Drugs for psychiatric disorders

Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Drugs for Psychiatric Disorders .p 53 Important Copyright Message The Medical Letter® publications are protected by US and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF US AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 11 (Issue 130) June 2013 www.medicalletter.org Tables Drugs for Depression SSRI and SNRI Drug Interactions Oral Drugs for Bipolar Disorder Antimanic and Anticonvulsant Drug Interactions Parenteral Antipsychotics Oral Antipsychotics Relative Adverse Effects of Second-Generation Antipsychotics Second-Generation Antipsychotic Drug Interactions Page Page Page Page Page Page Page 54 55 58 59 60 61 62 Page 62 Drugs for Psychiatric Disorders Related article(s) since publication Drugs are not the only treatment for psychiatric illness Psychotherapy remains an important component in the management of these disorders, and cognitive behavioral therapy (CBT) can be used for many of them as well Electroconvulsive therapy (ECT) has a long history of efficacy and safety when drugs are ineffective or cannot be used DRUGS FOR DEPRESSION Most of the drugs approved by the FDA for treatment of depression are listed in Table Improvement can occur within the first weeks of drug therapy, but it may take 4-8 weeks to achieve substantial benefit Antidepressant drugs produce a response in about 5060% of adults with major depression and a remission in about 30%; with multiple courses and/or multiple drugs, 80% of patients will eventually respond, at least temporarily SSRIs AND SNRIs — Selective serotonin reuptake inhibitors (SSRIs) are recommended for first-line treatment of major depression They are generally well tolerated and relatively safe There is no convincing evidence that any one SSRI is more effective than any other Fluoxetine is the only SSRI approved by the FDA for treatment of major depressive disorder in children and adolescents Escitalopram, the active enantiomer of citalopram, is approved for treatment of depression in adolescents Serotonin and norepinephrine reuptake inhibitors (SNRIs) are also considered a first-line option for treatment of major depression It is not clear that they offer any advantage in efficacy over SSRIs OTHER DRUGS — Bupropion can be used as an alternative to an SSRI for depressed patients who not have severe anxiety It is activating rather than sedating and has not been associated with weight gain, sexual side effects or an increased risk of bleeding Mirtazapine may be useful when insomnia is prominent, and its appetite-stimulating and weight-gain-promoting properties may be helpful in depressed patients with marked anorexia Trazodone, which is also sedating, is commonly used in a low dose as an adjunct to an SSRI in patients with insomnia.1 Vilazodone is an SSRI and partial serotonin 1a receptor agonist; limited data suggest it may be an effective antidepressant.2 Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) remain valuable alternatives for patients with moderate to severe treatmentresistant depression ADVERSE EFFECTS — SSRIs – Jitteriness and sleep disturbances can occur during treatment with an SSRI Other adverse effects include nausea, diarrhea, headache, dizziness, fatigue and sexual dysfunction (including decreased libido, impaired arousal and anorgasmia) An increase in motor activity is more common in children The long-term effects of these drugs on the growth, personality development and behavior of children are unknown Some patients gain significant amounts of weight with continued use of an SSRI SSRIs can cause hyponatremia, particularly in elderly patients They have been associated with a possible increase in the risk of nonvertebral fractures in older women.3 SSRIs can also increase the risk of bleeding by inhibiting serotonin uptake by platelets SSRIs have a variety of effects on CYP450 isoenzymes and may interact with many other drugs; these are summarized in Table Citalopram can cause significant QT interval prolongation.4 Escitalopram may also prolong the QT interval.5 Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines 53 Drugs for Psychiatric Disorders Table Some Drugs for Depression Drug SSRIs Citalopram – generic Celexa (Forest) Escitalopram – generic Lexapro (Forest) Fluoxetine – generic Prozac (Lilly) delayed release – generic Prozac Weekly Paroxetine hydrochloride – generic Paxil (GSK) extended release – generic Paxil CR Paroxetine mesylate – Pexeva (Noven) Sertraline – generic Zoloft (Pfizer) SNRIs Desvenlafaxine succinate – Pristiq (Pfizer) Desvenlafaxine – generic (Alembic) Duloxetine – Cymbalta (Lilly) Venlafaxine – generic extended release – generic Effexor XR (Pfizer) TCAs Amitriptyline – generic Desipramine – generic Norpramin (Sanofi) Imipramine – generic Tofranil (Mallinckrodt) Imipramine pamoate – generic Tofranil PM Nortriptyline – generic Pamelor (Mallinckrodt) MAOIs Isocarboxazid – Marplan (Validus) Phenelzine – generic Nardil (Pfizer) Selegiline – Emsam (Somerset) Tranylcypromine – generic Parnate (Covis) Other Bupropion – generic Wellbutrin (GSK) extended release (12 hour) – generic Wellbutrin SR Aplenzin (Sanofi) extended release (24 hour) – generic Wellbutrin XL Forfivo XL (Edgemont) Mirtazapine – generic Remeron (Organon) orally disintegrating – generic Remeron SolTab Nefazodone6 – generic Trazodone – generic extended release – Oleptro (Labopharm) Vilazodone – Viibryd (Forest) Some Available Formulations Initial Adult Dosage1 Usual Adult Dosage1 10, 20, 40 mg tabs, caps; 40 mg ODT; 10 mg/5mL PO soln 10, 20, 40 mg tabs; 10 mg/5 mL PO soln 5, 10, 20 mg tabs; mg/5 mL PO soln 10, 20, 40 mg caps; 10, 20, 60 mg tabs; 20 mg/5 mL PO soln 10, 20, 40 mg caps 90 mg cap 20 mg once/d 40 mg once/d3 $4.004 145.00 10 mg once/d 10-20 mg once/d 10-20 mg once/d 20 mg once/d 90 mg 1x/wk 90 mg 1x/wk 20 mg once/d 20 mg once/d 12.5-25 mg once/d 25 mg once/d 10, 20, 30, 40 mg tabs 25, 50, 100, 150, 200 mg tabs; 20 mg/mL PO conc 25, 50, 100 mg tabs; 20 mg/mL PO conc 10 mg once/d 25-50 mg once/d 20 mg once/d 50-100 mg once/d 50, 100 mg ER tabs 50, 100 mg ER tabs 20, 30, 60 mg delayed-release caps 25, 37.5, 50, 75, 100 mg tabs 37.5, 75, 150 mg caps; 37.5, 75, 150, 225 mg tabs 37.5, 75, 150 mg caps 50 mg once/d 50 mg once/d 30-60 mg once/d 10, 25, 50, 75, 100, 150 mg tabs 50-100 mg once/d 10, 25, 50, 75, 100, 150 mg tabs 10, 25, 50 mg tabs 50-100 mg once/d or divided 25-50 mg once/d 75, 100, 125, 150 mg caps 75 mg once/d 10, 25, 50, 75 mg caps 75-100 mg once/d 10 mg tabs 15 mg tabs 10 mg bid 15 mg tid 30-40 mg/d divided 30 mg bid 6, 9, 12 mg/24 hr patches 10 mg tabs mg/24 hr 10 mg once/d 6, 9, 12 mg/24 hr 20-30 mg bid 10, 20, 30, 40 mg tabs; 10 mg/5 mL PO susp 12.5, 25, 37.5 mg tabs Cost2 7.00 143.00 4.004 211.00 110.00 145.00 4.004 121.00 91.00 128.00 204.00 5.00 141.00 25 mg tid 37.5 mg once/d 50 mg once/d 50 mg once/d 60 mg once/d or divided bid 75 mg tid 225 mg once/d 161.00 139.00 199.00 64.00 240.00 522.00 150 mg once/d or divided 150 mg once/d or divided 100-150 mg once/d or divided 150 mg once/d or divided 150 mg once/d or divided 75, 100 mg tabs 100 mg bid 100 mg tid 100, 150, 200 mg tabs 150 mg once/d 150 mg bid 174, 348, 522 mg ER tabs 150, 300 mg tabs 174 mg once/d 150 mg once/d 348 mg once/d 300 mg once/d 450 mg ER tabs 7.5, 15, 30, 45 mg tabs 15, 30, 45 mg tabs 15, 30, 45 mg ODT See footnote 15 mg once/d at hs 450 mg once/d 30-45 mg once/d 50, 100, 150, 200, 250 mg tabs 50, 100, 150, 300 mg tabs 150, 300 mg tabs 10, 20, 40 mg tabs 100 mg bid 75 mg bid 150 mg once/d 10 mg once/d 200 mg bid 300 mg divided bid 150-375 mg once/d 40 mg once/d 5.00 151.00 205.00 20.00 349.00 348.00 549.00 14.00 1399.00 260.00 72.00 132.00 594.00 323.00 673.00 63.00 266.00 37.00 233.00 395.00 38.00 319.00 135.00 20.00 130.00 57.00 104.00 35.00 16.00 96.00 138.00 ODT = orally disintegrating tablet; ER = extended-release Dose may need to be adjusted for renal or hepatic impairment or for drug interactions Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the lowest usual daily dosage $ource® Monthly (Selected from FDB MedKnowledge™) May 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher The daily dose should not exceed 40 mg (20 mg in patients >60 years old, patients with hepatic impairment and for CYP2C19 poor metabolizers or those taking a CYP2C19 inhibitor) Cost of generics at some large discount pharmacies Initiate with another bupropion formulation Brand name nefazodone was withdrawn from the market due to hepatic toxicity 54 Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 Drugs for Psychiatric Disorders Table Some SSRI and SNRI Drug Interactions Drug CYP450 Comments Citalopram Metabolized by 2C191 and 3A4 Maximum dose of 20 mg/day in 2C19 poor metabolizers or with inhibitors of 2C19; higher serum concentrations increase the risk of QT prolongation; avoid use with other drugs that prolong the QT Interval Escitalopram Metabolized by 2C191 and 3A4 Fluoxetine Metabolized by 2D61 and 2C9 Strong inhibitor of 2D6 Moderate inhibitor of 2C19 Metabolized by 2D6 Strong inhibitor of 2D6 Metabolized by 2C19 Moderate inhibitor of 2D6 Metabolized by 2D61 and 3A4 Metabolized by 3A4 Weak inhibitor of 2D6 Metabolized by 1A21 and 2D6 Moderate inhibitor of 2D6 Low potential for interactions; dose adjustments may be needed with 2C19 inhibitors; may prolong the QT interval May decrease efficacy of tamoxifen; may increase concentrations of 2D6 substrates; long half-life is a problem when interactions occur Paroxetine Sertraline Venlafaxine Desvenlafaxine Duloxetine May decrease efficacy of tamoxifen; may increase concentrations of 2D6 substrates; lower doses of paroxetine may be needed with 2D6 inhibitors Low potential for interactions Low potential for interactions; serum concentrations may be increased by 3A4 inhibitors Low potential for interactions; reduce dose of 2D6 substrates if administered with 400 mg of desvenlafaxine Avoid strong inhibitors of 1A2; 2D6 inhibitors can increase duloxetine concentrations; duloxetine increases concentrations of drugs that are substrates of 2D6 Primary pathway When SSRIs are stopped abruptly, discontinuation symptoms including nervousness, anxiety, irritability, electric-shock sensations, bouts of crying or tearfulness, dizziness, lightheadedness, insomnia, confusion, trouble concentrating, nausea and vomiting can occur; these effects are most severe with paroxetine because of its short half-life and least likely to occur with fluoxetine because of its long half-life SNRIs – The adverse effects of venlafaxine, desvenlafaxine and duloxetine are similar to those of SSRIs, but can also include increased sweating, tachycardia and urinary retention Severe discontinuation symptoms can occur when these drugs are stopped, especially with venlafaxine and desvenlafaxine because of their short halflives SNRIs can cause a dose-dependent increase in blood pressure; blood pressure should be under control before starting an SNRI and monitored during treatment False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine or desvenlafaxine Other Drugs – TCAs commonly cause anticholinergic effects (urinary retention, constipation, dry mouth, blurred vision and confusion), orthostatic hypotension, weight gain, sedation and sexual dysfunction They can cause cardiac conduction delay, which can lead to arrhythmias TCAs are more dangerous than SSRIs in overdose Adverse effects of MAOIs include sleep disturbance, orthostatic hypotension, sexual dysfunction and weight gain Interactions with serotonergic drugs, bupropion, sympathomimetics, and tyramine-rich foods can result in serotonin syndrome or a hypertensive crisis, either of which can be fatal The enzymeinhibiting effects of MAOIs can persist for up to weeks after the drug is stopped Bupropion can cause agitation, anxiety, insomnia, headache, nausea, anorexia and hypersensitivity reactions Dose-related seizures may occur; the drug is contraindicated in patients with eating disorders because such patients have a higher incidence of seizures when treated with bupropion Mirtazapine can cause sedation, increased appetite, weight gain, dizziness, dry mouth and constipation; febrile neutropenia has occurred rarely Vilazodone has an adverse effect profile similar to that of SSRIs; available evidence is insufficient to support claims that it causes less weight gain or less sexual dysfunction.2 Trazodone can cause drowsiness, orthostatic hypotension and priapism Nefazodone has caused somnolence, dry mouth, nausea, dizziness and rarely, hepatic failure requiring liver transplantation, which has led to its withdrawal from the market in Canada and Europe and discontinuation of the branded version in the US Suicidality – All antidepressants carry a boxed warning about suicidality (suicidal ideation and behavior) An FDA analysis of placebo-controlled antidepressant studies, summarized in the package inserts of these drugs, found an increased risk of suicidality in children, adolescents and young adults (24 years old) being treated with an antidepressant A recent Cochrane review also found that antidepressants increased the risk of suicidal ideation and behavior in children and adolescents.6 No increase in completed suicides has been demonstrated (there were no suicides in the pediatric trials summarized by the FDA), and the subject continues to be debated All depressed children, adolescents and adults, whether they are treated with drugs or not, should be monitored for suicidal ideation and behavior Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 55 Drugs for Psychiatric Disorders Serotonin Syndrome – All serotonergic drugs can cause serotonin syndrome, a rare but potentially lifethreatening condition characterized by altered mental status, fever, tachycardia, hypertension, agitation, tremor, myoclonus, hyperreflexia, ataxia, incoordination, diaphoresis, shivering and gastrointestinal symptoms Serotonin syndrome occurs most commonly as a result of interactions with other drugs Because of the risk of serotonin syndrome, serotonergic drugs and MAOIs should not be used together or within weeks of each other Some drugs with MAOI activity, such as the antimicrobial agent linezolid (Zyvox), and some serotonergic drugs, such as the cough suppressant dextromethorphan, sumatriptan (Imitrex, and generics), tramadol (Ultram, and generics), methadone and St John’s wort, may not be recognized as serotonergic, but can cause serotonin syndrome when taken concurrently with an SSRI or SNRI.7 Mania – All antidepressants can induce mania, most often in patients with bipolar disorder Patients should be screened for personal or first-degree-relative history of mania, hypomania or other evidence of bipolar disorder before starting antidepressant therapy PREGNANCY — Both untreated maternal depression and use of SSRIs in pregnancy have been associated with delayed fetal development, preterm birth and low birth weight.8,9 Taking SSRIs in the third trimester has been associated with a self-limited neonatal behavioral syndrome, treatment in a neonatal intensive care unit, and a possible risk of persistent pulmonary hypertension.10,11 Paroxetine is classified as category D (positive evidence of human fetal risk) for use during pregnancy because of an increased risk of cardiovascular and other malformations in infants born to mothers taking it in the first trimester.12 The safety of other SSRIs in the first trimester has also been questioned13,14; all except paroxetine are classified as pregnancy category C (adverse fetal effects in animals or no animal reproductive studies, and no adequate human studies) Overall, the risk of congenital malformations after taking an SSRI during pregnancy appears to be very low.15,16 One study that controlled for maternal characteristics found no increase in perinatal mortality among a cohort of women treated with SSRIs.17 Pregnancy studies with SNRIs are limited,13 but exposure during the third trimester may cause a self-limited neonatal behavioral syndrome TCA use in late pregnancy has been associated with jitteriness and convulsions in newborns MAOIs are classified as category C for use during pregnancy, but because of the risk of drug interactions or foods causing a hypertensive crisis, some 56 clinicians recommend that they not be used Data on the safety of other classes of antidepressants during pregnancy are lacking Data on long-term behavioral effects of in utero antidepressant exposure are limited; one retrospective study found delays in sitting and walking (but within the normal range) in children exposed to antidepressants during pregnancy.18 CHOICE OF DRUGS — First-Line – An SSRI, an SNRI, bupropion or mirtazapine could be used for first-line treatment of major depression, but most expert clinicians begin with an SSRI The choice among SSRIs may be determined by adverse effect profiles and differences in drug interactions Taking these and cost into consideration, generic sertraline or generic escitalopram would be a reasonable first choice for treatment of depression in adults Generic fluoxetine would be a good choice for treatment of depressed children, adolescents or young adults Second-Line – When patients show little to no response to an adequate trial of an SSRI, many clinicians switch to another antidepressant, combine two antidepressants of different classes, such as an SSRI and bupropion, or add another drug, such as a secondgeneration antipsychotic.19 MAOIs should not be added to an SSRI or SNRI or to another MAOI because of the risk of serotonin syndrome In one controlled trial, among patients with major depressive disorder who had not responded to or could not tolerate 12 weeks’ treatment with the SSRI citalopram, switching antidepressants to sustained-release bupropion, sertraline or extended-release venlafaxine led to remissions in 26%, 27% and 28% of patients, respectively, but the study did not include a placebo group or one that continued on citalopram.20 Augmentation with antipsychotic drugs may be helpful when the response to antidepressant agents is inadequate, but they can cause adverse effects such as weight gain or akathisia.21,22 Quetiapine and oral aripiprazole are FDA-approved for adjunctive treatment of major depressive disorder A fixed-dose combination of olanzapine and fluoxetine is FDAapproved for treatment-resistant depression Maintenance – The goal of antidepressant treatment is complete remission of symptoms; partial response is associated with an increased risk of relapse For a first episode of depression, many experts recommend that antidepressant treatment continue at the same dose for at least 6-9 months following remission to consolidate recovery For patients with recurrent depressive Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 Drugs for Psychiatric Disorders episodes, long-term maintenance therapy can reduce the risk of recurrence NON-DRUG THERAPY — Psychotherapy, particularly cognitive behavioral therapy (CBT) and interpersonal therapy (IPT), is an effective treatment for depression ECT is highly effective for severe depression, depression with psychosis or bipolar disorder, and depression refractory to drugs23; it can be used during pregnancy Vagus nerve stimulation (VNS) and transcranial magnetic resonance stimulation (TMS) are FDA-approved for treatment-resistant depression, but a short-term trial of VNS did not find a statistically significant response.24,25 TMS, unlike ECT, does not require anesthesia and does not appear to have cognitive side effects Studies of TMS have demonstrated response and remission rates similar to those of antidepressant medications; it may be a reasonable treatment option when patients are unable to tolerate or not respond to antidepressant medications, but it is expensive and time-consuming (3-5 times a week for several weeks), and its efficacy has been limited in patients who have not responded to multiple medications DRUGS FOR BIPOLAR DISORDER Some oral drugs for treatment of bipolar disorder are listed in Table on the next page Even with maintenance treatment, recurrences of manic or (more frequently) depressive episodes are common.26 MAINTENANCE — Lithium is generally the drug of choice for maintenance treatment of bipolar disorder Antiepileptic drugs such as valproate and carbamazepine are also widely used for maintenance despite evidence suggesting that they are less effective than lithium in preventing recurrence The anticonvulsant lamotrigine is especially effective for prevention of recurrent depression in bipolar disorder Maintenance therapy with lithium alone or in combination with valproate, carbamazepine or lamotrigine decreases the risk of recurrent manic and depressive episodes Second-generation antipsychotics may also be effective in preventing recurrences of manic and depressive episodes, especially when taken in combination with lithium A long-acting form of risperidone, given intramuscularly every weeks, has been approved by the FDA for maintenance treatment and may be helpful for patients with frequent relapses, especially when adherence is an issue TREATMENT OF MANIA — For treatment of mania, lithium, valproate and second-generation antipsychotics have similar efficacy.27 Both lithium and valproate may take days to weeks to have a full therapeutic effect; manic patients often require adjunctive treatment with an antipsychotic drug or temporary treatment with a benzodiazepine TREATMENT OF DEPRESSION — Monotherapy with antidepressant drugs can precipitate mania in patients with bipolar disorder and is not recommended For treatment of depression in patients with bipolar disorder, lithium has protective effects against suicide and self-harm.28 The effectiveness of valproate in treating depression in bipolar patients is unclear.29 The antipsychotic quetiapine or a combination of olanzapine and fluoxetine have been shown to be effective in treating depression in bipolar patients Lamotrigine may also be effective for this indication ALTERNATIVES — A benzodiazepine such as lorazepam (Ativan, and generics) may be helpful when an adjunct is needed for insomnia, agitation or anxiety, but bipolar patients are at risk for substance dependence Some clinicians have used clozapine to treat mania resistant to other drugs ECT is effective for treatment of both acute mania and acute depression and may be particularly useful for drug-resistant mania and in pregnant women ADVERSE EFFECTS — Nausea and fatigue may occur in the first days to weeks of treatment with lithium, even when serum concentrations are in the recommended range Tremor, thirst, polyuria, edema and weight gain may persist for the duration of treatment Lithium-induced tremors can be treated by reducing the dosage or adding a beta-blocker such as propranolol Confusion and ataxia can occur Toxic renal effects, including tubular lesions, interstitial fibrosis and decreased creatinine clearance, have been reported with long-term use of lithium Nephrogenic diabetes insipidus can occur; it further increases the risk of lithium toxicity, and may be irreversible Hypothyroidism can occur with long-term lithium treatment and can contribute to exacerbations of bipolar illness Lithium may cause mild leukocytosis, induce or exacerbate psoriasis, and cause severe acne, folliculitis, hair loss and other skin reactions Many commonly used drugs, including most NSAIDs (but not aspirin), ACE inhibitors and diuretics, can increase serum lithium concentrations and should be avoided if possible Other medications, including theophylline and caffeine, can lower serum lithium concentrations Adverse effects of valproate include somnolence, fatigue, weight gain, nausea, diarrhea and tremor, but tremor is less common than with lithium Reversible hair loss can occur Thrombocytopenia may occur and appears to be dose-related Transient elevations of Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 57 Drugs for Psychiatric Disorders Table Some Oral Drugs for Bipolar Disorder Drug Some Available Formulations Initial Adult Dosage1 Usual Adult Dosage1 150, 300, 600 mg caps; 300 mg tabs; mEq/5 mL PO soln5 300, 450 mg tabs 300 mg tab 900-1800 mg divided tid or qid 900-1800 mg divided bid or tid 900-1200 mg divided tid or qid 900-1200 mg divided bid or tid 100, 200, 300, 400 mg tabs; 100, 200 mg chewable tabs; 100 mg/5 mL susp7 200 mg tabs; 100 mg chewable tabs; 100 mg/5 mL susp7 100, 200, 400 mg tabs; 100, 200, 300 mg caps 100, 200, 300 mg caps 100, 200, 300 mg caps 100, 200, 400 mg tabs 25, 100, 150, 200 mg tabs; 2, 5, 25 mg chewable tabs10 25, 50, 100, 200 mg ODT; 25, 50, 100, 200, 250, 300 mg tabs 200-600 mg divided tid-qid 600-1200 mg divided bid or tid Cost2 Antimanic Agent Lithium carbonate3,4 – generic extended release – generic Lithobid (Noven) Anticonvulsants Carbamazepine – generic6 Tegretol (Novartis)6 extended release – generic6 Equetro (Validus)3,9 Carbatrol (Shire)6 Tegretol XR (Novartis)6 Lamotrigine – generic4 Lamictal (GSK)4 Lamictal ODT4 extended release – generic6 Lamictal XR6 Valproate12 Valproic acid – generic Depakene6 (Abbott) delayed release – Stavzor3(Noven) Divalproex sodium – generic Depakote3 (Abbott) Depakote Sprinkle6 extended release – Depakote ER Second-Generation Antipsychotics Aripiprazole3,4,9 – Abilify (BMS/Otsuka) Abilify Discmelt Asenapine – Saphris (Merck)3,9 Olanzapine3,4,9 – generic Zyprexa (Lilly) orally disintegrating – generic Zyprexa Zydis Quetiapine – generic Seroquel (AstraZeneca)3,4,16 extended release – Seroquel XR3,4,9,16 Risperidone3,9 – generic Risperdal (Janssen) orally disintegrating – generic Risperdal M-Tab Ziprasidone – generic Geodon (Pfizer)3,4,9 Combination Olanzapine/fluoxetine16 – generic Symbyax (Lilly) $15.00 24.00 240.00 9.008 236.00 200-600 mg divided bid 200 mg bid 200-600 mg divided bid 25 mg once/d11 200 mg once/d 25 mg once/d11 200 mg once/d 250 mg cap; 250 mg/5 mL syrup 250 mg tid 1500-2000 mg divided bid 125, 250, 500 mg caps 125, 250, 500 mg tabs 750 mg/d divided 750 mg/d divided 125 mg cap 250, 500 mg tabs 25 mg/kg once/d13 67.00 607.00 227.00 29.00 214.00 479.00 25-40 mg/kg once/d13 412.00 15 mg once/d 15-30 mg once/d 10 mg bid 10-15 mg once/d 5-10 mg bid 5-20 mg once/d 50-100 mg once/d or divided bid 50-300 mg once/d 2-3 mg once/d 300-800 mg divided bid 300-800 mg once/d 4-6 mg once/d 40 mg bid 40-80 mg bid 6/25 mg once in the evening 6/25-12/50 mg once 348.00 in the evening 402.00 2, 5, 10, 15, 20, 30 mg tabs; mg/mL soln14,15 10,15 mg ODT 5, 10 mg sublingual tabs 2.5, 5, 7.5, 10, 15, 20 mg tabs15 600-1200 mg divided bid 5, 10, 15, 20 mg ODT 25, 50, 100, 150 200, 300, 400 mg tabs 25, 50, 100, 200, 300, 400 mg tabs 50, 150, 200, 300, 400 mg tabs 0.25, 0.5, 1, 2, 3, mg tabs; mg/mL soln17 0.25, 0.5, 1, 2, 3, mg ODT 0.5, 1, 2, 3, mg ODT 20, 40, 60, 80 mg caps 3/25, 6/25, 6/50, 12/25, 12/50 mg caps 89.00 138.00 106.00 120.00 12.00 252.00 248.00 350.00 416.00 669.00 797.00 690.00 29.00 367.00 226.00 397.00 89.00 754.00 497.00 38.00 513.00 373.00 616.00 237.00 543.00 ODT = orally disintegrating tablet Dose for maintenance Dosage may need to be adjusted for renal or hepatic impairment or when used concomitantly with lithium, valproate or carbamazepine Approximate wholesale acquisition cost (WAC) for 30 days’ treatment with tabs or caps for a 70-kg patient at the lowest usual daily dosage $ource® Monthly (Selected from FDB MedKnowledge™) May 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricingpolicy Actual retail prices may be higher FDA-approved for mania FDA-approved for maintenance treatment of bipolar disorder Available as lithium citrate Not FDA-approved for bipolar disorder Patients on conventional tablets can be switched to the suspension on a mg-per-mg basis, but in smaller, more frequent doses Cost using 200-mg tablets FDA-approved for mixed episode 10 Chewable tablets should be administered whole If necessary, the dose should be rounded down to the nearest whole tablet 11 For monotherapy, titrate to a goal of 200 mg/day as follows: 25 mg/day for weeks, then 50 mg/day for weeks, then 100 mg/day for week, then 200 mg/day 12 Also available in an IV formulation as valproate sodium (Depacon, and generics) 13 When switching from Depakote to Depakote ER, the dosage may need to be increased 8-20% to maintain serum concentrations 14 Aripiprazole PO solution should be given at the same dose (mg per mg) as the tablets, except that when patients receive the 30-mg tablet, 25 mg of the solution should be used 15 Also available for rapid intramuscular injection for agitation associated with bipolar mania 16 FDA-approved for depressive episode with bipolar disorder 17 Also available as a long-acting injectable for maintenance treatment of bipolar disorder 58 Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 Drugs for Psychiatric Disorders hepatic transaminases are common; fatal hepatotoxicity has occurred rarely, particularly in young children and with use of multiple anticonvulsants Polycystic ovary syndrome has been reported Rare idiosyncratic reactions include hemorrhagic pancreatitis, hyperammonemic encephalopathy and agranulocytosis Adverse effects of carbamazepine include rash, dizziness, diplopia, nausea, somnolence, headache, hyponatremia, elevated transaminases and, rarely, StevensJohnson syndrome, agranulocytosis and aplastic anemia Han Chinese may have a ten-fold increased risk of Stevens-Johnson syndrome because of genetic vulnerability.30 Eosinophilia and hepatic toxicity (“DRESS Syndrome”) have been reported.31 Because of the many drug interactions that occur with carbamazepine, oxcarbazepine, which causes less induction of hepatic enzymes, may be used instead Liver function and complete blood counts should be monitored in patients taking valproate Complete blood counts should be monitored in patients taking carbamazepine PREGNANCY — Lithium use during pregnancy has been associated with congenital cardiac abnormalities; the absolute risk is low High neonatal lithium concentrations are a risk factor for lower Apgar scores, longer hospital stays, and reversible neurologic toxicity; the risk could be minimized or avoided by withholding maternal lithium for 24 hours before delivery Valproate taken during pregnancy can cause neonatal toxicity, neural tube defects, cardiac and other major teratogenic effects, and adverse effects on neurocognitive development with measurable impairment of IQ.33 Unless there is no alternative, it should not be used during pregnancy Adverse effects of lamotrigine include nausea, dizziness and somnolence About 10% of patients develop mild rash; severe, life-threatening rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, has occured rarely Very gradual up-titration of the dose may minimize the risk of rash.32 Carbamazepine is not recommended for use during pregnancy, unless no alternatives exist, because of an increased risk of major malformations, including neural tube defects, low birth weight, and fetal and neonatal vitamin K deficiency, which can lead to neonatal hemorrhage Second-generation antipsychotics can cause somnolence, weight gain, diabetes, extrapyramidal symptoms, QT prolongation and elevated prolactin levels (see Table 7) Data on use of lamotrigine during pregnancy are inconsistent; it appears to have a lower risk of adverse fetal outcomes than valproate or carbamazepine, but midline clefts have been reported MONITORING — Lithium has a narrow therapeutic window and requires careful monitoring Serum lithium concentrations should be monitored every three months (every 6-12 months in a stable patient) to maintain serum concentrations within the therapeutic range and avoid toxicity Concentrations should be measured about 12 hours after the last dose For acute treatment, target serum concentrations are 0.8 to 1.2 mEq/L For maintenance, serum concentrations should be between 0.6 and 1.0 mEq/L Thyroid and renal function should be monitored at baseline and every six months In addition to laboratory monitoring, patients should be monitored for clinical signs of toxicity such as vomiting, diarrhea, tremor, lethargy, slurred speech and weakness Data on use of second-generation antipsychotics during pregnancy are limited; increased birth weight has been reported.34 CHOICE OF DRUGS — Lithium is generally the drug of choice for maintenance treatment of bipolar disorder Lamotrigine may be used to prevent recurrent depressive episodes Lithium, valproate, and second-generation antipsychotics are similarly effective for treatment of mania Quetiapine or a combination of olanzapine and fluoxetine are effective for treatment of depression in patients with bipolar disorder Lamotrigine may also be effective for treatment of bipolar depression Table Some Antimanic and Anticonvulsant Drug Interactions Drug Comments Carbamazepine Carbamazepine is a strong inducer of multiple hepatic enzymes, including 3A4; increase in dosage of 3A4 substrates may be required It is also a 3A4 substrate; dosage adjustments may be required with strong 3A4 inducers and inhibitors Diuretics, ACE inhibitors, and NSAIDs (except aspirin) reduce renal clearance of lithium; reduce dosage of lithium Carbamazepine increases the risk of neurotoxicity; a reduction in dosage of lithium may be required Valproate is a moderate inhibitor of 2C9; reduction in dosage of 2C9 substrates may be required Phenytoin, carbamazepine, phenobarbital, and rifampin increase renal clearance of valproate; increase dosage of proate Use with lamotrigine increases the risk of Stevens-Johnson syndrome; reduce dosage of lamotrigine Lithium Valproate Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 59 Drugs for Psychiatric Disorders PSYCHOTIC DISORDERS The oral antipsychotic drugs used for treatment of schizophrenia, schizoaffective disorder, delusional disorder and other manifestations of psychosis or mania are listed in Table Adverse effects such as movement disorders and metabolic effects, cost, and lack of access to nonpharmacological services (rehabilitation, psychotherapy, education and intensive case management) can interfere with patient adherence to these medications EFFECTIVENESS — Antipsychotic drugs are generally more effective for treating the “positive symptoms” of schizophrenia (agitation, hallucinations and delusions) than the “negative symptoms” (apathy, social withdrawal and blunted affect).35 Some symptoms of schizophrenia and acute psychoses may improve rapidly after treatment with antipsychotic drugs, but chronic schizophrenia usually takes many weeks to respond; some patients may continue to improve for months Maintenance treatment with antipsychotic medications reduces relapse rates in schizophrenia.36 Oral – Second-generation antipsychotics are now used more commonly than first-generation drugs, even though controlled trials have failed to demonstrate a clear advantage in efficacy with the newer drugs, except for clozapine and possibly olanzapine.37,38 Clozapine can be effective for treatment of psychotic symptoms in patients who have not responded to other drugs It also appears to be more effective than other antipsychotics in decreasing the risk of suicide.39,40 Olanzapine appears to be more effective than aripiprazole, quetiapine, risperidone and ziprasidone in reducing psychotic symptoms.41 The more recently FDA-approved antipsychotic drugs asenapine,42 iloperidone43 and lurasidone44 may be effective for some patients, but their efficacy and safety relative to other drugs in the class remain to be established Parenteral – The long-acting parenteral antipsychotics listed in Table are generally used in patients with a history of relapse due to poor adherence to oral maintenance therapy Data on the newer long-acting parenteral formulations such as paliperidone, olanzapine and aripiprazole are limited Short-acting parenteral antipsychotics can be helpful for rapid treatment of acute psychotic agitation or mania.45 Inhaled – The first-generation antipsychotic loxapine has been approved by the FDA as a powder for oral inhalation (Adasuve) for acute treatment of agitation associated with bipolar disorder or schizophrenia 60 ADVERSE EFFECTS — First-Generation – All first-generation antipsychotic drugs have been associated with sexual dysfunction, hyperprolactinemia, neuroleptic malignant syndrome and tardive dyskinesia The risk of extrapyramidal symptoms and tardive dyskinesia with the first-generation agents may be minimized if dosing is targeted to the lowest dose at which fine, rather than coarse, extrapyramidal motor effects first appear.46 Chlorpromazine commonly causes sedation, postural hypotension and weight gain, as well as anticholinergic and occasional extrapyramidal adverse effects Haloperidol and fluphenazine are less likely to cause sedation, postural hypotension or anticholinergic effects, but typically cause extrapyramidal symptoms Perphenazine and loxapine are generally less sedating than chlorpromazine and somewhat less likely than haloperidol or fluphenazine to cause extrapyramidal symptoms Table Some Parenteral Antipsychotics Drug Usual Adult Dosage Cost2 12.5-25 mg IM q2-3 wks 10-15 times previous daily oral dose IM q4 wks $108.003 Long-Acting1 First-Generation Fluphenazine decanoate – generic Haloperidol decanoate – generic Haldol (Janssen) Second-Generation Aripiprazole – Abilify Maintena (Otsuka/Lundbeck) Olanzapine pamoate – Zyprexa Relprevv (Lilly) Paliperidone palmitate – Invega Sustenna (Janssen) Risperidone – Risperdal Consta (Janssen) Short-Acting5 First-Generation Chlorpromazine – generic Droperidol – generic Fluphenazine hydrochloride – generic Haloperidol lactate – generic Haldol (Janssen) Second-Generation Aripiprazole – Abilify (BMS/Otsuka) Olanzapine – generic Zyprexa (Lilly) Ziprasidone – Geodon (Pfizer) 32.004 119.00 400 mg IM once/month 1450.00 150-300 mg IM q2 wks 795.00 or 300-405 mg IM q4 wks 117-234 mg IM q4 wks 859.00 25-50 mg IM q2 wks 25 mg IM 2.5-5 mg IM 1.25 mg IM 573.00 16.00 2.00 6.00 2-5 mg IM 2.00 6.00 9.75 mg IM 21.00 5-10 mg IM 16.00 20.00 9.00 10-20 mg IM Dosage for schizophrenia, based on patient’s stable oral maintenance dosage Approximate wholesale acquisition cost (WAC) for weeks’ or month’s treatment with the lowest usual adult dosage for long-acting, or cost of a single injection of the lowest usual dose for short-acting $ource® Monthly (Selected from FDB MedKnowledge™) May 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Cost of one 5-mL vial Cost of 100-mg dose Single dose for acute agitation; repeat doses may be needed Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 Drugs for Psychiatric Disorders Table Oral Antipsychotics Some Available Oral Formulations Initial Adult Dosage Usual Adult Dosage1 10-50 mg bid 2.5-5 mg divided q6-8h 200 mg bid 10 mg once/d mg once/d or divided mg bid Loxapine4 – generic Loxitane (Watson) Perphenazine – generic 10, 25, 50, 100, 200 mg tabs 1, 2.5, 5, 10 mg tabs; 2.5 mg/5 mL elixir; mg/mL conc 0.5, 1, 2, 5, 10, 20 mg tabs; mg/mL soln 5, 10, 25, 50 mg caps 5, 10 mg caps 2, 4, 8, 16 mg tabs 10 mg bid 129.00 371.00 139.00 Thioridazine5 – generic Thiothixene – generic Trifluoperazine – generic 10, 25, 50, 100 mg tabs 1, 2, 5, 10 mg caps 1, 2, 5, 10 mg tabs 50-100 mg tid mg tid 2-5 mg bid 60-100 mg in 2-4 divided doses 24 mg in divided doses 100-200 mg bid 10 mg bid 10 mg bid 2, 5, 10, 15, 20, 30 mg tabs; mg/mL soln6 10-15 mg once/d 10-30 mg once/d 669.00 10, 15 mg ODT 5, 10 mg sublingual tabs 25, 50, 100, 200 mg tabs 25, 100 mg tabs 12.5, 25, 100 mg ODT 12.5, 25, 100, 150, 200 mg ODT 1, 2, 4, 6, 8, 10, 12 mg tabs 10-15 mg once/d mg bid 12.5-25 mg bid 10-15 mg once/d 5-10 mg bid 100-300 mg tid 797.00 690.00 218.00 812.00 589.00 783.00 mg bid 6-12 mg bid 20, 40, 80, 120 mg tabs 40 mg once/d 40-160 mg once/d 2.5, 5, 7.5, 10, 15, 20 mg tabs 5-10 mg once/d 10-20 mg once/d 1.5, 3, 6, mg ER tabs mg once/d 6-12 mg once/d 25, 50, 100, 200, 300, 400 mg tabs 25 mg bid 300-800 mg in or divided doses 50, 150, 200, 300, 400 mg tabs 0.25, 0.5, 1, 2, 3, mg tabs; mg/mL soln 0.25, 0.5, 1, 2, 3, mg ODT 0.5, 1, 2, 3, mg ODT 20, 40, 60, 80 mg caps 300 mg once/d mg once/d or divided bid 400-800 mg once/d 4-8 mg once/d 20-40 mg bid 60-80 mg bid Drug Cost2 First-Generation Chlorpromazine3 – generic Fluphenazine3 – generic Haloperidol3 – generic Second-Generation Aripiprazole3 – Abilify (BMS/Otsuka) orally disintegrating – Abilify Discmelt Asenapine – Saphris (Merck) Clozapine7 – generic Clozaril (Novartis) orally disintegrating – generic FazaClo (Jazz) Iloperidone – Fanapt (Novartis) Lurasidone – Latuda (Sunovion) Olanzapine3 – generic Zyprexa (Lilly) orally disintegrating – generic Zyprexa Zydis Paliperidone3 – Invega (Janssen) Quetiapine – generic Seroquel (AstraZeneca) extended release – Seroquel XR Risperidone3 – generic Risperdal (Janssen) orally disintegrating – generic Risperdal M-TAB Ziprasidone – generic Geodon3 (Pfizer) mg tid 5, 10, 15, 20 mg ODT $140.00 11.00 14.00 24.00 26.00 57.00 697.00 553.00 23.00 553.00 340.00 583.00 604.00 72.00 600.00 585.00 42.00 513.00 362.00 616.00 292.00 659.00 ODT = orally disintegrating tablet Usual oral maintenance dosage for schizophrenia Approximate wholesale acquisition cost (WAC) for 30 days’ treatment with the lowest usual daily dosage $ource® Monthly (Selected from FDB MedKnowledge™) May 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Also available parenterally Also available as a powder for oral inhalation (Adasuve) for acute treatment of agitation associated with schizophrenia or bipolar disorder in adults Thioridazine is associated with dose-related prolongation of the QTc interval and should be reserved for schizophrenic patients who fail to resond to other drugs Aripiprazole PO solution should be given at the same dose, mg per mg, as the tablets, except that when patients receive the 30-mg tablet, 25 mg of the solution should be used Clozapine is associated with seizures and agranulocytosis and should be reserved for schizophrenic patients who fail to respond to other drugs Second-Generation – Second-generation antipsychotics have a relatively low risk of extrapyramidal effects, and are probably less likely than first-generation antipsychotics to cause tardive dyskinesia and neuroleptic malignant syndrome.47 Some second-generation drugs (particularly clozapine, olanzapine and quetiapine) cause more weight gain than others The FDA requires the manufacturers of all second-generation antipsychotics to include product-label warnings about hyperglycemia and diabetes, even though the risks are not equivalent for all drugs in the class, and about an increased risk of death among elderly patients with dementia.48 Table lists some relative adverse effects of second-generation antipsychotics Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 61 Drugs for Psychiatric Disorders Table Some Relative Adverse Effects of Second-Generation Antipsychotics Drug Diabetes Weight Gain Extrapyramidal Symptoms QTc Prolongation Elevated Prolactin Aripiprazole Asenapine* Clozapine Iloperidone* Lurasidone* Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone +/– + ++++ ++ +/– ++++ ++ ++ ++ +/– + ++ ++++ ++ +/– ++++ +++ +++ +++ +/– ++ ++ +/– +/– ++ + ++ +/– +++ + +/– + + ++ +/– + + + + ++ +/– ++ +/– +/– +/– + +++ +/– +++ + *Limited experience Clozapine causes granulocytopenia or agranulocytosis in about 1% of patients, requiring weekly monitoring of blood counts Seizures occur in 1-4% of patients and are dose-related Increased salivation and enuresis occur at higher doses Gastrointestinal hypomotility, which can be severe, marked sedation, diabetes, weight gain and hyperlipidemia are common with clozapine.49 Myocarditis, often occurring within the first few weeks of treatment and sometimes fatal, has been reported.50 Despite its structural similarity to clozapine, olanzapine is much less likely to cause agranulocytosis or seizures It does cause weight gain and other metabolic effects, including diabetes mellitus Postural hypotension, somnolence, constipation, hyperlipidemia, dizziness and akathisia can also occur Increases in serum hepatic transaminases have been reported The most common adverse effects of risperidone are postural hypotension, insomnia, constipation, dizziness, prolactin elevation, hyperglycemia and weight gain At doses higher than mg/day, the risk of extrapyramidal symptoms increases without an additional increase in efficacy The adverse effect profile of paliperidone (9-hydroxyrisperidone) resembles that of its parent compound risperidone, including extrapyramidal symptoms, prolactin elevation, nausea, somnolence, dizziness, tachycardia and QT interval prolongation.51 Quetiapine commonly causes somnolence, dizziness, constipation, postural hypotension, hyperglycemia and weight gain Though mentioned in the drug’s package insert with a recommendation for twice-yearly ophthalmologic monitoring, clinical use of quetiapine probably does not cause cataract formation.52 Ziprasidone seldom causes significant weight gain, hyperlipidemia or hyperglycemia Its adverse effects have included mild to moderate somnolence, prolongation of the QT interval, extrapyramidal symptoms in about 5% of patients and, occasionally, paradoxical excitement Aripiprazole can cause anxiety, headache, nausea, constipation, lightheadedness, agitation and akathisia It has a lower risk of hyperlipidemia, hyperglycemia or hyperprolactinemia compared to most second-generation antipsychotics.53 It appears to cause less weight gain than most other second-generation antipsychotics The most commonly reported adverse effects of asenapine are insomnia, somnolence, nausea, vomiting and weight gain.54 Iloperidone causes orthostatic hypotension, QT interval prolongation, dizziness, somnolence, dry mouth and weight gain, but is relatively free of extrapyramidal effects.55 Lurasidone can cause akathisia, nausea, extrapyramidal symptoms, agitation and somnolence, but does not appear to increase weight.56 Table Some Second-Generation Antipsychotic Drug Interactions Drug Metabolism by CYP/P-gp Comments Aripiprazole Asenapine Clozapine Iloperidone Lurasidone 3A4, 2D6 1A2 1A2, 3A4, 2D6, 2C19 3A4, 2D6 3A4 Olanzapine 1A2, 2D6 and P-gp Paliperidone Quetiapine Risperidone Ziprasidone 2D6, P-gp 3A4 3A4, 2D6 and P-gp 3A4 Dose adjustments required with strong 3A4 or 2D6 inhibitors and with 3A4 inducers Low potential for interactions Many interactions, primarily with 1A2 inhibitors and inducers Dose adjustments required with strong 3A4 or 2D6 inhibitors Contraindicated with strong 3A4 inducers and inhibitors; dose adjustments required with moderate 3A4 inhibitors Low potential for interactions; serum concentrations altered by strong 1A2 inhibitors or inducers Low potential for interactions Dose adjustments required with strong 3A4 inducers and inhibitors Dose adjustments required with 3A4 or 2D6 inhibitors and 3A4 inducers Serum concentrations modestly effected by 3A4 inhibitors and inducers 62 Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 Drugs for Psychiatric Disorders PREGNANCY — Data on use of antipsychotic drugs during pregnancy are limited None have been proven to be teratogenic Chlorpromazine was once used to treat morning sickness, apparently without teratogenesis Only clozapine and lurasidone are classified as category B for use during pregnancy (no human data; animal data suggest no risk); all the other antipsychotics are category C (adverse effects in animals or no animal reproductive studies, and no adequate studies in humans) The risks of hyperglycemia and weight gain are greater with the second-generation antipsychotics, which have been associated with high birth weight and babies that are large for gestational age.34 CHOICE OF DRUGS — Clozapine is the most effective antipsychotic drug, but it should be reserved for refractory disease because of its potential for serious hematologic toxicity and strict monitoring requirements Olanzapine may have some slight advantages over other drugs in efficacy, but its adverse effects on weight and metabolism may be unacceptable for longterm use Other second-generation antipsychotics are not clearly more effective than first-generation drugs, but they have a lower risk of tardive dyskinesia Some patients who not respond to one antipsychotic may respond to another Long-acting injectable antipsychotics may be useful when adherence is a problem 10 11 12 13 14 Extended-release trazodone (Oleptro) for depression Med Lett Drugs Ther 2010; 52:91 Vilazodone (Viibryd) – a new antidepressant Med Lett Drugs Ther 2011; 53:53 V Rabenda et al Risk of nonvertebral fractures among elderly postmenopausal women using antidepressants Bone 2012; 51:674 Citalopram (Celexa) and QT-interval prolongation Med Lett Drugs Ther 2012; 54:71 VM Castro et al QT interval and antidepressant use: a cross sectional study of electronic health records BMJ 2013; 346:f288 SE Hetrick et al Newer generation antidepressants for depressive disorders in children and adolescents Cochrane Database Syst Rev 2012; (11):CD004851 EW Boyer and M Shannon The serotonin syndrome N Engl J Med 2005; 352:1112 KL Wisner et al Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes Am J Psychiatry 2009; 166:557 N Lund et al Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes Arch Pediatr Adolesc Med 2009; 163:949 S Gentile On categorizing gestational, birth, and neonatal complications following late pregnancy exposure to antidepressants: the prenatal antidepressant exposure syndrome CNS Spectr 2010; 15:167 CD Chambers et al Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn N Engl J Med 2006; 354:579 A Bérard et al Paroxetine use during pregnancy and perinatal outcomes including types of cardiac malformations in Quebec and France: A short communication Curr Drug Saf 2012; 7:207 A Einarson et al Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study Can J Psychiatry 2009; 54:242 M Tuccori et al Use of selective serotonin reuptake inhibitors during pregnancy and risk of major and cardiovascular malformations: an update Postgrad Med 2010; 122:49 15 S Alwan et al Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects N Engl J Med 2007; 356:2684 16 C Louik et al First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects N Engl J Med 2007; 356:2675 17 O Stephansson et al Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality JAMA 2013; 309:48 18 LH Pedersen et al Fetal exposure to antidepressants and normal milestone development at and 19 months of age Pediatrics 2010; 125:e600 (epub Feb 22) 19 KR Connolly and ME Thase If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies Drugs 2011; 71:43 20 AJ Rush et al Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression N Engl J Med 2006; 354:1231 21 Adjunctive antipsychotics for major depression Med Lett Drugs Ther 2011; 53:74 22 BM Wright et al Augmentation with atypical antipsychotics for depression: a review of evidence-based support from the medical literature Pharmacotherapy 2013; 33:344 23 PE Holtzheimer and HS Mayberg Neuromodulation for treatmentresistant depression F1000 Med Rep 2012; 4:22 24 Repetitive transcranial magnetic stimulation (TMS) for medicationresistant depression Med Lett Drugs Ther 2009; 51:12 25 Vagus nerve stimulation for depression Med Lett Drugs Ther 2005; 47:50 26 JR Geddes and DJ Miklowitz Treatment of bipolar disorder Lancet 2013; 381:1672 27 ME Thase and T Denko Pharmacotherapy of mood disorders Annu Rev Clin Psychol 2008; 4:53 28 L Tondo and RJ Baldessarini Long-term lithium treatment in the prevention of suicidal behavior in bipolar disorder patients Epidemiol Psychiatr Soc 2009; 18:179 29 LA Smith et al Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis J Affect Disord 2010; 122:1 30 YW Shi et al Association between HLA and Stevens-Johnson syndrome induced by carbamazepine in Southern Han Chinese: genetic markers besides B*1502? Basic Chem Pharmacol Toxicol 2012; 111:58 31 P Cacoub et al The DRESS syndrome: a literature review Am J Med 2011; 124:588 32 SH Joe et al Feasibility of a slower lamotrigine titration schedule for bipolar depression: a naturalistic study Int Clin Psychopharmacol 2009; 24:105 33 FDA Drug Safety Communication: valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children Available at www.fda.gov/Drugs/DrugSafety /ucm350684.htm Accessed May 12, 2013 34 S Gentile Antipsychotic therapy during early and late pregnancy A systematic review Schizophr Bull 2010; 36:518 35 RJ Baldessarini Chemotherapy in Psychiatry, third edition New York: Springer Press 2013 36 S Leucht et al Maintenance treatment with antipsychotic drugs for schizophrenia Cochrane Database Syst Rev 2012; 5:CD008016 37 S Leucht et al Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis Lancet 2009; 373:31 38 L Hartling et al Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis Ann Intern Med 2012;157:498 39 HY Meltzer et al Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT) Arch Gen Psychiatry 2003; 60:82 40 J Tiihonen et al 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study) Lancet 2009; 374:620 41 S Leucht et al A meta-analysis of head-to-head comparisons of secondgeneration antipsychotics in the treatment of schizophrenia Am J Psychiatry 2009; 166:152 42 Asenapine (Saphris) sublingual tablets for schizophrenia and bipolar Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 63 Drugs for Psychiatric Disorders disorder Med Lett Drugs Ther 2010; 52:9 43 Iloperidone (Fanapt) - another second-generation antipsychotic Med Lett Drugs Ther 2010; 52:13 44 Lurasidone (Latuda) for schizophrenia Med Lett Drugs Ther 2011; 53:13 45 R Emsley et al Long-acting injectable antipsychotics in early psychosis: a literature review Early Interv Psychiatry Jan 2013 (epub ahead of print) 46 O Freudenreich and JP McEvoy Optimizing outcome with antipsychotic treatment in first-episode schizophrenia: balancing efficacy and side effects Clin Schizophr Relat Psychoses 2012; 6:115 47 CU Correll and EM Schenk Tardive dyskinesia and new antipsychotics Curr Opin Psychiatry 2008; 21:151 48 R Liperoti et al All-cause mortality associated with atypical and conventional antipsychotics among nursing home residents with dementia: a retrospective cohort study J Clin Psychiatry 2009; 70:1340 49 J Fitzsimons et al A review of clozapine safety Expert Opin Drug Saf 2005; 4:731 50 KJ Ronaldson et al Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases Schizophr Res 2011; 128:161 51 R Emsley et al Efficacy and safety of oral paliperidone extendedrelease tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies Int Clin Psychopharmacol 2008; 23:343 52 FW Fraunfelder Twice-yearly exams unnecessary for patients taking quetiapine Am J Ophthalmol 2004; 138:870 53 CU Pae A review of the safety and tolerability of aripiprazole Expert Opin Drug Saf 2009; 8:373 54 J Weber and PL McCormack Asenapine CNS Drugs 2009; 23:781 55 JM Kane et al Long-term efficacy and safety of iloperidone: results from clinical trials for the treatment of schizophrenia J Clin Psychopharmacol 2008; 28(2 Suppl 1):S29 56 L Citrome Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic Int J Clin Pract 2011; 65:189 Coming Soon in Treatment Guidelines: Drugs for Bacterial Infections – July 2013 Drugs for Atrial Fibrillation – August 2013 Follow us on Twitter @MedicalLetter Treatment Guidelines ® from 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physician assistants may earn credits with this exam MISSION: The mission of The Medical Letter's Continuing Medical Education Program is to support the professional development of healthcare professionals including physicians, nurse practitioners, pharmacists and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are free of industry influence The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action, clinical trials, dosage and administration, adverse effects and drug interactions The Medical Letter delivers educational content in the form of self-study material The expected outcome of the CME Program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in materials contained in Treatment Guidelines The Medical Letter will strive to continually improve the CME program 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be able to select and prescribe, or confirm the appropriateness of the prescribed usage of the drugs and other therapeutic modalities discussed in Treatment Guidelines with specific attention to clinical evidence of effectiveness, adverse effects and patient management Upon completion of this program, the participant will be able to: Explain the current approach to the management of patients with psychiatric disorders Discuss the pharmacologic agents available for treatment of depression, bipolar disorder and psychosis and compare them based on their efficacy, dosage and administration, potential adverse effects and drug interactions Determine the most appropriate therapy given the clinical presentation of an individual patient Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software (SSL) is used for commerce transactions through VeriSign, Inc No credit card information is stored IT 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Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 130 Questions First-line treatments for major depression include: a SSRIs b SNRIs c bupropion d all of the above The only SSRI FDA-approved for treatment of major depressive disorder in children is: a sertraline b fluoxetine c citalopram d paroxetine A 33-year-old woman with depression has been taking paroxetine She is considering becoming pregnant Which of the following could you tell her about treatment of depression during pregnancy? a paroxetine is classified as category D for use during pregnancy b untreated depression has not been associated with preterm birth c all antidepressants are classified as category A for use during pregnancy d all of the above The antidepressant least likely to cause sexual side effects is: a bupropion b fluoxetine c amitriptyline d venlafaxine The drug of choice for maintenance treatment of bipolar disorder is: a sertraline b lithium c carbamazepine d lorazepam A 64-year-old otherwise healthy woman with bipolar disorder has had multiple relapses because she forgets to take her daily doses of quetiapine Which of the following long-acting injectable antipsychotics is FDA-approved for maintenance treatment of bipolar disorder? a olanzapine b aripiprazole c risperidone d paliperidone Which of the following drugs is not recommended as monotherapy for maintenance treatment of bipolar disorder? a lithium b lamotrigine c risperidone d citalopram A higher incidence of Stevens-Johnson syndrome has been reported in some patients of Asian ancestry taking: a carbamazepine b olanzapine c aripiprazole d lithium Negative symptoms of schizophrenia include: a apathy b social withdrawal c blunted affect d all of the above 10 All second-generation antipsychotics have a FDA-required warning label about: a thrombocytopenia b hyperglycemia c gastrointestinal bleeding d hypotension 11 A 19-year-old woman newly diagnosed with schizophrenia is very concerned about possible weight gain associated with antipsychotic treatment Which of the following might be a good option for her? a clozapine b ziprasidone c quetiapine d olanzapine 12 Which of the following antipsychotics is thought to be the most effective in preventing suicide and may be effective in patients who have not responded to other antipsychotics? a haloperidol b clozapine c lurasidone d loxapine ACPE UPN: 0379-0000-13-130-H01-P; Release: May 2013, Expire: May 2014 Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 130) • June 2013 ... imposes severe fines 53 Drugs for Psychiatric Disorders Table Some Drugs for Depression Drug SSRIs Citalopram – generic Celexa (Forest) Escitalopram – generic Lexapro (Forest) Fluoxetine – generic... Page Page Page 54 55 58 59 60 61 62 Page 62 Drugs for Psychiatric Disorders Related article(s) since publication Drugs are not the only treatment for psychiatric illness Psychotherapy remains an... Medical Letter • Vol 11 ( Issue 130) • June 2013 57 Drugs for Psychiatric Disorders Table Some Oral Drugs for Bipolar Disorder Drug Some Available Formulations Initial Adult Dosage1 Usual Adult Dosage1