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NEWER ANTIDEPRESSANTS
CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
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NEWER ANTIDEPRESSANTS Beyond Selective Serotonin Reuptake Inhibitor Antidepressants Brian J. McConville, MD, Robert 0. Chaney, BS, Kerri L. Browne, BS, Loren Friedman, MS, Elizabeth Cottingham, MD, and Dan Nelson, MD
. Major depressive disorder in children and adolescents is a significant problem and is also a predictive indicator of severe long-term difficulties.z2,43 Although the phenomenology of child and adolescent depression versus adult depression is held to be child and adolescent depression has not been shown to clearly respond to treatment with tricyclic antidepressants (TCAs) in double-blind studies. More evidence may be available for children than for adolescents.'", 19, 42 These generally negative findings have been reviewed,2O and the sudden unexplained deaths in children receiving desipraminez9,32, 33, 39 have caused widespread concern about use of TCAs in children and adolescents. Citing the lack of rigorous scientific evidence supporting the superiority of TCAs in child and adolescent depression compared with placebo, along with these sudden unexplained deaths, Geller" and W e r r ~ have ~ ~expressed concern about the routine use of TCAs in children and adolescents. As noted in the article by Labellarte and colleagues elsewhere in this issue, the emergence of selective serotonin reuptake inhibitors (SSRIs) has allowed for further psychopharmacologic methods for treating child and adolescent depression. Fluoxetine, fluvoxamine, sertraline, and paroxetine have been found in open studies to provide effectiveantidepressant activity without the sedating, anticholinergic, or cardiotoxic reactions observed with TCAs, although the incidence of insomnia, nervousness, restlessness, and anxiety are higher?, 21, 50 McConville and colleagues= found positive effects for sertraline in treating major depressive disorder in adolescents and also noted that scale ratings of depression frequently varied, being worsened by adverse events and improved by positive From the Department of Psychiatry, University of Cincinnati College of Medicine (BJM, ROC, KB, LF); and the Division of Psychiatry, Children's Hospital Medical Center (EC, DN), Cincinnati, Ohio
PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 45 * NUMBER 5 OCTOBER 1998
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life circumstances. There may also be an emergence of an endogenous component in early childhood and adolescence, either as a pure syndrome or following repeated ~ t r e s s o r sIf. ~repeated ~ stressors can be shown to lead to a nonreactive pattern, a strong argument can be made for early psychopharmacologic and psychotherapeutic intervention in children and adolescents with major depressive disorders and double depressions (eg., dysthymia and major depressive disorder). Follow-up of child and adolescent depressives suggests that these disorders can become long-term, causing debilitating problems, including not only depression but also impairment in psychosocial and educational functioning.", 37 A few double-blind studies on SSRIs in child and adolescent depression have been conducted. Simeon and colleague^^'^ did not find statistically significant differences between fluoxetine versus placebo for depression; however, in an important study by Emslie and colleagues,'z in which 96 children and adolescents were treated with either fluoxetine or placebo, a significant difference was found among treated and untreated groups on the Children's Depression Rating Scale Revised36and the Clinical Global Impression Scale for depression.**In this study, placebo effect was similar to drug effect in the first week of outpatient treatment; however, over the 8-week period of the trial, significant differences emerged in the criteria noted earlier.3 Therefore, a significant difference in efficacy may exist among drug versus placebo studies for both TCAs and SSRIs in depressed children and adolescents provided that a sufficiently largc?sample is used in studies to indicate differences between placebo and drug response. In addition, careful measurements must be taken both within single centers and between centers to ensure inter-rater reliability. Although the current clinical preference is to use SSRIs rather than TCAs in the treatment of child and adolescent depression, the hard evidence for efficacy from controlled studies is minimal. Moreover, a connection between the clinical effectiveness of these medications and their degree of serotonin reuptake inhibition seems to be lacking. Further studies of the "traditional" TCAs and SSRIs are needed, including multidose studies of SSRIs in children and adolescents with depressive disorders; however, also needed is more exploration of newer or alternate antidepressive agents. The following section begins with an overview of these compounds and leads into a discussion of the most common alternate antidepressants used by practitioners, as well as some newer developments. BEYOND THE SELECTIVE SEROTONIN REUPTAKE INHIBITORS: ALTERNATIVE ANTIDEPRESSANTS Many alternative antidepressants to the TCAs and SSRIs are either being developed or are in use. Historically, as is common in psychopharmacology, the early antidepressants were discovered by chance. Tricyclic antidepressants were developed in hopes of developing antipsychotics, and monoamine oxidase inhibitors (MAOIs) were found while investigating antitubercular drugs. Since then, the evolution of antidepressants and other psychopharmacologic agents has gone to a more rational drug design involving molecular targeting for "designer drugs." Because all pharmacologic agents have many actions-both wanted and unwanted-one of the goals of newer drug development has been to produce agents with improved tolerability and safety. But drugs with a more specific spectrum of clinical activity may also have a more limited range of actions. In addition, depression does not necessarily represent a particular pattern of either psychopathology or pathophysiology; rather, it probably represents a heteroge-
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Table 1. GENERAL CLASSIFICATION OF ANTIDEPRESSANT PHARMACOTHERAPY BY PRESUMED MECHANISM OF ACTION
Classfication
Examples
Mixed serotonin effects--BHT, receptor antagonism Mixed NE/DA reuptake inhibitors Monoamine oxidase inhibitors Irreversible Reversible Mixed NWS-HT reuptake inhibitors Selective serotonin reuptake inhibitors
Phenylpiperazines,such as trazodone, nefazodone Aminoketones, such as bupropion Phenelzine, tranylcypromine, moclobemide TCAs, venlafaxine Fluoxetine, sertraline, paroxetine, fluvoxamine
5-HT, serotonin; NE, norepinephrine; DA, dopamine; TCAs, tricyclic antidepressants. From Burke MJ, Preskorn SH: Short-term treatment of mood disorders with standard antidepressants. In Bloom FE, Kupfer DJ (eds): The Fourth Generation of Progress. New York, Raven Press, 1995, p 1054; with permission.
neous group of conditions. In general, the TCAs, which are mixed norepinephrine and SSRIs, can be seen as being at one end of a spectrum, and the SSRIs can be seen as being at thepther end in terms of specific neurotransmitter action. In adult studies, some data suggest that those who fail to respond to TCAs may respond to SSRIs and vice versa.5No such comparisons have been performed in children and adolescents, largely because of the limited number of antidepressant trials performed in the pediatric population. Even in this era, when multiple analogs of a basic antidepressant may be synthesized, chemical structure by itself does not necessarily determine function. The SSRIs, for example, have very different chemical structures, and no clear relationship exists between the molecular structure, function, and psychobiologic activity of a particular agent (C. McDougle, MD, personal communication, 1998), a point that should be considered as newer compounds are investigated. Considering the neurotransmitter mechanisms of antidepressant action may be a more useful approach than the study of chemical structure? Although the connection between the mechanisms of neurotransmitter action and antidepressant response is still largely hypothetical, for heuristic purposes, this approach has been widely used. Table 1 indicates such a classification of antidepressant pharmacotherapy by presumed mechanism of action.
Common Alternate or Atypical Agents The most frequently used atypical antidepressants include: Trazodone (Desyrel), a 5-HT2, antagonist, SSm Nefazodone (Serzone), a 5-HT2, antagonist, norepinephrine and serotonin reuptake inhibitor Bupropion (Wellbutrin), a norepinephrine and dopamine reuptake inhibitor Venlafaxine (Effexor), a norepinephrine and serotonin reuptake inhibitor Buspirone (Buspar), a 5-HTln agonist Mirtazapine (Remeron), an a,-antagonist and 5-HT2,,, antagonist Monoamine oxidase inhibitors, which inhibit degradation of serotonin, norepinephrine, and dopamine Two basic texts for most of these medications and their use in child and adolescent clinical pharmacology are Child and Adolescent Clinical Psychopharma-
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coIogy (Green HG, Williams & Wilkins, 1995)Is and Child and AdoIescent Psychophavmacology (Kutcher SP, WB Saunders, 1997).24 Trazodone
Trazodone (Desyrel) is different from the TCAs and tetracyclic antidepressants in terms of its novel structure and differing pharmacologic effects.8 In animals, trazodone selectively inhibits serotonin reuptake in the brain and has an antagonistic effect at 5-HT2Areceptors. It is recommended that trazodone be taken soon after eating because as much as 20% more drug may be absorbed than when taken on an empty stomach. The maximum serum concentration is also achieved more slowly and with a lesser peak so that there is less risk for dizziness and lightheadedness. Trazodone is eliminated through the liver and kidneys, with an initial half-life between 3 and 6 hours, and with the second phase between 5 and 9 hours. Increased phenytoin levels have been reported when this is administered along with trazodone, and trazodone should also not be administered with MAOIs because the effect of their interaction is not known but may result in hypertensive crises. The most common side effetts are drowsiness, or lightheadedness, dry mouth, nausea, and vomiting. Priapism, which can necessitate surgical intervention and has resulted in some cases of permanent impairment of sexual function, has been reported with an incidence of about 1 in 15,000 patients. Trazodone-treated patients with prolonged or inappropriate erections must be informed to discontinue the trazodone; contact their physician; and, if erections persist, go to an emergency room, where medical or possible surgical intervention may be required. One case of trazodone-induced priapism of the clitoris has been reported.30 The indications for trazodone use in child and adolescent psychiatry are shown in Table 2. Trazodone given in children and adolescents for depression has not been reported, although some reports exist of it being used in the treatment of Table 2. TRAZODONE (DESYREL): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE
Indications for use in child and adolescent psychiatry Trazodone is approved only for the treatment of major depressive disorder in individuals at least 18 years of age. The drug is not recommended for use in the pediatric age group because its safety and effectiveness have not been established for this age range. Dosage schedule for children and adolescents USPDI (1992) reports the following pediatric doses guidelines when trazodone is used as an antidepressant: Children under 6 years of age: Dosage not determined. Children 6 to 18 years of age: Begin with 1.5-2 mg/kg/day in divided doses. Titrate dosage gradually at 3-to 4-day intervals to a maximum of 6 mglkglday. Dose forms available Tablets: 50 mg scored, 100 mg scored Divided-dose tablets: 150 mg and 300 mg (both tablets scored to divide into three equal parts) USPDI, United States Pharmacopeia Dispensing from Green HG: Child and Adolescent Clinical Psychopharmacology. Williams & Wilkins, 1995, p 178; with permission.
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children and adolescents for aggression.16, 54 In an overview of trazodone trials in adults in the United States, Feighner and BoyerI4 suggested that trazodone should be considered for depressed patients with anxiety, insomnia, marked agitation, and the inability to tolerate anticholinergic side effects. One common use of this medication is for sedation, and this is particularly useful in depressed female children and adolescents, with its use in male children and adolescents being more problematic for obvious reasons. Metz and Shader27reported excessive sedation when using low doses of trazodone (25-75 mg) in adults to treat insomnia associated with fluoxetine. Nefazodone Nefazodone (Serzone) is a potent inhibitor of the postsynaptic 5-HT2*receptor and a moderate inhibitor of serotonin and norepinephrine reuptake." One open-label study exists of the pharmacokinetics of nefazodone in children (aged 7-12 years) and adolescents (aged 12-17 years) conducted by Findling and colleag~es.~~ During the 8-week trial, subjects were started at 50 mg twice a day and titrated to a maximum daily dosage of 300 mg/day for children and 600 mg/day for adolescents. The authors found nefazodone to be safe and well tolerated at these doses, with a similar biodisposition to that of adults and an improvement in depressive symptoms sufficiently significant to indicate further controlled trials. Some of the more common side effects are dry mouth, nausea, constipation, dizziness, confusion, and blurred vision; however, nefazodone does seem to have a lower incidence of sexual dysfunction, gastrointestinal disturbances, and activating symptoms than do SSRIs. It is also important to note that priapism is less of a concern with nefazodone as it is with trazodone. The more common features are shown in Table 3. Several clinical trials have been performed comparing nefazodone with placebo, TCAs, and SSRIs in the treatment of major depression in adults. Six studies in adults have been performed, showing that nefazodone has significantly greater efficacy than does placebo." Four of these studies have shown equal efficacy to imipramine." Baldwin and colleagues' showed efficacy equivalent to paroxetine, Feiger and colleague^'^ showed the same with sertraline, and Rioux and colleagues4oshowed that nefazodone was equivalent to fluoxetine in efficacy. Table 3. NEFAZODONE (SERZONE): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE Indications for use in child and adolescent psychiatry Nefazodone is approved for the treatment of depression disorder in individuals at least 18 years of age. The drug is not recommended for use in the pediatric are group because its safety and effectiveness have not been established for this age range. Dose schedule for children and adolescents Begin dosing with 50 mg twice a day and titrate to an effective dose by 50 mg every 3 days. Maximum dose for children under 12 years of age should not exceed 300 mgl day and 600 mg/day for those 12 years and older. Dose forms available Tablets: 100 mg and 150 mg bisect scored on both tablet faces, 200 mg and 250 mg unscored Data from Findling RL, Magnus RD, Pieskorn SH,et al: Open pharmacokinetic study of nefazodine in children and adolescents with depression [abstract no. NR-961. 44th Annual Meeting of the American Academy of Childhood and Adolescent Psychiatry, Toronto, October 1997
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Bupropion
Bupropion (Wellbutrin) is in the aminoketone class of antidepressants and has not been approved for use in children and adolescents. It is, however, fairly widely used clinically, and the indications are shown in Table 4. The major concern with the use of bupropion is that seizures occur in 0.4% of patients at doses of 450 mg/day or more, and this is about four times the incidence of seizures with other approved antidepressants. The incidence of seizures increased with higher daily doses. The most common side effects include agitation, dry mouth, insomnia, headache, nausea, vomiting, constipation, and tremor. Other side effects may include akasthisia, skin rash, tachycardia, and dizziness; however, bupropion does not have a negative effect on memory performance, in contrast to several other antidepressants. One clinical feature is that bupropion may tend to lose its antidepressant effectiveness over time, although the evidence for this is unclear. At least three studies indicate the use of this compound in children and adolescents.6,7,10 In adults, bupropion has been shown to be effective in patients who are not responders to TCAs and has been found useful in the treatment of primary depression but not necessarily in depression secondary to anxiety or panic disorder? Casat and colleagues> have conducted two trials using bupropion in ADHD. Conners and colleagues10found that bupropion may be a useful addition to the curren6 medications available to treat ADHD. In a retrospective analysis, Spencer and colleagues47indicated that bupropion, like psychostimulants, exacerbated tics in the treatment of comorbid ADHD and chronic motor tic disorder or Tourette syndrome. Stoll and colleagues49brought up concerns that bupropion can induce rapid cycling or an affective shift to mania, and that it may be associated with milder states of mania compared with TCAs and fluoxetine. Vedafaxine
Venlafaxine (Effexor) has been reported to have a rapid onset, and few studies have been performed in children and adolescents. The overall effect is inhibition of both norepinephrine and serotonin reuptake. Doses are 25 mg Table 4. BUPROPION (WELLBUTRIN): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE Indications in child and adolescent psychiatry Bupropion is not approved for any use in children and adolescents under age 18 years. Adolescents at least 18 years of age: used to treat depression, especially major depressive disorder. Dosage schedule for children and adolescents Children and adolescents under 18 years of age: Not recommended. Adolescents at least 18 years of age: An initial dosage of 100 mg twice daily is suggested. Based on clinical response, this may be increased to 100 mg three times daily but not before day 4 of treatment. If no clinical improvement occurs within 4 weeks, dosage may gradually be increased. Because of increased risk for seizure, a dose of 150 mg should not be exceeded within a 4-hour time period. The maximum daily dosage should not exceed 450 mg. Dose forms available Tablets: 75 mg, 100 mg From Green HG: Child and Adolescent Clinical Psychopharmacology.Baltimore, MD, Williams 8 Wilkins, 1995, p 181: with permission.
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titrated toward 200 mg/day in the ordinary preparation, and an extended release form has recently been introduced that requires only once daily dosing of either the 37.5 mg/day, 75.0 mg/day, or 150.0 mg/day. Mandoki and colleaguesz6 recently completed a double-blind, placebo-controlled study of venlafaxine and psychotherapy versus placebo and psychotherapy. Although both groups showed cliiical improvement, no significant difference was found among drug and placebo groups. In addition, the authors also found no evidence to indicate a rapid-onset effect. They did make an important point that the study duration of 6 weeks may not have been long enough and that the low dosages of venlafaxine (37.5 mg for children aged 8-12 years and 75 mg for adolescents aged 13-17 years) may also have been a factor in the nonresponse. The main features of this medication are shown in Table 5. Buspirone Buspirone (BuSpar) is essentially an anxiolytic with some antidepressant properties. Buspirone has a high affinity for the 5-HT1, serotonin receptor. It does not have cross-tolerancewith the benzodiazepines, does not suppress panic attacks, and lacks anticonvulsant activity. At therapeutic doses, buspirone is less sedating than the benzodiazepines. Buspirone has been approved by the FDA as clinically effective for the management of anxiety disorders or the short-term relief of the symptom%of anxiety. Peak plasma levels occur between 40 and 90 minutes after an oral dose of buspirone. The elimination half-life of buspirone after a 10-mg to 40-mg dose is usually between 2 and 3 hours. Adverse effects include dizziness, drowsiness, nausea, headache, insomnia, and lightheadedness. It may be given in dosages of 15 mg/day to 30 mg/day, divided into either twice-a-day or thrice-a-day dosing. The major features of this medication are shown in Table 6. Simeon and colleagues4" reported the use of buspirone in 13 adolescents and adults aged 12 to 20 years (mean age, 16 years), with various diagnoses, including five with either anxiety or depressive di~orders.~ Improvements in mood were reported, but clear correlation between improvement and diagnosis was not shown. Table 5. VENLAFAXINE (EFFEXOR): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE ~~~~~~~~~~~~~~~~~~~~~~
~
~~~
~~~~~~~~~
Indications for use in child and adolescent psychiatry Venlafaxine is approved for the treatment of depression in individuals at least 18 years of age. The drug is not recommended for use in the pediatric age group because its safety and effectiveness have not been established. Dosage schedule for children and adolescents For children aged 8-12 years, begin at 12.5 rng/day for 3 days, increase to 12.5 mg twice a day for the next 3 days, and then increase again to 12.5 rng three times a day as required. For adolescents aged 13-17 years, begin at 25 rng/day for 3 days, increase to 25 rng twice a day for the next 3 days, and then increase again to 25 mg three times a day. These doses may need to be increased further for maximum efficacy. (These recommendations are based on current literature findings.) Dose forms available Tablet: 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg Data from Mandoki MW, Tapia MR, Tapia MA, et al: Venlafaxine in the treatment of children and adolescents with major depression. PsychopharmacolBiol 33:149-I 54, 1997
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Table 6. BUSPIRONE (BUSPAR): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE
FORMS Indications in child and adolescent psychiatry Buspirone is approved only for treatment of anxiety disorders and the short-term relief of anxiety in individuals at least 18 years of age. Its safety and efficacy in children and adolescents remain to be determined. Its antidepressant activities are unclear. Dosage schedule for treating anxiety Children and adolescents: Not approved. Coffeysa,however, has cautiously suggested the following doses if a clinician elects to use buspirone in this age group. Prepubescent children: an initial dose of 2.5-5.0 mg with increases of 2.5 mg every 3 or 4 days to a maximum of 20 mglday. Adolescents: An initial dose of 5-10 mg with increases of 5-10 mg every 3 to 4 days to a maximum of 60 mglday. Persons 18 years of age and older: Initiate treatment with 5 mg three times daily. Titrate to optimal therapeutic response by increases of 5 mg every 2 or 3 days to a maximum daily dose of 60 mg. Usual optimal doses in clinical trials were 20-30 mglday in divided doses. Dose forms available Tablets (scored): 5 mg, 10 mg From Green HG: Child and Adolesceit Clinical Psychopharmacology. Baltimore, MD, Williams & Wilkins, 1995, p 216; with permission.
Mirtazapine Stimmel and colleagues4* described mirtazapine (Remeron), a n e w l y introduced antidepressant, the activity of w h i c h is thought to be primarily caused by its a,-antagonist effect. It also has a potent antagonistic effect at the 5-HTZA,3 receptor. The combined antagonistic effects of these receptors result in an increase in norepinephrine activity, together with an increase in 5-HT1, activity. Mirtazapine also seems to lack many of the side effects of the TCAs and the SSRIs. The most common side effects are somnolence, increased appetite, and weight gain. Mirtazapine has a half-life of approximately 20 to 40 hours, so i t can be given once daily, preferably at bedtime because of its sedative effects. The initial dosage should be 15 mg/day at bedtime, with an affective range between 15 m g / d a y and 45 mg/day. No studies conducted with children and adolescents were identified by literature searches. The m a i n features of this drug are indicated in Table 7.
Table 7. MIRTAZAPINE (REMERON): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE ~
~~
Indications for use in child and adolescent psychiatry Remeron is approved for the treatment of depression in adults. The drug is not recommendedfor use in the pediatric age group because its safety and effectiveness have not been established for this age range. Dosage schedule for adults Begin dosing with 15 mglday at bedtime, effective range of 15-45 mglday Dose forms available Tablets (scored): 15 mg, 30 mg ~~
Data from Physicians Desk Reference. Montvale, NJ, Medical Economics Company, 1998, pp 1956-1 959.
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Table 8. MONOAMINE OXIDASE INHIBITORS: INDICATIONS AND DOSE SCHEDULES ~
Indications for use in child and adolescent psychiatry Phenelzine (Nardil) is not recommended for individuals under 16 years of age Tranylcypromine (Parnate) is recommended for treatment of adults with major depressive disorder episode without melancholia Dose schedule for adults Phenelzine: Initial: 15 mg three times a day. Early phase treatment: increase to at least 60 mg/day. Maintenance: decrease slowly over several weeks, may be as low as 15 mglday or every other day. Tranylcypromine: 30 mg/day in divided doses
Monoamine Oxidase Inhibitors Marketed monoamine oxidase inhibitors (MAOIs) include phenelzine (Nardil), which has been approved for use only in individuals at least 16 years of age, and tranylcypromine (Parnate), approved only for adults. MAOIs have been shown to be effective for adults with mood reactivity, irritability, hypersensitivity to rejection, hypersomnia, hyperphagia, and psychomotor agitation, collectively referred to as reversed vegetative symptoms or atypical depressive disorder. The reports indicating a risk of inducing mania in depressed bipolar patients are unsustained other than by anecdotal reports and uncontrolled studies. It may be that anergic bipolar patients respond particularly well to MAOIS.~Other MAOIs that have been used in children and adolescents include clorgyline, a selective MAO-A inhibitor, and tranyl~ypromine.~~ Green18 notes that, because of potentially serious drug interactions, the use of MAOIs in children and adolescents usually is not recommended. If they are to be used, it is important to have a minimum of a 2-week washout period after stopping an MA01 and beginning a TCA, or changing from one MA01 to another MAOI. MAOIs may interact with other drugs. Food rich in tyramines, such as cheese, wine, beer, yeast, and fava beans, must be avoided (a diet list is usually available from dietitians or pharmacists). Hypertensive crises or seizures have also been reported when MAOIs are used with TCAs and sympathomimetic drugs, such as amphetamines, methylphenidate, cocaine, dopamine, caffeine, epinephrine, norepinephrine, or similar compounds. MAOIs may also cause dizziness, sleep disturbances, sedation, fatigue, weaknesses, hyperreflexia, dry mouth, and gastrointestinal disturbances. An MA01 may be added to an ongoing treatment regimen to augment a TCA that has been only partially effective. Ryan and colleagues44reported an open trial of tranylcypromine sulfate and phenelzine sulfate, both alone and in combination with a TCA, and found that MAOIs seem to be useful in treating some adolescents with major depression who had not responded satisfactorily to TCAs; however, 30% had dietary noncompliance. Reversible MAOIs (RIMAs), with less risk for hypertensive crises (RIMAs), are marketed in Europe and Canada. These are of interest because clinical trials of moclobemide have been shown to be equal in efficacy to TCAs and fluoxetine, but, at this time, concerns about side effects have delayed their introduction in the United States (P. Keck, MD, personal communication, 1998). Details about common MAOIs are shown in Table 8.
AUGMENTATION STRATEGIES Several agents can be used for augmentation or substitution strategies in antidepressants.
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Table 9. AUGMENTATION STRATEGIES OF POTENTIAL BENEFIT IN CHILDREN OR ADOLESCENTS WHO ARE PARTIAL RESPONDERS TO SSRI MONOTHERAPY
Dosage and Issues
Medication Lithium Triiodothyronine L-Tryptophan Carbarnazepine Buspirone
Total daily dose usually 600-900 mg; may show rapid (l-week) or gradual (4-6-week) response. Total daily dose is 25-50 pg; usually shows response in 2-3 weeks Total daily dose is 1-4 g given at bedtime; usually shows a response in 3-4 weeks and may be difficult to take in tablet form Total daily dose determined by blood levels. SSRI medications may alter plasma levels Total daily dose is 20-60 mg; usually shows a delayed response of 4-6 weeks
SSRI, selective serotonin reuptake inhibitor. from Kutcher SP: Child and Adolescent Psychopharmacology. Philadelphia, WB Saunders, 1997, p 190; with permission.
As KutcheP points out, 40% to 60% of adult depressed patients who are nonresponders to initial pharmacotherapy may respond when switched to another antidepressant, such as an SSRI or (in Canada) a reversible selective MAOA-inhibiting antidepressant (RIMA). Alternatively substitution strategies may involve switching from one compound to another within a similar class (e.g., fluoxetine to paroxetine). Little substantive literature documents the effectiveness of this in children and adolescents either for SSRIs or MAOIs, and even less for the newer or nontraditional antidepressants; however, given that only 60% to 70% of children and adolescents may respond to an initial antidepressant, there is no clear way of determining whether any individual will have a positive or negative response to a particular antidepressant. This is true both within a chemical group (as in the SSRIs) and between groups of chemically dissimilar antidepressants. Hence, substitution strategies are commonly used and intuitively attractive. More research is needed in this area. Several other augmentation strategies may be of benefit to children and adolescents who are partial responders, and Table 9 suggests augmentation strategies to partial antidepressant responders, including lithium, triiodothyronine, carbamazepine, and buspirone. Other nonpharmacologic augmentation strategies include light therapy, particularly for the treatment of seasonal affective disorder. This has been incompletely evaluated in children and adolescents, although it may be useful in areas that have either long winters or inadequate periods of sunlight.41 OTHER NOVEL ANTIDEPRESSANTS
Several other novel or alternative antidepressants are being studied.27a, 31 Some of these are noted for general interest and because they may come into the United States market in the future. Other Serotonergic Antidepressants S-HT,, Partial Agonisfs These include flesinoxan, gepirone, and ipsapirone. Flesinoxan and ipsapirone are currently in phase-3 clinical trials in the United States. All compounds
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show potential antidepressant effects in animal models, and flesinoxan and ipsapirone were superior to placebo in adult studies under double-blind conditions. 5-HTMc Antagonists
These include etoperidone and mianserin, used in Europe but not available in the United States, have similar antagonist properties. Serotonin Uptake Modulators
Tianeptine, which is approved in some European countries, seems to enhance 5-HT uptake in vivo and may be useful in the treatment of depression. Citalopram is used in several countries and its manufacturer received a letter for approval from the FDA in May 1998. Combined Serotonin aqd Norepinephrine Reuptake Inhibitors These drugs combine serotonin- and norepinephrine-uptake-inhibiting effects but lack tricyclic interactions with neurotransmitter receptors. Venlafaxine (already discussed) and duloxetine (in phase3 trials in Japan) are examples of these. Novel Dopaminergic Antidepressants Drugs that directly or indirectly enhance dopamine function have also been used in the treatment of depression. These include the psychostimulantsamphetamine and methylphenidate, and the anti-Parkinson agent bromocriptine. It is of interest that facilitation of dopamine function occurs after repeated electroconvulsive therapy, but whether the antidepressant effects on dopamine are primary or secondary because of facilitation of serotonin is unknown. Drugs Affecting Dopamine Uptake and Release An example of a drug that affects dopamine uptake and release is amineptine, which is available in European countries as an atypical TCA that inhibits uptake of dopamine at lower concentrations, while at higher concentrations causes release of dopamine, norepinephrine, and serotonin.
Dopamine Receptor Agonists and Antagonists Several direct dopamine agonists have been investigated, one of which, bromocriptine, has a high incidence of adverse effects and loss of efficacy with continued administration. Interestingly, some drugs that block D2 and D1 receptors, such as sulpiride (Europe) and clozapine (United States) and are marketed as antipsychotics also have antidepressant properties.
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Novel Adrenergic Antidepressants
Only norepinephrine uptake inhibition has been consistently associated with antidepressant action in double-blind, placebo-controlled trials. Alpha-2 antagonists, including mianserin, may be useful in patients who have failed to respond to monotherapy. Other norepinephrine uptake inhibitors include tomoxetine, viloxazine, and lofepramine. Mirtazapine (Remeron) was the first a2-antagonistto be approved for use in the United States as an antidepressant, as was discussed earlier. Novel Monoamine Oxidase Inhibitors
Traditional monoamine oxidase inhibitors prevent the degradation of these neurotransmitters in the cytoplasm of the presynaptic terminal. The first true antidepressants were nonselective and irreversible inhibitors of MAO-A and MAO-B (phenelzine and tranylcypromine); however, antidepressant efficacy requires only MAO-A5, and reversible inhibitors of MAO-A (RIMA) can attenuate the potentiation of pressor responses to tyramine because MAO-A is largely responsible for tyramine degradation. “Reversible” refers to the fact that when substrate (i.e., tyramine) availability is high, the substitute can displace the RIMA from the enzyme MAO-A and still be metabolized to a degree with less potentiation of the hypertensivg action of tyramine. At least 10 new MAO-A inhibitors are under development, none of which are available in the United States. Moclobemide is the most extensively studied RIMA available in Europe and Canada. Dietary restrictions for moclobemide are much less than those of standard MAOls, and the drug may be taken after meals to lessen effects. To be effective, moclobemide must be given in very high doses, and, at these levels, it ceases to be reversible. Because of this, the introduction of moclobemide will probably be delayed in the United States (I? Keck, MD, personal communication, 1998). Several selective MAO-B inhibitors that may have antidepressant effects are under development, including selegiline. Minaprine
Minaprine is a non-TCA, launched in some European countries and in phase3 trials in the United States. It enhances dopaminergic, serotonergic, and cholinergic transmission and was found effective in one placebo-controlled study. It may potentially increase cognition in memory-impaired subjects. ADDITIONAL ALTERNATIVE ANTIDEPRESSANTS
Several other agents are under consideration that will be mentioned solely for completeness. These include phosphodiesterase inhibitors (e.g., rolipram), inositol, angiotensin-convertingenzyme inhibitors (e.g.,captopril), calcium channel modulators, glucocorticoid antagonists, and N-methyl-D-aspartic acid receptor partial agonists and antagonists. SUMMARY
This article outlines the use of alternative agents to TCAs and SSRIs. Features of the more commonly used alternative antidepressant agents are outlined.
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In addition, antidepressant agents that are currently either under development or used in other countries are indicated for completeness because it seems likely that many of these will be introduced in the United States within the next few years. Many of these agents will be used by pediatricians and child psychiatrists for treatment of depression in children, and although much further research is needed, the future for alternative antidepressants and augmenting strategies is extremely promising. References 1. Ambrosini P, Bianchi M, Rabinovich H, et al: Antidepressant treatments of affective disorders. J Am Acad Child Adolesc Psychiatry 32:l-6, 1993 la. Amrein R, Hetzel N, Stab1 M, et al: R I M A A safe concept in the treatment of depression with moclobemide. Can J Psychiatry 37(suppl 1):7-11, 1992 2. Baldwin DS, Hawley CJ, Abed RT, et al: A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression. J Clin Psychiatry 57(supp1)2:46-52, 1996 3. Birmaher B, Ryan ND, Williamson DE, et al: Childhood and adolescent depression: A review of the past 10 years: Part 11. J Am Acad Child Adolesc Psychiatry 3515751583, 1997 4. Boulos C, Kutcher S, Gardner D, et al: An open-naturalistic trial of fluoxetine in adolescents and young adults with treatment-resistant major depression. J Child Adolesc Psychopharmacol2:103-111, 1992 5. Burke MJ, Preskom S H The short-term treatment of mood disorders with standard antidepressants. In Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, 1995, pp 1053-1141 6 . Casat CD, Pleasants DZ, Schroeder DH, et al: Bupropion in children with attention deficit disorder. Psychopharmacol Bull 25:198-201, 1989 7. Casat CD, Pleasants DZ, Van Wyck Fleet J: A double-blind trial of bupropion in children with attention deficit disorder. Psychopharmacol Bull 23120-122, 1987 8. Cioli V, Corradino C, Piccinelli D, et a1 A comparative pharmacological study of trazodone, etoperidone, and I-(m-chloropheny1)piperazine.Pharmacol Res Commun 1685-100, 1984 9. Clay TH, Gualtieri CT, Evens RW, et al: Clinical and neuropsychological effects of the novel antidepressant bupropion. Psychopharmacol Bull 24143-148, 1988 9a. Coffey BJ: Anxiolytics for children and adolescents: Traditional and new drugs. J Child Adolesc Psychopharmacol 1:57-83, 1990 10. Conners CK, Casat CD, Gualtieri CT, et al: Bupropion hydrochloride in attentiondeficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 35313141321, 1996 11. Davis R, Whittington R, Bryson H Nefazodone: A review of its pharmacology and clinical efficacy in the management of major depression. Drugs 53:608-636, 1997 12. Emslie G, Rush AJ, Weinberg AW, et al: A double-blind, randomized, placebocontrolled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry, 541031-1037, 1997 13. Feiger A, Kiev A, Shrivastava RK, et a1 Nefazodone versus sertraline in outpatients with major depression: Focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry 57(Suppl 2):53-62, 1996 14. Feighner JP, Boyer W F Overview of USA controlled trials of trazodone in clinical depression. Psychopharmacol Bull 95(suppl):50-53,1988 15. Findling RL, Magnus RD, Preskorn SH, et al: Open pharmacokinetic study of nefazodone in children and adolescents with depression [abstract no. NR-961. 44th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Toronto, October 1997 16. Fras I: Trazadone and violence [letter]. J Am Acad Child Adolesc Psychiatry 26453, 1987
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17. Geller B: Commentary on unexplained deaths of children on Norpramin. J Am Acad Child Adolesc Psychiatry 30682-684,1991 . 18. Green HG: Child and Adolescent Clinical Psychopharmacology. Baltimore, MD, Williams & Wilkins, 1995 19. Hazel1 P, O’Connell D, Heathcote D, et al: Efficacy of tricyclic drugs in treating child and adolescent depression: A meta-analysis. Br Med J 3102397-901, 1995 20. Jensen PS, Elliott GR (eds): Why don’t antidepressants seem to work for depressed adolescents? J Child Adolesc Psychopharmacology 2:745, 1992 21. Josh PT, Walkup JT, Capozzoli JA, et al: The use of fluoxetine in the treatment of major depressive disorder in children and adolescents [abstract]. Annual Meeting of the American Academy of Child and Adolescent Psychiatry, San Francisco, October 1991 22. Kashani J, Carlson G, Beck N Depression, depressive symptoms and depressed mood in a community sample of adolescents. Am J Psychiatry 144:931-934, 1987 23. Kovacs M, Feinberg TL, Crouse-Novak M, et al: Depressive disorder in childhood: 11. A longitudinal study of the risk for a subsequent major depression. Arch Gen Psychiatry 41: 643-649, 1984 24. Kutcher SP: Child and Adolescent Psychopharmacology. Philadelphia, WB Saunders, 1997 25. McConville BJ, Minnery KL, Sorter MT, et a1 An open study of the effects of sertraline on adolescent major depression. J Child Adolesc Psychopharmacol641-51, 1996 26. Mandoki MW, Tapia MR, Tapia MA, et al: Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacol Bull 33:149-154, 1997 27. Metz A, Shader RI: Adverse interactions encountered when using trazodone to treat insomnia associated with fluoxetine. Int Clin Psychopharmacol5:191-194, 1990 27a. Murphy DC, Mitchell PB, Potter WZ: Novel pharmacological approaches to the treatment of depression. In Bloom FE, Kupfer DJ (eds): Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, 1995, pp 1143-1153 28. National Institute of Mental Health: CGI (Clinical Global Impressions) scale. Psychopharmacol Bull 21:839-843, 1985 29. Nee1 E: Preventable sudden death: The ”long Q-T syndrome.” J Adolesc Health Care 2:49-51, 1981 30. Pescatori ES, Engelman JC, Davis G, et al: Priapism of the clitoris: A case report following trazodone use. J Urol 149:1557-1559, 1993 31. Pharmaprojects: CD v2.0 PJB Publications Ltd, Richmond, Surrey, UK, 1997 32. Popper CW, Elliott G: Sudden death and tricyclic antidepressants: Clinical considerations for children. J Child Adolesc Psychopharmacol 1:125-132, 1990 33. Popper CW, Zimnitzky B: Sudden death putatively related to desipramine treatment in youth A fifth case and a review of speculative mechanisms. J Child Adolesc Psychopharmacol5:283-300, 1995 34. Post RM: Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999-1010, 1992 35. Poznanski EO, Cook SC, Carroll BJ, et al: Use of the children’s depression rating scale in an inpatient psychiatric population. J Clin Psychiatry 44:200-203, 1983 36. Poznanski EO, Freeman LN, Mokros HB: Children’s Depression Rating Scale-Revised. Psychopharmacol Bull 21:979-990, 1985 37. Puig-Antich J, Goetz D, Davies M, et a 1 A controlled family history study of prepubertal major depressive disorder. Arch Gen Psychiatry 46:406-420, 1988 38. Riddle MA, Geller 8, Ryan N Another sudden death in a child treated with desipiramine. J Am Acad Child Adolesc Psychiatry 32:792-797, 1993 39. Riddle MA, Nelson J, Kleinman C, et al: Sudden death in children receiving Norpramin: A review of three reported cases and commentary. J Am Acad Child Adolesc Psychiatry 30104-108, 1991 40. Rioux P, Kibleur Y, Frachon 0, et al: A double-blind comparison of nefazodone and fluoxetine in depressed patients [abstract no. NR3591. 149th Meeting of the American Psychiatric Association, New York, 1996 41. Rosenthal NE, Carpenter CJ, James SP, et al: Seasonal affective disorder in children and adolescents. Am J Psychiatry 143:35&358, 1986
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42. Ryan ND: Heterocyclic antidepressants in children and adolescents. J Child Adolesc Psychopharmacol 121-31, 1990 43. Ryan ND, Puig-Antich J: Affective illness in adolescence. In Frances AJ, Hales RE (eds): Annual Review of the American Psychiatric Association. Washington, DC, American Psychiatric Press, 1986, pp 420450 44. Ryan ND, Puig-Antich J, Rabinovich H, et al: MAOIs in adolescent major depression unresponsive to tricyclic antidepressants. J Am Acad Child Adolesc Psychiatry 27755-758, 1988 45. Simeon JG: Buspirone effects in adolescent psychiatric disorders. Eur Neuropsychopharmacol 1:421,1991 45a. Simeon J, Dinicola V, Ferguson H, et al: Adolescent depression: A placebo-controlled fluoxetine treatment study and follow-up. Prog Neuropsychopharm Biol Psychiatr 14:791-795, 1990 46. Simeon JG, Ferguson HB, Fleet JVW Bupropion effects in attention deficit and conduct disorder. Can J Psychiatry 31:581-585, 1986 47. Spencer T, Biederman J, Steingard R, et a1 Bupropion exacerbates tics in children with attention-deficit hyperactivity disorder and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 32%-214, 1993 48. Stimmel GL, Dopheide JA, Stahl SM: Mirtazapine: An antidepressant with noradrenergic and specific serotonergic effects. Pharmacotherapy 1710-21, 1997 49. Stoll AL, Mayer PV, Kolbrener M, et al: Antidepressant-associated mania: A controlled comparison with spontaneous mania. Am J Psychiatry: 151:1642-1645,1994 50. Strober M Effects of imipramine, lithium, and fluoxetine in the treatment of adolescent major depression [abstract]. Annual Meeting, New Clinical Drug Evaluation Unit (NCDEU), National Institute of Mental Health, Washington, DC, May 1989 50a. United States Pharmacopeia Dispensing Information: Drug Information for the Health Care Professional. Rockville, MD, US Pharmacopeial Convention, 1997, p 2891 51. Weller E, Weller R Mood disorders. In Lewis M (ed): Child and Adolescent Psychiatry: A Comprehensive Approach. Baltimore, Williams & Wilkins, 1995, pp 6.50465 52. Werry J S The safety of desipramine [letter]. J Am Acad Child Adolesc Psychiatry 33~588-589,1994 53. Zametkin AJ, Rapoport JL: Noradrenergic hypothesis of attention-deficit disorder with hyperactivity: A critical review. In Meltzer HY (ed): Psychopharmacology: The Third Generation of Progress. New York, Raven, 1987, pp 837-842 54. Zubieta JK, Alessi NE: Acute and chronic administration of trazodone in the treatment of disruptive behavior disorders in children. J Clin Psychopharmacol12:346-351,1992
Address reprint requests to Brian J. McConville, MD Department of Psychiatry University of Cincinnati College of Medicine 231 Bethesda Avenue Cincinnati, OH 45267-0559
0031-3955/98 $8.00
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NEWER ANTIDEPRESSANTS Beyond Selective Serotonin Reuptake Inhibitor Antidepressants Brian J. McConville, MD, Robert 0. Chaney, BS, Kerri L. Browne, BS, Loren Friedman, MS, Elizabeth Cottingham, MD, and Dan Nelson, MD
. Major depressive disorder in children and adolescents is a significant problem and is also a predictive indicator of severe long-term difficulties.z2,43 Although the phenomenology of child and adolescent depression versus adult depression is held to be child and adolescent depression has not been shown to clearly respond to treatment with tricyclic antidepressants (TCAs) in double-blind studies. More evidence may be available for children than for adolescents.'", 19, 42 These generally negative findings have been reviewed,2O and the sudden unexplained deaths in children receiving desipraminez9,32, 33, 39 have caused widespread concern about use of TCAs in children and adolescents. Citing the lack of rigorous scientific evidence supporting the superiority of TCAs in child and adolescent depression compared with placebo, along with these sudden unexplained deaths, Geller" and W e r r ~ have ~ ~expressed concern about the routine use of TCAs in children and adolescents. As noted in the article by Labellarte and colleagues elsewhere in this issue, the emergence of selective serotonin reuptake inhibitors (SSRIs) has allowed for further psychopharmacologic methods for treating child and adolescent depression. Fluoxetine, fluvoxamine, sertraline, and paroxetine have been found in open studies to provide effectiveantidepressant activity without the sedating, anticholinergic, or cardiotoxic reactions observed with TCAs, although the incidence of insomnia, nervousness, restlessness, and anxiety are higher?, 21, 50 McConville and colleagues= found positive effects for sertraline in treating major depressive disorder in adolescents and also noted that scale ratings of depression frequently varied, being worsened by adverse events and improved by positive From the Department of Psychiatry, University of Cincinnati College of Medicine (BJM, ROC, KB, LF); and the Division of Psychiatry, Children's Hospital Medical Center (EC, DN), Cincinnati, Ohio
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life circumstances. There may also be an emergence of an endogenous component in early childhood and adolescence, either as a pure syndrome or following repeated ~ t r e s s o r sIf. ~repeated ~ stressors can be shown to lead to a nonreactive pattern, a strong argument can be made for early psychopharmacologic and psychotherapeutic intervention in children and adolescents with major depressive disorders and double depressions (eg., dysthymia and major depressive disorder). Follow-up of child and adolescent depressives suggests that these disorders can become long-term, causing debilitating problems, including not only depression but also impairment in psychosocial and educational functioning.", 37 A few double-blind studies on SSRIs in child and adolescent depression have been conducted. Simeon and colleague^^'^ did not find statistically significant differences between fluoxetine versus placebo for depression; however, in an important study by Emslie and colleagues,'z in which 96 children and adolescents were treated with either fluoxetine or placebo, a significant difference was found among treated and untreated groups on the Children's Depression Rating Scale Revised36and the Clinical Global Impression Scale for depression.**In this study, placebo effect was similar to drug effect in the first week of outpatient treatment; however, over the 8-week period of the trial, significant differences emerged in the criteria noted earlier.3 Therefore, a significant difference in efficacy may exist among drug versus placebo studies for both TCAs and SSRIs in depressed children and adolescents provided that a sufficiently largc?sample is used in studies to indicate differences between placebo and drug response. In addition, careful measurements must be taken both within single centers and between centers to ensure inter-rater reliability. Although the current clinical preference is to use SSRIs rather than TCAs in the treatment of child and adolescent depression, the hard evidence for efficacy from controlled studies is minimal. Moreover, a connection between the clinical effectiveness of these medications and their degree of serotonin reuptake inhibition seems to be lacking. Further studies of the "traditional" TCAs and SSRIs are needed, including multidose studies of SSRIs in children and adolescents with depressive disorders; however, also needed is more exploration of newer or alternate antidepressive agents. The following section begins with an overview of these compounds and leads into a discussion of the most common alternate antidepressants used by practitioners, as well as some newer developments. BEYOND THE SELECTIVE SEROTONIN REUPTAKE INHIBITORS: ALTERNATIVE ANTIDEPRESSANTS Many alternative antidepressants to the TCAs and SSRIs are either being developed or are in use. Historically, as is common in psychopharmacology, the early antidepressants were discovered by chance. Tricyclic antidepressants were developed in hopes of developing antipsychotics, and monoamine oxidase inhibitors (MAOIs) were found while investigating antitubercular drugs. Since then, the evolution of antidepressants and other psychopharmacologic agents has gone to a more rational drug design involving molecular targeting for "designer drugs." Because all pharmacologic agents have many actions-both wanted and unwanted-one of the goals of newer drug development has been to produce agents with improved tolerability and safety. But drugs with a more specific spectrum of clinical activity may also have a more limited range of actions. In addition, depression does not necessarily represent a particular pattern of either psychopathology or pathophysiology; rather, it probably represents a heteroge-
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Table 1. GENERAL CLASSIFICATION OF ANTIDEPRESSANT PHARMACOTHERAPY BY PRESUMED MECHANISM OF ACTION
Classfication
Examples
Mixed serotonin effects--BHT, receptor antagonism Mixed NE/DA reuptake inhibitors Monoamine oxidase inhibitors Irreversible Reversible Mixed NWS-HT reuptake inhibitors Selective serotonin reuptake inhibitors
Phenylpiperazines,such as trazodone, nefazodone Aminoketones, such as bupropion Phenelzine, tranylcypromine, moclobemide TCAs, venlafaxine Fluoxetine, sertraline, paroxetine, fluvoxamine
5-HT, serotonin; NE, norepinephrine; DA, dopamine; TCAs, tricyclic antidepressants. From Burke MJ, Preskorn SH: Short-term treatment of mood disorders with standard antidepressants. In Bloom FE, Kupfer DJ (eds): The Fourth Generation of Progress. New York, Raven Press, 1995, p 1054; with permission.
neous group of conditions. In general, the TCAs, which are mixed norepinephrine and SSRIs, can be seen as being at one end of a spectrum, and the SSRIs can be seen as being at thepther end in terms of specific neurotransmitter action. In adult studies, some data suggest that those who fail to respond to TCAs may respond to SSRIs and vice versa.5No such comparisons have been performed in children and adolescents, largely because of the limited number of antidepressant trials performed in the pediatric population. Even in this era, when multiple analogs of a basic antidepressant may be synthesized, chemical structure by itself does not necessarily determine function. The SSRIs, for example, have very different chemical structures, and no clear relationship exists between the molecular structure, function, and psychobiologic activity of a particular agent (C. McDougle, MD, personal communication, 1998), a point that should be considered as newer compounds are investigated. Considering the neurotransmitter mechanisms of antidepressant action may be a more useful approach than the study of chemical structure? Although the connection between the mechanisms of neurotransmitter action and antidepressant response is still largely hypothetical, for heuristic purposes, this approach has been widely used. Table 1 indicates such a classification of antidepressant pharmacotherapy by presumed mechanism of action.
Common Alternate or Atypical Agents The most frequently used atypical antidepressants include: Trazodone (Desyrel), a 5-HT2, antagonist, SSm Nefazodone (Serzone), a 5-HT2, antagonist, norepinephrine and serotonin reuptake inhibitor Bupropion (Wellbutrin), a norepinephrine and dopamine reuptake inhibitor Venlafaxine (Effexor), a norepinephrine and serotonin reuptake inhibitor Buspirone (Buspar), a 5-HTln agonist Mirtazapine (Remeron), an a,-antagonist and 5-HT2,,, antagonist Monoamine oxidase inhibitors, which inhibit degradation of serotonin, norepinephrine, and dopamine Two basic texts for most of these medications and their use in child and adolescent clinical pharmacology are Child and Adolescent Clinical Psychopharma-
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coIogy (Green HG, Williams & Wilkins, 1995)Is and Child and AdoIescent Psychophavmacology (Kutcher SP, WB Saunders, 1997).24 Trazodone
Trazodone (Desyrel) is different from the TCAs and tetracyclic antidepressants in terms of its novel structure and differing pharmacologic effects.8 In animals, trazodone selectively inhibits serotonin reuptake in the brain and has an antagonistic effect at 5-HT2Areceptors. It is recommended that trazodone be taken soon after eating because as much as 20% more drug may be absorbed than when taken on an empty stomach. The maximum serum concentration is also achieved more slowly and with a lesser peak so that there is less risk for dizziness and lightheadedness. Trazodone is eliminated through the liver and kidneys, with an initial half-life between 3 and 6 hours, and with the second phase between 5 and 9 hours. Increased phenytoin levels have been reported when this is administered along with trazodone, and trazodone should also not be administered with MAOIs because the effect of their interaction is not known but may result in hypertensive crises. The most common side effetts are drowsiness, or lightheadedness, dry mouth, nausea, and vomiting. Priapism, which can necessitate surgical intervention and has resulted in some cases of permanent impairment of sexual function, has been reported with an incidence of about 1 in 15,000 patients. Trazodone-treated patients with prolonged or inappropriate erections must be informed to discontinue the trazodone; contact their physician; and, if erections persist, go to an emergency room, where medical or possible surgical intervention may be required. One case of trazodone-induced priapism of the clitoris has been reported.30 The indications for trazodone use in child and adolescent psychiatry are shown in Table 2. Trazodone given in children and adolescents for depression has not been reported, although some reports exist of it being used in the treatment of Table 2. TRAZODONE (DESYREL): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE
Indications for use in child and adolescent psychiatry Trazodone is approved only for the treatment of major depressive disorder in individuals at least 18 years of age. The drug is not recommended for use in the pediatric age group because its safety and effectiveness have not been established for this age range. Dosage schedule for children and adolescents USPDI (1992) reports the following pediatric doses guidelines when trazodone is used as an antidepressant: Children under 6 years of age: Dosage not determined. Children 6 to 18 years of age: Begin with 1.5-2 mg/kg/day in divided doses. Titrate dosage gradually at 3-to 4-day intervals to a maximum of 6 mglkglday. Dose forms available Tablets: 50 mg scored, 100 mg scored Divided-dose tablets: 150 mg and 300 mg (both tablets scored to divide into three equal parts) USPDI, United States Pharmacopeia Dispensing from Green HG: Child and Adolescent Clinical Psychopharmacology. Williams & Wilkins, 1995, p 178; with permission.
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children and adolescents for aggression.16, 54 In an overview of trazodone trials in adults in the United States, Feighner and BoyerI4 suggested that trazodone should be considered for depressed patients with anxiety, insomnia, marked agitation, and the inability to tolerate anticholinergic side effects. One common use of this medication is for sedation, and this is particularly useful in depressed female children and adolescents, with its use in male children and adolescents being more problematic for obvious reasons. Metz and Shader27reported excessive sedation when using low doses of trazodone (25-75 mg) in adults to treat insomnia associated with fluoxetine. Nefazodone Nefazodone (Serzone) is a potent inhibitor of the postsynaptic 5-HT2*receptor and a moderate inhibitor of serotonin and norepinephrine reuptake." One open-label study exists of the pharmacokinetics of nefazodone in children (aged 7-12 years) and adolescents (aged 12-17 years) conducted by Findling and colleag~es.~~ During the 8-week trial, subjects were started at 50 mg twice a day and titrated to a maximum daily dosage of 300 mg/day for children and 600 mg/day for adolescents. The authors found nefazodone to be safe and well tolerated at these doses, with a similar biodisposition to that of adults and an improvement in depressive symptoms sufficiently significant to indicate further controlled trials. Some of the more common side effects are dry mouth, nausea, constipation, dizziness, confusion, and blurred vision; however, nefazodone does seem to have a lower incidence of sexual dysfunction, gastrointestinal disturbances, and activating symptoms than do SSRIs. It is also important to note that priapism is less of a concern with nefazodone as it is with trazodone. The more common features are shown in Table 3. Several clinical trials have been performed comparing nefazodone with placebo, TCAs, and SSRIs in the treatment of major depression in adults. Six studies in adults have been performed, showing that nefazodone has significantly greater efficacy than does placebo." Four of these studies have shown equal efficacy to imipramine." Baldwin and colleagues' showed efficacy equivalent to paroxetine, Feiger and colleague^'^ showed the same with sertraline, and Rioux and colleagues4oshowed that nefazodone was equivalent to fluoxetine in efficacy. Table 3. NEFAZODONE (SERZONE): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE Indications for use in child and adolescent psychiatry Nefazodone is approved for the treatment of depression disorder in individuals at least 18 years of age. The drug is not recommended for use in the pediatric are group because its safety and effectiveness have not been established for this age range. Dose schedule for children and adolescents Begin dosing with 50 mg twice a day and titrate to an effective dose by 50 mg every 3 days. Maximum dose for children under 12 years of age should not exceed 300 mgl day and 600 mg/day for those 12 years and older. Dose forms available Tablets: 100 mg and 150 mg bisect scored on both tablet faces, 200 mg and 250 mg unscored Data from Findling RL, Magnus RD, Pieskorn SH,et al: Open pharmacokinetic study of nefazodine in children and adolescents with depression [abstract no. NR-961. 44th Annual Meeting of the American Academy of Childhood and Adolescent Psychiatry, Toronto, October 1997
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Bupropion
Bupropion (Wellbutrin) is in the aminoketone class of antidepressants and has not been approved for use in children and adolescents. It is, however, fairly widely used clinically, and the indications are shown in Table 4. The major concern with the use of bupropion is that seizures occur in 0.4% of patients at doses of 450 mg/day or more, and this is about four times the incidence of seizures with other approved antidepressants. The incidence of seizures increased with higher daily doses. The most common side effects include agitation, dry mouth, insomnia, headache, nausea, vomiting, constipation, and tremor. Other side effects may include akasthisia, skin rash, tachycardia, and dizziness; however, bupropion does not have a negative effect on memory performance, in contrast to several other antidepressants. One clinical feature is that bupropion may tend to lose its antidepressant effectiveness over time, although the evidence for this is unclear. At least three studies indicate the use of this compound in children and adolescents.6,7,10 In adults, bupropion has been shown to be effective in patients who are not responders to TCAs and has been found useful in the treatment of primary depression but not necessarily in depression secondary to anxiety or panic disorder? Casat and colleagues> have conducted two trials using bupropion in ADHD. Conners and colleagues10found that bupropion may be a useful addition to the curren6 medications available to treat ADHD. In a retrospective analysis, Spencer and colleagues47indicated that bupropion, like psychostimulants, exacerbated tics in the treatment of comorbid ADHD and chronic motor tic disorder or Tourette syndrome. Stoll and colleagues49brought up concerns that bupropion can induce rapid cycling or an affective shift to mania, and that it may be associated with milder states of mania compared with TCAs and fluoxetine. Vedafaxine
Venlafaxine (Effexor) has been reported to have a rapid onset, and few studies have been performed in children and adolescents. The overall effect is inhibition of both norepinephrine and serotonin reuptake. Doses are 25 mg Table 4. BUPROPION (WELLBUTRIN): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE Indications in child and adolescent psychiatry Bupropion is not approved for any use in children and adolescents under age 18 years. Adolescents at least 18 years of age: used to treat depression, especially major depressive disorder. Dosage schedule for children and adolescents Children and adolescents under 18 years of age: Not recommended. Adolescents at least 18 years of age: An initial dosage of 100 mg twice daily is suggested. Based on clinical response, this may be increased to 100 mg three times daily but not before day 4 of treatment. If no clinical improvement occurs within 4 weeks, dosage may gradually be increased. Because of increased risk for seizure, a dose of 150 mg should not be exceeded within a 4-hour time period. The maximum daily dosage should not exceed 450 mg. Dose forms available Tablets: 75 mg, 100 mg From Green HG: Child and Adolescent Clinical Psychopharmacology.Baltimore, MD, Williams 8 Wilkins, 1995, p 181: with permission.
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titrated toward 200 mg/day in the ordinary preparation, and an extended release form has recently been introduced that requires only once daily dosing of either the 37.5 mg/day, 75.0 mg/day, or 150.0 mg/day. Mandoki and colleaguesz6 recently completed a double-blind, placebo-controlled study of venlafaxine and psychotherapy versus placebo and psychotherapy. Although both groups showed cliiical improvement, no significant difference was found among drug and placebo groups. In addition, the authors also found no evidence to indicate a rapid-onset effect. They did make an important point that the study duration of 6 weeks may not have been long enough and that the low dosages of venlafaxine (37.5 mg for children aged 8-12 years and 75 mg for adolescents aged 13-17 years) may also have been a factor in the nonresponse. The main features of this medication are shown in Table 5. Buspirone Buspirone (BuSpar) is essentially an anxiolytic with some antidepressant properties. Buspirone has a high affinity for the 5-HT1, serotonin receptor. It does not have cross-tolerancewith the benzodiazepines, does not suppress panic attacks, and lacks anticonvulsant activity. At therapeutic doses, buspirone is less sedating than the benzodiazepines. Buspirone has been approved by the FDA as clinically effective for the management of anxiety disorders or the short-term relief of the symptom%of anxiety. Peak plasma levels occur between 40 and 90 minutes after an oral dose of buspirone. The elimination half-life of buspirone after a 10-mg to 40-mg dose is usually between 2 and 3 hours. Adverse effects include dizziness, drowsiness, nausea, headache, insomnia, and lightheadedness. It may be given in dosages of 15 mg/day to 30 mg/day, divided into either twice-a-day or thrice-a-day dosing. The major features of this medication are shown in Table 6. Simeon and colleagues4" reported the use of buspirone in 13 adolescents and adults aged 12 to 20 years (mean age, 16 years), with various diagnoses, including five with either anxiety or depressive di~orders.~ Improvements in mood were reported, but clear correlation between improvement and diagnosis was not shown. Table 5. VENLAFAXINE (EFFEXOR): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE ~~~~~~~~~~~~~~~~~~~~~~
~
~~~
~~~~~~~~~
Indications for use in child and adolescent psychiatry Venlafaxine is approved for the treatment of depression in individuals at least 18 years of age. The drug is not recommended for use in the pediatric age group because its safety and effectiveness have not been established. Dosage schedule for children and adolescents For children aged 8-12 years, begin at 12.5 rng/day for 3 days, increase to 12.5 mg twice a day for the next 3 days, and then increase again to 12.5 rng three times a day as required. For adolescents aged 13-17 years, begin at 25 rng/day for 3 days, increase to 25 rng twice a day for the next 3 days, and then increase again to 25 mg three times a day. These doses may need to be increased further for maximum efficacy. (These recommendations are based on current literature findings.) Dose forms available Tablet: 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg Data from Mandoki MW, Tapia MR, Tapia MA, et al: Venlafaxine in the treatment of children and adolescents with major depression. PsychopharmacolBiol 33:149-I 54, 1997
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Table 6. BUSPIRONE (BUSPAR): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE
FORMS Indications in child and adolescent psychiatry Buspirone is approved only for treatment of anxiety disorders and the short-term relief of anxiety in individuals at least 18 years of age. Its safety and efficacy in children and adolescents remain to be determined. Its antidepressant activities are unclear. Dosage schedule for treating anxiety Children and adolescents: Not approved. Coffeysa,however, has cautiously suggested the following doses if a clinician elects to use buspirone in this age group. Prepubescent children: an initial dose of 2.5-5.0 mg with increases of 2.5 mg every 3 or 4 days to a maximum of 20 mglday. Adolescents: An initial dose of 5-10 mg with increases of 5-10 mg every 3 to 4 days to a maximum of 60 mglday. Persons 18 years of age and older: Initiate treatment with 5 mg three times daily. Titrate to optimal therapeutic response by increases of 5 mg every 2 or 3 days to a maximum daily dose of 60 mg. Usual optimal doses in clinical trials were 20-30 mglday in divided doses. Dose forms available Tablets (scored): 5 mg, 10 mg From Green HG: Child and Adolesceit Clinical Psychopharmacology. Baltimore, MD, Williams & Wilkins, 1995, p 216; with permission.
Mirtazapine Stimmel and colleagues4* described mirtazapine (Remeron), a n e w l y introduced antidepressant, the activity of w h i c h is thought to be primarily caused by its a,-antagonist effect. It also has a potent antagonistic effect at the 5-HTZA,3 receptor. The combined antagonistic effects of these receptors result in an increase in norepinephrine activity, together with an increase in 5-HT1, activity. Mirtazapine also seems to lack many of the side effects of the TCAs and the SSRIs. The most common side effects are somnolence, increased appetite, and weight gain. Mirtazapine has a half-life of approximately 20 to 40 hours, so i t can be given once daily, preferably at bedtime because of its sedative effects. The initial dosage should be 15 mg/day at bedtime, with an affective range between 15 m g / d a y and 45 mg/day. No studies conducted with children and adolescents were identified by literature searches. The m a i n features of this drug are indicated in Table 7.
Table 7. MIRTAZAPINE (REMERON): INDICATIONS, DOSAGE SCHEDULE, AND DOSAGE FORMS AVAILABLE ~
~~
Indications for use in child and adolescent psychiatry Remeron is approved for the treatment of depression in adults. The drug is not recommendedfor use in the pediatric age group because its safety and effectiveness have not been established for this age range. Dosage schedule for adults Begin dosing with 15 mglday at bedtime, effective range of 15-45 mglday Dose forms available Tablets (scored): 15 mg, 30 mg ~~
Data from Physicians Desk Reference. Montvale, NJ, Medical Economics Company, 1998, pp 1956-1 959.
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Table 8. MONOAMINE OXIDASE INHIBITORS: INDICATIONS AND DOSE SCHEDULES ~
Indications for use in child and adolescent psychiatry Phenelzine (Nardil) is not recommended for individuals under 16 years of age Tranylcypromine (Parnate) is recommended for treatment of adults with major depressive disorder episode without melancholia Dose schedule for adults Phenelzine: Initial: 15 mg three times a day. Early phase treatment: increase to at least 60 mg/day. Maintenance: decrease slowly over several weeks, may be as low as 15 mglday or every other day. Tranylcypromine: 30 mg/day in divided doses
Monoamine Oxidase Inhibitors Marketed monoamine oxidase inhibitors (MAOIs) include phenelzine (Nardil), which has been approved for use only in individuals at least 16 years of age, and tranylcypromine (Parnate), approved only for adults. MAOIs have been shown to be effective for adults with mood reactivity, irritability, hypersensitivity to rejection, hypersomnia, hyperphagia, and psychomotor agitation, collectively referred to as reversed vegetative symptoms or atypical depressive disorder. The reports indicating a risk of inducing mania in depressed bipolar patients are unsustained other than by anecdotal reports and uncontrolled studies. It may be that anergic bipolar patients respond particularly well to MAOIS.~Other MAOIs that have been used in children and adolescents include clorgyline, a selective MAO-A inhibitor, and tranyl~ypromine.~~ Green18 notes that, because of potentially serious drug interactions, the use of MAOIs in children and adolescents usually is not recommended. If they are to be used, it is important to have a minimum of a 2-week washout period after stopping an MA01 and beginning a TCA, or changing from one MA01 to another MAOI. MAOIs may interact with other drugs. Food rich in tyramines, such as cheese, wine, beer, yeast, and fava beans, must be avoided (a diet list is usually available from dietitians or pharmacists). Hypertensive crises or seizures have also been reported when MAOIs are used with TCAs and sympathomimetic drugs, such as amphetamines, methylphenidate, cocaine, dopamine, caffeine, epinephrine, norepinephrine, or similar compounds. MAOIs may also cause dizziness, sleep disturbances, sedation, fatigue, weaknesses, hyperreflexia, dry mouth, and gastrointestinal disturbances. An MA01 may be added to an ongoing treatment regimen to augment a TCA that has been only partially effective. Ryan and colleagues44reported an open trial of tranylcypromine sulfate and phenelzine sulfate, both alone and in combination with a TCA, and found that MAOIs seem to be useful in treating some adolescents with major depression who had not responded satisfactorily to TCAs; however, 30% had dietary noncompliance. Reversible MAOIs (RIMAs), with less risk for hypertensive crises (RIMAs), are marketed in Europe and Canada. These are of interest because clinical trials of moclobemide have been shown to be equal in efficacy to TCAs and fluoxetine, but, at this time, concerns about side effects have delayed their introduction in the United States (P. Keck, MD, personal communication, 1998). Details about common MAOIs are shown in Table 8.
AUGMENTATION STRATEGIES Several agents can be used for augmentation or substitution strategies in antidepressants.
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Table 9. AUGMENTATION STRATEGIES OF POTENTIAL BENEFIT IN CHILDREN OR ADOLESCENTS WHO ARE PARTIAL RESPONDERS TO SSRI MONOTHERAPY
Dosage and Issues
Medication Lithium Triiodothyronine L-Tryptophan Carbarnazepine Buspirone
Total daily dose usually 600-900 mg; may show rapid (l-week) or gradual (4-6-week) response. Total daily dose is 25-50 pg; usually shows response in 2-3 weeks Total daily dose is 1-4 g given at bedtime; usually shows a response in 3-4 weeks and may be difficult to take in tablet form Total daily dose determined by blood levels. SSRI medications may alter plasma levels Total daily dose is 20-60 mg; usually shows a delayed response of 4-6 weeks
SSRI, selective serotonin reuptake inhibitor. from Kutcher SP: Child and Adolescent Psychopharmacology. Philadelphia, WB Saunders, 1997, p 190; with permission.
As KutcheP points out, 40% to 60% of adult depressed patients who are nonresponders to initial pharmacotherapy may respond when switched to another antidepressant, such as an SSRI or (in Canada) a reversible selective MAOA-inhibiting antidepressant (RIMA). Alternatively substitution strategies may involve switching from one compound to another within a similar class (e.g., fluoxetine to paroxetine). Little substantive literature documents the effectiveness of this in children and adolescents either for SSRIs or MAOIs, and even less for the newer or nontraditional antidepressants; however, given that only 60% to 70% of children and adolescents may respond to an initial antidepressant, there is no clear way of determining whether any individual will have a positive or negative response to a particular antidepressant. This is true both within a chemical group (as in the SSRIs) and between groups of chemically dissimilar antidepressants. Hence, substitution strategies are commonly used and intuitively attractive. More research is needed in this area. Several other augmentation strategies may be of benefit to children and adolescents who are partial responders, and Table 9 suggests augmentation strategies to partial antidepressant responders, including lithium, triiodothyronine, carbamazepine, and buspirone. Other nonpharmacologic augmentation strategies include light therapy, particularly for the treatment of seasonal affective disorder. This has been incompletely evaluated in children and adolescents, although it may be useful in areas that have either long winters or inadequate periods of sunlight.41 OTHER NOVEL ANTIDEPRESSANTS
Several other novel or alternative antidepressants are being studied.27a, 31 Some of these are noted for general interest and because they may come into the United States market in the future. Other Serotonergic Antidepressants S-HT,, Partial Agonisfs These include flesinoxan, gepirone, and ipsapirone. Flesinoxan and ipsapirone are currently in phase-3 clinical trials in the United States. All compounds
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show potential antidepressant effects in animal models, and flesinoxan and ipsapirone were superior to placebo in adult studies under double-blind conditions. 5-HTMc Antagonists
These include etoperidone and mianserin, used in Europe but not available in the United States, have similar antagonist properties. Serotonin Uptake Modulators
Tianeptine, which is approved in some European countries, seems to enhance 5-HT uptake in vivo and may be useful in the treatment of depression. Citalopram is used in several countries and its manufacturer received a letter for approval from the FDA in May 1998. Combined Serotonin aqd Norepinephrine Reuptake Inhibitors These drugs combine serotonin- and norepinephrine-uptake-inhibiting effects but lack tricyclic interactions with neurotransmitter receptors. Venlafaxine (already discussed) and duloxetine (in phase3 trials in Japan) are examples of these. Novel Dopaminergic Antidepressants Drugs that directly or indirectly enhance dopamine function have also been used in the treatment of depression. These include the psychostimulantsamphetamine and methylphenidate, and the anti-Parkinson agent bromocriptine. It is of interest that facilitation of dopamine function occurs after repeated electroconvulsive therapy, but whether the antidepressant effects on dopamine are primary or secondary because of facilitation of serotonin is unknown. Drugs Affecting Dopamine Uptake and Release An example of a drug that affects dopamine uptake and release is amineptine, which is available in European countries as an atypical TCA that inhibits uptake of dopamine at lower concentrations, while at higher concentrations causes release of dopamine, norepinephrine, and serotonin.
Dopamine Receptor Agonists and Antagonists Several direct dopamine agonists have been investigated, one of which, bromocriptine, has a high incidence of adverse effects and loss of efficacy with continued administration. Interestingly, some drugs that block D2 and D1 receptors, such as sulpiride (Europe) and clozapine (United States) and are marketed as antipsychotics also have antidepressant properties.
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Novel Adrenergic Antidepressants
Only norepinephrine uptake inhibition has been consistently associated with antidepressant action in double-blind, placebo-controlled trials. Alpha-2 antagonists, including mianserin, may be useful in patients who have failed to respond to monotherapy. Other norepinephrine uptake inhibitors include tomoxetine, viloxazine, and lofepramine. Mirtazapine (Remeron) was the first a2-antagonistto be approved for use in the United States as an antidepressant, as was discussed earlier. Novel Monoamine Oxidase Inhibitors
Traditional monoamine oxidase inhibitors prevent the degradation of these neurotransmitters in the cytoplasm of the presynaptic terminal. The first true antidepressants were nonselective and irreversible inhibitors of MAO-A and MAO-B (phenelzine and tranylcypromine); however, antidepressant efficacy requires only MAO-A5, and reversible inhibitors of MAO-A (RIMA) can attenuate the potentiation of pressor responses to tyramine because MAO-A is largely responsible for tyramine degradation. “Reversible” refers to the fact that when substrate (i.e., tyramine) availability is high, the substitute can displace the RIMA from the enzyme MAO-A and still be metabolized to a degree with less potentiation of the hypertensivg action of tyramine. At least 10 new MAO-A inhibitors are under development, none of which are available in the United States. Moclobemide is the most extensively studied RIMA available in Europe and Canada. Dietary restrictions for moclobemide are much less than those of standard MAOls, and the drug may be taken after meals to lessen effects. To be effective, moclobemide must be given in very high doses, and, at these levels, it ceases to be reversible. Because of this, the introduction of moclobemide will probably be delayed in the United States (I? Keck, MD, personal communication, 1998). Several selective MAO-B inhibitors that may have antidepressant effects are under development, including selegiline. Minaprine
Minaprine is a non-TCA, launched in some European countries and in phase3 trials in the United States. It enhances dopaminergic, serotonergic, and cholinergic transmission and was found effective in one placebo-controlled study. It may potentially increase cognition in memory-impaired subjects. ADDITIONAL ALTERNATIVE ANTIDEPRESSANTS
Several other agents are under consideration that will be mentioned solely for completeness. These include phosphodiesterase inhibitors (e.g., rolipram), inositol, angiotensin-convertingenzyme inhibitors (e.g.,captopril), calcium channel modulators, glucocorticoid antagonists, and N-methyl-D-aspartic acid receptor partial agonists and antagonists. SUMMARY
This article outlines the use of alternative agents to TCAs and SSRIs. Features of the more commonly used alternative antidepressant agents are outlined.
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In addition, antidepressant agents that are currently either under development or used in other countries are indicated for completeness because it seems likely that many of these will be introduced in the United States within the next few years. Many of these agents will be used by pediatricians and child psychiatrists for treatment of depression in children, and although much further research is needed, the future for alternative antidepressants and augmenting strategies is extremely promising. References 1. Ambrosini P, Bianchi M, Rabinovich H, et al: Antidepressant treatments of affective disorders. J Am Acad Child Adolesc Psychiatry 32:l-6, 1993 la. Amrein R, Hetzel N, Stab1 M, et al: R I M A A safe concept in the treatment of depression with moclobemide. Can J Psychiatry 37(suppl 1):7-11, 1992 2. Baldwin DS, Hawley CJ, Abed RT, et al: A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression. J Clin Psychiatry 57(supp1)2:46-52, 1996 3. Birmaher B, Ryan ND, Williamson DE, et al: Childhood and adolescent depression: A review of the past 10 years: Part 11. J Am Acad Child Adolesc Psychiatry 3515751583, 1997 4. Boulos C, Kutcher S, Gardner D, et al: An open-naturalistic trial of fluoxetine in adolescents and young adults with treatment-resistant major depression. J Child Adolesc Psychopharmacol2:103-111, 1992 5. Burke MJ, Preskom S H The short-term treatment of mood disorders with standard antidepressants. In Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, 1995, pp 1053-1141 6 . Casat CD, Pleasants DZ, Schroeder DH, et al: Bupropion in children with attention deficit disorder. Psychopharmacol Bull 25:198-201, 1989 7. Casat CD, Pleasants DZ, Van Wyck Fleet J: A double-blind trial of bupropion in children with attention deficit disorder. Psychopharmacol Bull 23120-122, 1987 8. Cioli V, Corradino C, Piccinelli D, et a1 A comparative pharmacological study of trazodone, etoperidone, and I-(m-chloropheny1)piperazine.Pharmacol Res Commun 1685-100, 1984 9. Clay TH, Gualtieri CT, Evens RW, et al: Clinical and neuropsychological effects of the novel antidepressant bupropion. Psychopharmacol Bull 24143-148, 1988 9a. Coffey BJ: Anxiolytics for children and adolescents: Traditional and new drugs. J Child Adolesc Psychopharmacol 1:57-83, 1990 10. Conners CK, Casat CD, Gualtieri CT, et al: Bupropion hydrochloride in attentiondeficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 35313141321, 1996 11. Davis R, Whittington R, Bryson H Nefazodone: A review of its pharmacology and clinical efficacy in the management of major depression. Drugs 53:608-636, 1997 12. Emslie G, Rush AJ, Weinberg AW, et al: A double-blind, randomized, placebocontrolled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry, 541031-1037, 1997 13. Feiger A, Kiev A, Shrivastava RK, et a1 Nefazodone versus sertraline in outpatients with major depression: Focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry 57(Suppl 2):53-62, 1996 14. Feighner JP, Boyer W F Overview of USA controlled trials of trazodone in clinical depression. Psychopharmacol Bull 95(suppl):50-53,1988 15. Findling RL, Magnus RD, Preskorn SH, et al: Open pharmacokinetic study of nefazodone in children and adolescents with depression [abstract no. NR-961. 44th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Toronto, October 1997 16. Fras I: Trazadone and violence [letter]. J Am Acad Child Adolesc Psychiatry 26453, 1987
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42. Ryan ND: Heterocyclic antidepressants in children and adolescents. J Child Adolesc Psychopharmacol 121-31, 1990 43. Ryan ND, Puig-Antich J: Affective illness in adolescence. In Frances AJ, Hales RE (eds): Annual Review of the American Psychiatric Association. Washington, DC, American Psychiatric Press, 1986, pp 420450 44. Ryan ND, Puig-Antich J, Rabinovich H, et al: MAOIs in adolescent major depression unresponsive to tricyclic antidepressants. J Am Acad Child Adolesc Psychiatry 27755-758, 1988 45. Simeon JG: Buspirone effects in adolescent psychiatric disorders. Eur Neuropsychopharmacol 1:421,1991 45a. Simeon J, Dinicola V, Ferguson H, et al: Adolescent depression: A placebo-controlled fluoxetine treatment study and follow-up. Prog Neuropsychopharm Biol Psychiatr 14:791-795, 1990 46. Simeon JG, Ferguson HB, Fleet JVW Bupropion effects in attention deficit and conduct disorder. Can J Psychiatry 31:581-585, 1986 47. Spencer T, Biederman J, Steingard R, et a1 Bupropion exacerbates tics in children with attention-deficit hyperactivity disorder and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 32%-214, 1993 48. Stimmel GL, Dopheide JA, Stahl SM: Mirtazapine: An antidepressant with noradrenergic and specific serotonergic effects. Pharmacotherapy 1710-21, 1997 49. Stoll AL, Mayer PV, Kolbrener M, et al: Antidepressant-associated mania: A controlled comparison with spontaneous mania. Am J Psychiatry: 151:1642-1645,1994 50. Strober M Effects of imipramine, lithium, and fluoxetine in the treatment of adolescent major depression [abstract]. Annual Meeting, New Clinical Drug Evaluation Unit (NCDEU), National Institute of Mental Health, Washington, DC, May 1989 50a. United States Pharmacopeia Dispensing Information: Drug Information for the Health Care Professional. Rockville, MD, US Pharmacopeial Convention, 1997, p 2891 51. Weller E, Weller R Mood disorders. In Lewis M (ed): Child and Adolescent Psychiatry: A Comprehensive Approach. Baltimore, Williams & Wilkins, 1995, pp 6.50465 52. Werry J S The safety of desipramine [letter]. J Am Acad Child Adolesc Psychiatry 33~588-589,1994 53. Zametkin AJ, Rapoport JL: Noradrenergic hypothesis of attention-deficit disorder with hyperactivity: A critical review. In Meltzer HY (ed): Psychopharmacology: The Third Generation of Progress. New York, Raven, 1987, pp 837-842 54. Zubieta JK, Alessi NE: Acute and chronic administration of trazodone in the treatment of disruptive behavior disorders in children. J Clin Psychopharmacol12:346-351,1992
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