: all equally efficacious, so choice based on avoidance of side effects (not on preference for specific side ef­fects, eg, somnolence); also consider drug interactions, past treatment response, and co-occurring general med­ical conditions; if patient does not respond to first SSRI, chances of responding to second SSRI still 50%, but drop off sharply thereafter

Enzyme interactions: fluoxetine, paroxetine, and duloxetine (Cymbalta) inhibit cytochrome P₄₅₀2D6 (CYP2D6); fluvoxamine inhibits cytochromes P₄₅₀ 1A2 through 3A4; caffeine metabolized by CYP1A2, so combination of caffeine and fluoxetine may cause anxiety; sertraline at low doses (eg, 50-100 mg) “not much of a” CYP2D6 inhibitor, but inhibition activated at higher doses (eg, 150-200 mg); citalopram (Celexa) becomes CYP2D6 in­hibitor at »60 mg; escitalopram (Lexapro) does not inhibit any enzyme, so does not have drug interactions; venlafaxine (Effexor) does not interact with liver P₄₅₀ system, but evidence suggests less efficacy for OCD than with medications above

Psychotherapy: CBT for OCD that utilizes primarily behavioral techniques (eg, exposure and response prevention) has best evidentiary support; some data support cognitive therapy; psychodynamic psychotherapy may help pa­tients to overcome resistance to treatment or to address interpersonal consequences of OCD, but analysis focused on sex and aggression not helpful for OCD; family therapy possibly useful because families sometimes inadver­tently sabotage therapy

Implementing pharmacotherapy: to avoid nausea, start SSRI at half of manufacturer’s recommended dose for sev­eral days, then titrate to maximum tolerated dose over several weeks; continue SSRI for 8 to 12 wk, including 4 to 6 wk at maximum tolerated dose, before switching to another SSRI; manage side effects; follow up few days to 2 wk after starting new medication; after dose stable, usually 3 to 4 mo from initiation of SSRI, taper down by half-dose increment every 2 mo; if symptoms do not recur after 2 mo at any dose, safe to drop another half dose

Managing side effects: bruxism  —  buspirone (BuSpar), 15 mg; sweating  —  benztropine (Cogentin), 1 mg/day or terazosin (Hytrin), 1 mg/day (warn patient about possible postural hypotension after first dose); other options in­clude mirtazapine (Remeron; 7.5-15 mg) and cyproheptadine (Periactin; 1-3 mg); sexual dysfunction  — remember that not all sexual dysfunction due to medication; may be due to, eg, depression, marital disharmony; bupropion (Wellbutrin) helps »40% of people with delayed orgasm, difficulty with erection, or lack of desire; in double-blind, placebo-controlled trials, sildenafil (eg, Viagra) found helpful in men and women

Implementation of CBT: if necessary, refer patient to local practitioner; adequate trial usually 13 to 20 sessions weekly or twice weekly; can be done in individual sessions, group sessions, or family sessions; booster sessions necessary every 1 to 2 mo for ³6 mo after completion of course

Obsessive-compulsive Foundation: advocacy group for people with OCD; information on website (www.ocfounda­tion.org) reliable; therapy does not generally cure patients, only improves them, so OC Foundation can provide important ongoing support

Combination therapy: CBT can be added to medication or vice versa; best-supported strategy to augment SSRI with atypical antipsychotic; speaker prefers risperidone (Risperdol) or aripiprazole (Abilify); quetiapine (Seroquel) not effective at doses <300 mg; speaker avoids olanzapine (Zyprexa) because it causes most weight gain; other strategies  —  add clomipramine to SSRI; switch to another SSRI or to venlafaxine; augment with buspirone; no sig­nificant benefit noted with pindolol; 1 trial supports augmenting with morphine or inositol; trials under way or re­cently completed in which SSRI augmented with memantine, N-acetylcysteine, and topiramate; 1-day trial of augmentation with dextroamphetamine showed positive results; if augmenting duloxetine with dextroamphet­amine, use lower dose of duloxetine; placebo for dextroamphetamine trial was caffeine (administered as NoDoz); case reports show »25% response with caffeine augmentation of SSRIs; no good data on monoamine oxidase in­hibitors (MAOIs); small trial (8 patients) supports use of tramadol; speaker recommends against using ondansetron

Pathologic gambling: evidence for efficacy of Gamblers Anonymous “totally inconclusive”; speaker recommends asking patients to attend Gamblers Anonymous as measure of their motivation to get better; spousal attendance may help spouse cope, but does not help with abstinence; mood stabilizers effective only in individuals with bi­polar-spectrum disorders in addition to gambling addiction; in small trial (27 participants), 60% responded to N-acetylcysteine (nontoxic and has minimal side effects, so further investigation warrented)

CBT: effective in large study, but no studies using CBT for pathologic gambling replicated; speaker recommends workbook by Petry (see “Suggested Reading”)

Pharmacotherapy: SSRIs no better than placebo; naltrexone (ReVia) shown beneficial in 2 double-blind, placebo-controlled trials; monitoring of liver function required for doses >50 mg (irritation of liver possibly due to combi­nation of naltrexone with nonsteroidal anti-inflammatory drugs or acetaminophen); discontinue naltrexone if liver function deteriorates

Compulsive buying: nationwide study showed 6% of women and 5.5% of men meet diagnostic criteria for compul­sive buying; mixed results with citalopram and escitalopram; case reports indicate naltrexone possibly effective

Skin picking: little literature on efficacy of CBT; treatment of choice SSRI in modest doses; 50% of patients respond to any SSRI, and response evident within 4 wk; if no response to first SSRI, try second one; if no benefit, switch to naltrexone

Antipsychotic Medications for Youth: Are They the Same as for Adults?

S. Charles Schulz, MD, Donald W. Hastings Endowed Chair, Professor, and Head, Department of Psychiatry, University of Minnesota Medical School, Minneapolis

Introduction: psychotic symptoms frequently begin before 19 yr of age in individuals who develop schizophrenia; data suggest poorer outcomes in patients with earlier-onset schizophrenia, but no large-scale studies undertaken

Brain images: in teens with schizophrenia, images similar to those in adults (difference in size of ventricles and cor­tex compared to controls); no gender differences seen; images of patients with bipolar disorder similar to those of patients with schizophrenia

Neuropsychologic testing: found that adolescents with schizophrenia had generalized cognitive dysfunction, with greatest difficulties seen in attention and working memory

Traditional antipsychotic medications: study revealed that 90% of adolescents who took traditional antipsychotic (eg, haloperidol) without simultaneous benztropine had extrapyramidal symptoms (EPS); 65% had dystonia; other symptoms included akathisia and parkinsonism

Atypical antipsychotic medications: in early 8-wk study, 16 patients given olanzapine, starting at low dose and ti­trating up; statistically significant improvement seen in scores on Positive and Negative Syndrome Scale (PANSS); medication generally well tolerated; few drop-outs from study; movement rating scales showed little change from baseline; average dose of olanzapine 12.5 mg/day (same dose given to adults); average weight gain 13 lb

Olanzapine and metabolic parameters in teens: in meta-analysis, adults experienced 35% increase in metabolic parameters, adolescents 65%; adolescents had smaller changes than adults in fasting glucose and triglyceride lev­els; authors concluded that metabolic effects of olanzapine in adolescents different from those in adults

Comparison studies

Risperidone, olanzapine, and haloperidol: 8-wk randomized double-blind trial in psychotic youth; response rates to olanzapine 88%, to risperidone 74%, and to haloperidol 53%; no statistically significant differences between groups; EPS seen in many participants, with significantly higher frequency in haloperidol group; weight gain seen in all groups

Olanzapine, risperidone, and quetiapine: 12-wk open study; no differences in PANSS scores or in movement rating scales; 63% of subjects had weight gain >7% over 12 wk

Efficacy and safety of second-generation antipsychotic medications: risperidone and aripiprazole have FDA ap­proval for use in patients <18 yr of age; olanzapine not approved for this age group

Olanzapine: 6-wk double-blind, placebo-controlled trial in patients <18 yr of age; increase in weight gain and pro­lactin levels in olanzapine group greater than those in placebo group and greater than those expected in adults

Risperidone: 6-wk dosing study compared low-dose risperidone, higher dose risperidone, and placebo; both risper­idone groups showed more improvement than placebo group, but risk-benefit ratio favored low-dose risperidone; adverse effects included somnolence, agitation, and headache in low-dose group and EPS in high-dose group

Aripiprazole: 6-wk dosing study compared low-dose aripiprazole, high-dose aripiprazole, and placebo; both doses superior to placebo; 5% of participants, most in high-dose group, discontinued medication due to adverse events

Molindone and benztropine: study compared olanzapine, risperidone, and molindone combined with benztropine; similar efficacy outcomes, but olanzapine arm terminated due to weight gain; author concluded that risperidone and olanzapine did not show superiority to molindone-benztropine; more EPS occurred in molindone group, more weight gain in risperidone and olanzapine groups; comparative risk for tardive dyskinesia not assessed, but older data indicate »5% of patients on traditional antipsychotics develop tardive dyskinesia

Clozapine: study compared clozapine and haloperidol in treatment-refractory teenagers with schizophrenia; found clozapine superior to haloperidol in this subgroup; another study compared clozapine and high-dose olanzapine, also in treatment-refractory teenagers; response rates 66% for clozapine, 33% for olanzapine

Conclusions: schizophrenia in adolescents serious; controlled trials of atypical antipsychotic medications in adoles­cents emerging, and may raise safety issues; no response to antipsychotic medications in 30% to 40% of patients

Suggested Reading

Findling RL et al: A prospective, open-label trial of olanzapine in adolescents with schizophrenia. J Am Acad Child Ado­lesc Psychiatry 42:170, 2003; Grant JE, Potenza MN: Escitalopram treatment of pathological gambling with co-occurring anxiety: an open-label pilot study with double-blind discontinuation. Int Clin Psychopharmacol 21:203, 2006; Hollander E et al: A randomized double-blind fluvoxamine/placebo crossover trial in pathologic gambling. Biol Psychiatry  47:813, 2000; James AC et al: Evidence for non-progressive changes in adolescent-onset schizophrenia: follow-up magnetic reso­nance imaging study. Br J Psychiatry 180:339, 2002; Jensen JB et al: A comparative pilot study of second-generation anti­psychotics in children and adolescents with schizophrenia-spectrum disorders. J Child Adolesc Psychopharmacol  18:317, 2008; Koran LM: Obsessive-Compulsive and Related Disorders in Adults: A Comprehensive Clinical Guide. New York: Cambridge University Press, 1999; Kumra S et al: Childhood-onset psychotic disorders: magnetic resonance imaging of volumetric differences in brain structure. Am J Psychiatry 157:1467, 2000; Kumra S et al: Clozapine versus “high-dose” olanzapine in refractory early-onset schizophrenia: an open-label extension study. J Child Adolesc Psychopharmacol 18:307, 2008; Petry NM et al: Cognitive-behavioral therapy for pathological gamblers. J Consult Clin Psychol 74:555, 2006; Petry NM: Pathological Gambling: Etiology, Comorbidity, and Treatment. Washington, DC: American Psychologi­cal Association, 2004; Pinto A et al: The Brown Longitudinal Obsessive Compulsive Study: clinical features and symp­toms of the sample at intake. J Clin Psychiatry 67:703, 2006; Röpcke B, Eggers C: Early-onset schizophrenia: a 15-year follow-up. Eur Child Adolesc Psychiatry 14:341, 2005; Saiz-Ruiz J et al: Sertraline treatment of pathological gambling: a pilot study. J Clin Psychiatry  66:28, 2005; White T et al: Gyrification abnormalities in childhood- and adolescent-onset schizophrenia. Biol Psychiatry 54:418, 2003.