An introduction to pediatric psychopharmacology

An Introduction to Pediatric Psychopharmacology  by Sandra DeJong, MD, Associate Training Director, Child Psychiatry, Cambridge Hospital, Harvard Medical School October 2007 The information below is intended as general guidelines to the pediatrician. In no way is this information intended to guide specific practice with specific patients. DO NO HARM - As with all medications, psychotropic medications work best when the diagnosis is correct. In certain cases, they can make thoughts, feelings and behaviors worse, or cause physical problems. When in doubt regarding a diagnosis or treatment, an evaluation by a qualified mental health professional is advised. MULTIMODAL TREATMENT - Medications alone are rarely the optimal treatment for a psychiatric problem. Other treatment modalities such as individual psychotherapy, family therapy, individual tutoring, school accommodations, group therapy, community supports such as social clubs, etc., are often warranted. FDA APPROVAL - Until recently, the FDA did not require that psychiatric medications under development be studied in children. As a result, many medications that are increasingly used in children and adolescents have not been FDA approved. While in most cases there is some clinical evidence supporting the use of these medications for specific disorders, placebo-controlled randomized clinical trials with sufficient numbers of subjects are frequently lacking. START LOW, GO SLOW – Psychotropic medications for children should be initiated at a careful dose, and dose increases should be cautious. • ADHD • Depression • Anxiety disorders • Sleep problems • Stimulants still the first-line agent in those without tics, severe anxiety, glaucoma, mood instability, arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known sensitivity to sympathomimetics • FDA blackbox warnings on stimulants: “high potential for abuse…drug should be prescribed or dispensed sparingly” and “Misuse…may cause sudden death and serious cardiovascular effects.” Personal and family cardiac history, and an EKG, are recommended before initiating treatment. Consider an echocardiogram in the setting of positive history or abnormal EKG, or consider nonstimulant treatment options. • Isolated single active isomers • Long-acting preparations • Transdermal methylphenidate, “Daytrana,” approved by FDA in 2006 and now • New prodrug, “Vyvanase,” (converts to dextroamphetamine) now available • Modafinil (Provigil) not FDA-approved for an ADHD indication due to concerns • Atomoxetine (Strattera) – nonstimulant ADHD medication, now second in line after stimulants; inhibits norepinephrine reuptake; approved by FDA in 2002; Black Box warning imposed in 2005 due to 5 cases of suicidal ideation and one attempted suicide in 1300 clinical trial patients; additional concern re potential liver injury after 2 documented cases (monitoring for jaundice, dark urine, unexplained flu-like symptoms and abnormal LFTS recommended); may be preferable in context of stimulant side effects including tic exacerbation and insomnia • Multimodal Treatment of ADHD Study (Arch Gen Psychiatry. 1999; 56:1073-1086) 0.5 mg/kg – 1.2 CYP2D6 inhibitor; GI Monitor for liver up to 150 mg/day, anticholinergic side stopping. Don't Symptoms of Depression: "SIGECAPS" DEPRESSED MO0D + • SLEEP disturbance • Loss of INTEREST/pleasure • GUILT/worthlessness • Decreased ENERGY • Decreased CONCENTRATION • Change in APPETITE • PSYCHOMOTOR retardation or agitation • SUICIDALITY • Increased sleep • Irritability; negativistic or mixed mood state • Increased po intake and weight gain • Social withdrawal • Decline in academic performance • Masking by comorbid disorders (e.g. substance abuse, conduct disorder) How to distinguish from juvenile-onset bipolar disorder • JBPD is not like stereotype of adult 'manic-depression," but phenomenology is • More chronic, continuous with long episodes • Frequently mixed depressed/irritable/manic • Mania characterized by hyperactivity, agitation, developmentally-dependent • A complicated disorder that requires child psychiatry How to approach depression in the pediatric office • Identify depression and any comorbidities • Ask about family history of mood disorders and suicide • Assess stressors, family's dysfunction, other supports including school • Provide psychoeducation and support, including re safety issues (e.g. lock up Tylenol, • Consider possible medical causes, e.g. anemia, hypothyroidism, lead, substance • Consider psychotherapy referral, SSRI and/or atypical antidepressant trial Examples of questions to ask the patient • Do you feel bad (sad, grumpy, mad) inside most days? • Are you acting differently because of how bad you're feeling? • Do you feel so bad that life doesn't seem worth living? • Have you actually thought of ways you might hurt yourself, or even kill yourself? • Multimodal approach (TADS study supports combined fluoxetine and cognitive- • Manage psychosocial stressors • Include parents • Address school issues • Psychoeducation of child and family On October 15, 2004, the Food and Drug Administration issued a requirement that all antidepressants prescribed for children and adolescents carry a black box warning in their package insert. The warning concerns increased suicidal thinking and behavior that may occur in children and adolescents during the early phase of treatment. the warning is based on pooled analyses of short-term (4-16 weeks) placebo-controlled trials of SSRIs and other antidepressants in a variety of diagnoses in over 4400 patients. The FDA reported an increased risk of suicidal thinking or behavior during the first few month of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. In light of these findings, the FDA recommends that observation for clinical worsening, suicidality or unusual changes in behavior during the first few months of antidepressant medication therapy include weekly visits during the first four weeks, biweekly visits for the next eight weeks, then visits as clinically indicated. Organizations of psychiatrists such as the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatrists have expressed their protest to this warning, focusing on the potential for antidepressants to save lives and the deterrence to treatment that the black box may represent. (One study reported in Psychiatric News 9/02/05 reported 20% decline in antidepressant prescribing to youth since 10/04.) They also point out the lack of any research basis for the monitoring recommendations. Finally, they raise concerns re the mixed nature of the evidence. Nonetheless, it is recommended that practitioners do their best to follow the FDA recommendations, and that they complete an informed consent process with parents before prescribing antidepressants for juveniles. • Selective Serotonin Reuptake Inhibitors (SSRIs) • Atypical antidepressants (bupropion, venlafaxine, nefazodone, mirtazapine) • Tricyclic antidepressants • Monoamine Oxidase Inhibitors (MAOIs) (phenelzine, tranylcypromine, selegiline) Antidepressants and the Pediatrician: Suggestions • Consider becoming familiar with ONE SSRI and ONE atypical antidepressant • Prioritize your treatment: start with a safety evaluation; arrange for a next visit for further evaluation and assessment of treatment needs, including medication • Discuss with your practice group what billing codes you may use for further visits • PROVIDE AND DOCUMENT AN INFORMED CONSENT PROCESS BEFORE STARTING ANY • REMEMBER: No treatment can be less safe than treatment; consider a referral to a • Delayed efficacy (3-6 weeks) • Annoying but not life-threatening side effects • Generally safe in overdose • Fluoxetine approved for use in juveniles; controlled data support the use of fluoxetine (most recently the NIMH-funded 2004 Treatment of Adolescent Depression Study TADS), sertraline and citalopram in children; paroxetine is also supported by one controlled study but see FDA warning below. • Most common side effects 1) Sexual dysfunction 2) Nausea 3) Sleep disturbance or sedation 4) Headaches. Weight gain possible • Beware of activation, precipitating a mania. A child who is activated on an antidepressant, or who has an underlying bipolar disorder and has been precipitated into a manic phase by the antidepressant, may be agitated, hyperactive, unable to sleep. Treatment is to stop the medication. • Discuss sexual dysfunction, change in appetite • MAY NOT BE SAFE IN PREGNANCY, ACCORDING TO RECENT EVIDENCE; FEMALE PATIENTS SHOULD HAVE A PREGNANCY TEST PRIOR TO INITIATING TREATMENT AND SHOULD TAKE APPROPRIATE PRECAUTIONS TO PREVENT PREGNANCY WHILE ON AN SSRI • New SSNRI Duloxetine HCl (Cymbalta) associated with hepatic injury in postmarketing SSRI Side-Effects (Kutcher, 1997): Relatively common • Sexual dysfunction • Dizziness • Sweating • Diarrhea • GI distress • Sexual disturbances • Headaches • Fatigue • Restlessness • Initial insomnia • Weight gain SSRI Side-Effects (Kutcher, 1997): Relatively uncommon • Delayed micturition • Blurred vision • Hypomanic symptoms • Tachycardia • Seizures • Skin rashes • Hypersomnia • Sexual dysfunction • Dry mouth • Tremor • Constipation • Bleeding/bruising • Side-effects are very idiosyncratic in children; if a child develops a symptom on the • Determine with the child and family how impairing the side effect(s) is (are) and make a risk-benefit analysis re continuing the medication SSRI Discontinuation Syndrome Most documented with paroxetine (Paxil) and fluvoxamine (Luvox), probably because they have shorter half-lives and no active metabolite • Dizziness, paresthesias, asthenia, nausea, visual disturbance and headache • Taper all SSRIs except possibly fluoxetine (Prozac) because of its long half-life • Start at ¼ to ½ of adult starting dose • For young children, if well tolerated go up to half of adult starting dose after 1-2 • For adolescents, if well tolerated go up to adult starting dose after 1-2 weeks and • If some evidence of response, consider more time OR slow dose increase • If no evidence of response, consider slow dose increase, augmentation with lithium, or switching to another SSRI; if prohibitive side effects, switch to another SSRI The SSRIs are known to inhibit metabolism of various cytochrome P450 isoenzymes. The effect is to raise the level of any co-administered medication which may be metabolized by the same isoenzyme. For example, sertraline (Zoloft), citalopram (Celexa, Lexapro), fluoxetine (Prozac) and fluvoxamine (Luvox) are all metabolized by the P450 IIIA4 isoenzymes. So is erythromycin. Thus, coadministration of, say, sertraline and erythromycin may actually increase erythromycin levels, thus increasing the risk of side effects from erythromycin. • Usually occurs with the addition of a serotonergic agent to other meds • Characterized by mental status changes, agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, fever • Need to rule out sepsis, neuroleptic malignant syndrome Evidence suggests these are not significantly better than placebo in treating child/adolescent depression. Atypical antidepressants (second-line treatment for depression in children/adolescents) • Venlafaxine (Effexor) (not effective in one placebo-controlled study of juveniles with • Nefazodone (Serzone) (not effective in one placebo-controlled study of juveniles with depression; brand name medication removed from market due to association with liver problems) • Mirtazapine (Remeron) • Bupropion (Wellbutrin) Atypical antidepressants: Venlafaxine (Effexor) • Can cause diastolic hypertension, discontinuation syndrome • May cause anxiety, nausea, insomnia, sedation, dizziness, constipation, • Usually clinically inconsequential medication interactions Atypical antidepressants: Nefazodone (Serzone brand removed from market) • Serotonin and NE reuptake inhibition • Indicated for depression; ? also useful for anxiety • New blackbox warning re liver failure; monitor liver function tests at baseline, with dose increases, and at regular intervals on stable dose • May cause nausea, sedation (slow titration), agitation, dry mouth, constipation, • Few sexual side effects • Less activating • A metabolic inhibitor with med-med interactions like the SSRIs Atypical antidepressants: Mirtazapine (Remeron) • Controlled studies do not support its use for depression in children/adolescents; may • Alpha-2 presynaptic autoreceptor inhibition (like yohimbine) • Also stimulates serotonin and NE release • Blocks post-synaptic serotonin receptors, so may cause sedation, weight gain, nausea Atypical antidepressants: Bupropion (Wellbutrin) • Affects both dopamine and NE systems • Effective anti-ADHD agent • Effective for depression in adults • Anti-smoking (Zyban) • No sexual dysfunction, ?less manicogenic • Not to be used with seizures, bulimia • May cause appetite suppression, sleep disturbance, tic exacerbation, irritability (esp • Caution in combining with other drugs that can lower seizure threshold • Now available in one-a-day dosing (Wellbutrin XL) • Examples: Phenelzine (Nardil), Tranylcypromine (Parnate) • Complicated to use (dietary restrictions and med interactions) • BEWARE OF COMBINING WITH: Sympathomimetics, (e.g. Pseudoephedrine) (hypertensive crisis); Demerol, dextromethorphan, serotonergic agents (serotonin syndrome); TCAs (get symptoms like serotonin syndrome) • Do not recommend use by pediatricians • Generalized anxiety disorder • Social phobia, selective mutism • Panic disorder • Obsessive-compulsive disorder • Post-traumatic and acute stress disorders • Separation anxiety • Specific phobia • Adjustment disorder with anxiety • Most common psychiatric condition in children and primary cause of inattention • If child meets criteria for one anxiety disorder, frequently meets others • Controversial diagnostically because of this and comorbidity with other psychiatric • Good evidence for cognitive-behavioral treatment • Highly familial • Relationship to temperament (Chess and Thomas, Kagan's "inhibited child" work) • Course tends to be chronic (remission/relapse) • Medical conditions such as hyperthyroidism, hypoglycemia, pheochromocytoma, and substance-induced anxiety, need to be ruled out Obsessive Compulsive Disorder - PANDAS (controversial) • Neuropsychiatric • Disorders • Associated with strep When to check for Strep (throat culture, ASO titer, anti-Dnase-B titer) Any patient with tics, chorea, Obsessive Compulsive Disorder, choreiform movements who has: • Abrupt onset of symptoms • Abrupt exacerbation of symptoms • Loss of a medication response • History of good behavior with sudden dramatic behavioral difficulties (Leonard, 1999) Consider first: Cognitive Behavioral Therapy, family work, stress reduction, etc. Consider meds if important functional impairment (e.g. not able to go on playdates, not going to school). How to handle anxiety in the pediatric office • Identify anxiety and functional impairment • Identify comorbidities • Take family history • Rule out possible medical causes including substance abuse • Provide psychoeducation, advice re relaxation techniques (exercise, pleasure • Ask patient to keep a journal of the A, B, Cs of his or her anxiety symptoms (antecedent, behavior, consequence, including any efforts to contain) • SSRIs • Tricyclics • Buspirone • Benzodiazapenes • Beta-blockers NOTE: SEE BLACK BOX WARNING RE ANTIDEPRESSANTS ABOVE Increasing usage, although little data, for: • Panic disorder • Social phobia • Generalized anxiety disorder • Separation anxiety disorder • 5HT-1A receptor agonist • Clinical effects not uniform • No pharmacokinetic studies in children • May be helpful for GAD, ? with ADHD, in med-sensitive populations (e.g. brain- • Start 2.5-5 mg TID, up to 30-60 mg/d • Delayed onset of anxiolytic action • Advantages: mild side effects, no addictive potential • Can cause hypertension • Alprazolam (Xanax) • Lorazepam (Ativan) Longer half-life • Clonazepam (Klonopin) • Diazepam (Valium) • Sedation, cognitive impairment • Disinhibition • Dependence/tolerance • Potentiate effects of other medications • Withdrawal side effects (need to taper) • Short-term treatment of disabling symptoms, e.g. for school avoidance until an SSRI • Recurrent panic disorder, as a prn or "security blanket" (NOTE: clonazepam and alprazolam most effective for panic in adults) • RARELY for short-term sleep difficulties Problem: 9 yo with school avoidance secondary to social phobia and separation anxiety; develops panic symptoms when approaching school in parents' car Solution: 0.25-0.5 mg of clonazepam (Klonopin) given 30-45 minutes before arrival at school to offset panic symptoms and allow desensitization therapy to occur; may need to adjust timing of dosing given wide range of time to onset Sleep medications for children/adolescents • Diphenhydramine (Benadryl) 25-50 mg • Trazodone (Desyrel) 25-50 mg (Key potential side effect is priapism in males) • Zolpidem (Ambien) 5-10 mg • Clonidine (Catapres) 0.05-0.10 • Mirtazapine (Remeron) 7.5 mg • Melatonin 0.5 up to max of 10mg qhs (controlled data accumulating) Always begin by emphasizing sleep hygiene. 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