Antidepressant Drugs
Christina Weston
Note: In October 2004, the FDA directed manufacturers of antidepressant medications to add the following Black Box Warning to their labeling. “Warning: Suicidality in Children and Adolescents—Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of [drug name] or any other antidepressant in a child or adolescent must balance this risk with the clinical needs. Patients who have started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Drug name] is not approved for use in pediatric patients except for patients with [Any approved pediatric claims here]. (See Warnings and Precautions: Pediatric Use.)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with MDD, obsessivecompulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving more than 4,400 patients have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.”
Furthermore, in the labeling under “Warnings,” the following is indicated: “All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Ideally, such observation would include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then biweekly visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or comorbid depression in the setting of other psychiatric illness taking antidepressants should also be observed for clinical worsening and suicidality, especially during the first few months of treatment, or at times of dose increases or decreases.”
INTRODUCTION
The selective serotonin reuptake inhibitor (SSRI) antidepressants are now the most frequently prescribed antidepressants for children and adolescents and continue to be prescribed with increasing frequency because of their significantly safer untoward-effects profile, in particular, the reduced risks of cardiotoxicity and lethality of overdose compared with the risks associated with tricyclic antidepressants (TCAs). For these reasons, Ambrosini et al. (1993) recommended prescribing SSRIs, and not tricyclics, to depressed patients with suicidal and/or impulsive tendencies. The SSRIs have also been approved for the treatment of several other psychiatric disorders and are used off-label for several additional ones. In 2005, the FDA, directed manufacturers of all antidepressants, including SSRIs, to label their package inserts with a warning of increased suicidal thoughts and behavior in children and adolescents, noting that a pooled analysis of short-term studies in subjects <18 years old showed an increase from 2% in subjects receiving a placebo to 4% in subjects receiving an antidepressant.
SUICIDAL RISK AND ANTIDEPRESSANTS
Since the FDA issued a “Black Box” warning for increased suicidal risk during treatment in young patient for all antidepressants in October 2004, there has been debate about the warnings and how they have effected the use of antidepressants in this population group. Several authors have examined SSRI prescription rates in many countries before and after the warnings were issued. The warnings were initially concerning paroxetine and a warning for this drug was issued initially in June 2003 by the UK equivalent of the FDA. This was followed by the FDA’s Black Box warning more than a year later. Olfson and colleagues (2008) examined antidepressant prescription rates among three physician groups, namely, psychiatrists, primary care physicians, and other physicians during three periods, namely, prewarning, paroxetine warning, and after the Black Box warnings. Youth antidepressant use during the prewarning study period increased by 36% per year (P < .001), which was followed by a decrease of -0.8% and -9.6% per year during the paroxetine and Black Box warning study periods, respectively. They noted that youth paroxetine use increased during the prewarning study period (30% per year; P < .001) before decreasing during the paroxetine warning study period (-44.2% per year; P < .001). They did not find similar changes in antidepressant use in older age groups. They found that all groups of physicians increased their use of SSRIs in youth during the prewarning period. They found that use of paroxetine decreased first by psychiatrists during the prewarning period (-23.0% per year; P = .06) while that of primary care physicians increased (+21.2% per year; P = 1.0). During the paroxetine warning period, use of paroxetine decreased by -49.4% per year (P < .001) among psychiatrists, -38.1% per year among primary care physicians, and -32.2% per year among other physicians. This may be indicative of psychiatrists having greater knowledge of regulatory developments affecting antidepressants.
Kurian and colleagues (2007) found that during the 2 years before the UK warnings in 2003, there was no change in monthly SSRI users aged 2 to 17 years with 23 new users per 10,000 persons per month. This proportion decreased by 33% in the 21 months following the UK warnings (95% confidence interval [CI], 23% to 41%; P < .001). They found that the decrease was most pronounced for antidepressants, other than fluoxetine, which dropped by 54%. New users of fluoxetine, however, increased by 60%. These data suggest that warnings about the relative safety of fluoxetine in comparison with other SSRIs were headed by practitioners. Clarke and colleagues (2012) analyzed prescription rates for antidepressants in youth at a large HMO, from 2000 through 2009. They found that the
rates of antidepressant prescriptions to youth ages 10 to 17 continued to decline through 2009 as had been noted by other authors. They also found that rates of prescription refills decreased, which suggests that prescribers wanted to encourage return visits to monitor for improvement and adverse effects (AEs) after the warnings were issued, which mandated close follow-up.
rates of antidepressant prescriptions to youth ages 10 to 17 continued to decline through 2009 as had been noted by other authors. They also found that rates of prescription refills decreased, which suggests that prescribers wanted to encourage return visits to monitor for improvement and adverse effects (AEs) after the warnings were issued, which mandated close follow-up.
Kurdyak and colleagues (2007) found that in Ontario the rate of paroxetine prescriptions in children and adolescents declined by 54% immediately following the first paroxetine warnings issued in June 2003. Paroxitine prescriptions were unchanged in other age groups. Dutch researchers (Volkers et al., 2007) found that use of SSRIs prescribed by general practitioners decreased from 1.2 to 1.1 per 1,000 children and adolescents between 2001 and 2005. The use of other antidepressant types and TCAs also decreased (0.3 to 0.2 and 0.8 to 0.7, respectively). In Australia, researchers found that use of all SSRIs decreased over time in children and adolescents whereas its use increased in adults (Dean et al., 2007). This decrease in prescription rates of SSRIs have alarmed some who fear that depressed and anxious children are receiving treatment for their disorders.
The Black Box warnings have also affected research studies. The warnings were issued while the treatment of resistant depression in adolescents (TORDIA) multisite trial was recruiting subjects. Wagner et al. (2012) describe the difficulties continuing the trial after the warnings. As a result of the paroxetine warnings, no further subjects were randomized to receive paroxetine and a citalopram arm replaced it. When additional warnings and the Black Box warnings were released, additional informed consents of the new warnings were required. Recruitment to the study was adversely affected following the warnings. Gibbons and colleagues (2007) analyzed dropping SSRI prescription rates in children and adolescents and compared them with youth suicide rates. US and Dutch prescriptions rates for SSRIs were compared from 2003 to 2005, the years before and after the warnings. Suicide rates from the US through 2004 and in the Netherlands through 2005 were compared. It was found that SSRI prescriptions for youth decreased by 22% in both the US and the Netherlands after the warnings were issued. In the Netherlands, the youth suicide rate increased by 49% between 2003 and 2005. In the US, the suicide rates increased by 14% between 2003 and 2004. This was the largest year-to-year change in the suicide rate for this population ever seen since the CDC started collecting data.
Simon et al. (2006) provided an excellent and succinct review of the events leading up to the FDA’s issuing a warning about increased suicidal risk in children and adolescents being treated with newer antidepressants. The authors identified 65,103 patients with 82,285 episodes of antidepressant treatment over a period of 121/2 years ending June 30, 2003. The subjects were members of the Group Health Cooperative (GHC), a mixed-model prepaid health plan with about 500,000 members in the states of Washington and Idaho. An “episode” was defined as an outpatient antidepressant prescription filled (the index prescription) during the study period with no prior antidepressant prescription filed in the preceding 180 days and a ICD-9 diagnosis of unipolar major depressive disorder (MDD), dysthymia, or depressive disorder NOS made during a treatment visit within 30 days before or after the index prescription. Data were obtained from four computerized record systems, including GHC pharmacies where about 95% of members fill their prescriptions, outpatient visit registration records, hospital discharge data, and mortality records (Simon et al., 2006). A total of 11,436 patients had two or more treatment episodes and 5,107 (6.2%) of the episodes occurred in patients <17 years. Females comprised 69.5% of the sample.
The authors evaluated the risks of death by suicide and serious suicide attempts (defined as leading to hospitalization), whether these risks increased during the month after starting an antidepressant, and whether the 10 newer antidepressants (bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone,
paroxetine, sertraline, escitalopram, and venlafaxine) initially identified by the FDA warnings were associated with higher risks of serious suicidal attempts or death by suicide compared with older antidepressants.
paroxetine, sertraline, escitalopram, and venlafaxine) initially identified by the FDA warnings were associated with higher risks of serious suicidal attempts or death by suicide compared with older antidepressants.
During the 3 months before the index prescription, a total of 73 serious suicide attempts were identified. During the 6-month follow-up period after the index prescription was filled, there were 76 (93/100,000) serious suicide attempts and 31 (40/100,000) completed suicides. The probability of death by suicide was much higher in males (OR = 6.6; 95% CI = 2.9 to 14.7) but did not vary significantly with age. The probability of serious suicide attempts was not significantly different between males and females; however, it strongly correlated with younger age (Z = 3.18, P < .001) with an absolute rate of 314/100,000 (95% CI = 160 to 468) in children and adolescents and of 78/100,000 in adults (95% CI = 58 to 98).
The highest risk of serious suicide attempts was during the month before the index prescription and was primarily because of the increased risk in the 7 days preceding the index prescription; the authors attributed this to the fact that such an attempt may result in beginning treatment with antidepressants. Compared with the month before treatment, there was a decrease in serious suicide attempts during the first month after the index prescription; however, the number of attempts during the first month was greater than in any of the following 5 months, over which a continuing gradual decline occurred. This risk of suicide death during the first month after the index prescription was not significantly higher than in the subsequent 5 months (OR = 1.2; 95% CI = 0.5 to 2.9). During the 6-month follow-up, there were a total of three suicide deaths in adolescents. The pattern of serious suicide attempts in adolescents over the 6-month period (N = 17) was similar to that in adults with the highest risk in the month before the index prescription, a sharp decline immediately after starting treatment and continuing to gradually decline over the next 5 months.
The authors found differences in the risks between the 10 newer antidepressants and older antidepressants (primarily tricyclics and trazodone). The risk of suicidal death over the 6-month follow-up period was 34/100,000 for the 10 newer antidepressants and 51/100,000 for the older antidepressants. The risk of serious suicidal attempts was 76/100,000 for the 10 newer antidepressants and 129/100,000 for the older antidepressants. Patients treated with the 10 newer antidepressants had the highest risk of serious suicidal behavior in the month before starting antidepressants and the risk in the first months after the index prescription was not significantly different from that in months 2 through 5 (OR = 1.6; 95% CI = 0.9 to 3.1). Patients treated with the older antidepressants had the highest risk in the first month of treatment, which was significantly higher than in months 2 through 6 (OR = 3.6; 95% CI = 1.8 to 6.9).
The authors concluded that their data did not support the contention of increased risk of suicide deaths or serious suicidal attempts during the first month of antidepressant therapy; however, the risk of serious suicidal attempts was higher during the first week of therapy. The risk of suicide deaths appeared to be relatively constant during the first 6 months of therapy. The authors found no evidence that the newer antidepressants increased the risk of suicidal deaths or serious suicidal attempts compared with the risks of older antidepressants (Simon et al., 2006).
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
The SSRIs approved by the FDA for the treatment of depression only in adults are sertraline hydrochloride (Zoloft), paroxetine hydrochloride (Paxil), and citalopram hydrobromide (Celexa). Fluoxetine hydrochloride (Prozac) is approved for treating depression in individuals 8 years of age or older. Escitalopram oxalate (Lexapro) is approved for treating depression in individuals 12 years of age or older. The FDA has approved for treating obsessive-compulsive disorder (OCD)
the following SSRIs: sertraline for individuals 6 years of age or older, fluoxetine for individuals 7 years of age or older, fluvoxamine maleate (Luvox) for individuals 8 years of age or older, and paroxetine only for adults. Fluoxetine, paroxetine, and sertraline are approved for treating panic disorder only in adults. Paroxetine and sertraline are approved for treating social anxiety disorder and posttraumatic stress disorder (PTSD) in adults. Fluoxetine is approved for treating bulimina nervosa disorder only in adults. Fluoxetine and sertraline are approved to treat premenstrual dysphoric disorder (PMDD) only in adults. Finally, escitalopram and paroxetine are approved to treat generalized anxiety disorder (GAD) only in adults. Table 7.1 summarizes the FDA-approved uses of these SSRIs.
the following SSRIs: sertraline for individuals 6 years of age or older, fluoxetine for individuals 7 years of age or older, fluvoxamine maleate (Luvox) for individuals 8 years of age or older, and paroxetine only for adults. Fluoxetine, paroxetine, and sertraline are approved for treating panic disorder only in adults. Paroxetine and sertraline are approved for treating social anxiety disorder and posttraumatic stress disorder (PTSD) in adults. Fluoxetine is approved for treating bulimina nervosa disorder only in adults. Fluoxetine and sertraline are approved to treat premenstrual dysphoric disorder (PMDD) only in adults. Finally, escitalopram and paroxetine are approved to treat generalized anxiety disorder (GAD) only in adults. Table 7.1 summarizes the FDA-approved uses of these SSRIs.
With the exception of escitalopram, which is the S-enantiomer of racemic citalopram, these SSRIs are chemically unrelated to each other or to tricyclic or tetracyclic antidepressants, or to other antidepressants currently used in clinical practice (PDR, 2006). As the term SSRI suggests, at therapeutic levels, these drugs act primarily to inhibit serotonin reuptake; they also have relatively little effect on catecholaminergic (norepinephrine) reuptake mechanisms. At least five types and several subtypes of serotonin receptors with both distinct and overlapping functions have been identified in the central nervous system (Sussman, 1994a). These SSRIs have differing specificities in the serotonin receptors whose reuptake they inhibit, which explains their efficacy in treating disorders other than depression and the fact that they have somewhat different untoward effects. SSRI antidepressants also do not have clinically significant direct effects on the adrenergic, muscarinic, or histaminergic systems, resulting in fewer and less severe untoward effects than the TCAs. The most common untoward effects of the SSRIs parallel the symptoms caused by the administration of exogenous serotonin and include headache, nausea, vomiting, diarrhea, nervousness, sleep disturbance, and sexual dysfunction (Sussman, 1994a).
Safer and Zito (2006) conducted a meta-analysis of placebo-controlled studies, which reviewed the incidence of treatment-emergent adverse events (TEAEs) in SSRIs in children, adolescents, and adults. They found that children had a two-to-three-times higher incidence of behavioral activation and vomiting than did adolescents, with adults having the lowest rates. Behavioral activation is described as restlessness, hyperkinesis, hyperactivity, and agitation. Activation in children was seen on average in 10.7% of children on SSRIs and 3.4% of children on placebo. Adolescents had activation rates of 2.1% on SSRIs and 1.9% on placebo. They found that somnolence increased with age occurring in 3% of children on SSRIs versus 3.4% on placebo, increasing to 11.3% of adolescents on SSRIs and 5.0% on placebo. Adults had an incidence of somnolence of 16.5% on average on SSRIs and 7.6% on placebo (Safer and Zito, 2006). Gualtieri and Johnson (2006) conducted a retrospective chart review of 128 children and adolescents treated with SSRIs. They found that 28% developed behavioral side effects. Behavioral side effects are characterized as hyperactivity and disinhibition, which occurred in 17; anger and aggression, which occurred in 17 youth; and dysphoria and extreme emotional reactivity, which occurred in 13. They found self-injurious behavior occurring in 12 and suicidal ideation threats or attempts occurring in 9. They analyzed the severity of the events and found that most were managed by discontinuing the drug or lowering the dose. In all, 34 of 36 youth who developed behavioral toxicity were able to continue to be treated with antidepressants after their side effects resolved with either a lower dose of the same drug or a different agent (Gualtieri and Johnson, 2006).
Zuckerman and colleagues (2007) conducted a retrospective chart review of children below 7 years of age on SSRIs. They found 39 children who were prescribed citalopram, fluvoxamine, paroxetine, fluoxetine, or sertraline. Seven patients in the sample needed to discontinue their SSRI due to adverse events (AEs). One youth had gastrointestinal distress that resolved after discontinuation, and six youth developed behavioral activation which required discontinuation. In their sample, 28% of youth below 7 years of age developed AEs with behavioral activation occurring in 21% (Zuckerman et al., 2007).
TABLE 7.1 ≫ Summary of Selective Serotonin Reuptake Inhibitor Indications by Age for FDA-Approved Advertising | |||||||||||||||||||||||||||||||||||||||||||||||||
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SSRI-induced sexual dysfunction is of particular concern in adolescents. Sharko (2004) reviewed the literature and reported a paucity of reported cases of sexual dysfunction—only 1 male of 1,346 pediatric subjects in 31 clinical studies of SSRIs reported such an AE, erectile dysfunction. During 11 years, only eight subjects, all male, were reported to MedWatch for sexual dysfunction secondary to treatment with an SSRI: four reported loss of orgasm, three reported loss in interest, and one reported loss of physical arousal. Scharko noted that in adults, on adequate doses of SSRIs, sexual dysfunction has been reported by 30% to 40% of patients and that this was probably a low estimate because of the difficulties many adults have in discussing sexual matters. He further speculated that the surprisingly low incidence reported was because it was even more difficult for adolescents to talk to their doctors/psychiatrists, but also noted that only 3 of 15 controlled clinical trials cited used ratings to assess AEs (two studies used the Systematic Assessment for Treatment-Emergent Events and one study used the Side Effects Form for Children and Adolescents) and that neither measure asks directly about sexual dysfunction and relies on self-report. In adults treated with SSRIs, it is known that relying on spontaneous self-report greatly underestimates the actual frequency of SSRI-related sexual dysfunction (Sharko, 2004). It is likely that clinicians and researchers fail to adequately address this area and do not directly ask adolescents about sex and sexual functioning as a part of their medication management. Doing this is likely to be the best way to assess sexual dysfunction of our adolescent patients (Sharko, 2004), and neglecting to do so is a disservice to them and may also increase rates of noncompliance with treatment.
A discontinuation syndrome has been identified for the SSRIs. Hosenbocus and Chahal (2011) reviewed the literature on discontinuation-emergent symptoms in children and adults taking SSRIs and noted that dizziness occurs in 60% of cases followed by nausea in almost 40% of adults. The most common symptoms seen in children are dizziness, lightheadedness, drowsiness, poor concentration, nausea, headache, and fatigue. These symptoms are seen when SSRIs are abruptly discontinued (Hosenbocus and Chahal, 2011). Rosenbaum et al. (1998) conducted a 4-week, prospective double-blind, placebo-substitution, discontinuation study of 242 adults receiving long-term maintenance (duration 4 to 24 months) with SSRIs for remitted depression (81 subjects on fluoxetine, 79 subjects of sertraline, and 82 subjects on paroxetine). Effects of the abrupt withdrawal of medication were evaluated by baseline ratings on the Symptom Questionnaire (SQ), the Discontinuation-Emergent Signs and Symptoms (DESS) Checklist, and two depression rating scales, namely, the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Asberg Depression Rating Scale. Medication was abruptly interrupted for 5 to 8 days; 83% were randomly assigned to receive placebo and 17% to continue on their medication. Following this phase, all subjects on placebo resumed their usual maintenance dose of the SSRI they were previously taking. Two hundred twenty (91%) of the subjects completed the entire protocol. Following medication withdrawal during placebo, scores both on the DESS and the SQ increased significantly for patients who had been on sertraline or paroxetine (P < .001 for both) but not for patients who were receiving fluoxetine (P = .578). There were many more discontinuation-emergent symptoms reported on the DESS under inquiry than reported spontaneously; fluoxetine-treated patients reported significantly fewer such symptoms than sertraline-treated patients (P = .001) or paroxetine-treated patients (P < .001). Reported symptoms (ranked from most to least frequent) that occurred in at least 10% of the 185 subjects who underwent withdrawal from medication in decreasing frequency were the following: worsened mood, irritability, agitation, dizziness, confusion, headache, nervousness, crying, fatigue, emotional
lability, trouble sleeping, dreaming, anger, nausea, amnesia, sweating, depersonalization, muscle aches, unsteady gait, panic, sore eyes, diarrhea, shaking, muscle tension, and chills. Overall, a SSRI discontinuation syndrome occurred in 14% of patients withdrawn from fluoxetine, 60% of patients withdrawn from sertraline, and 66% of patients withdrawn from paroxetine. There appeared to be a relationship between a longer half-life and the development of fewer discontinuationemergent symptoms (e.g., patients abruptly discontinued from fluoxetine developed fewer clinically significant such effects than did patients withdrawn from sertraline or paroxetine). In addition, patients treated with either sertraline or paroxetine were rated as having a significant increase in depressive symptoms during the withdrawal period on placebo (P < .001). Subjects who were taking fluoxetine did not experience this reemergence of depressive symptoms. Following restabilization on medication, there were no significant rating scale differences among the three drugs (Rosenbaum et al., 1998). Discontinuation symptoms are best managed by restarting the SSRI or serotonergic noradrenergic reuptake inhibitor (SNRI) and following a more gradual tapering of the medication (Hosenbocus and Chahal, 2011). In cases where SSRIs are unable to be tapered due to reemergence of symptoms, it is possible to overlap with a longer half-life SSRI such as fluoxetine. The first SSRI is tapered off slowly and then the fluoxetine can be discontinued.
lability, trouble sleeping, dreaming, anger, nausea, amnesia, sweating, depersonalization, muscle aches, unsteady gait, panic, sore eyes, diarrhea, shaking, muscle tension, and chills. Overall, a SSRI discontinuation syndrome occurred in 14% of patients withdrawn from fluoxetine, 60% of patients withdrawn from sertraline, and 66% of patients withdrawn from paroxetine. There appeared to be a relationship between a longer half-life and the development of fewer discontinuationemergent symptoms (e.g., patients abruptly discontinued from fluoxetine developed fewer clinically significant such effects than did patients withdrawn from sertraline or paroxetine). In addition, patients treated with either sertraline or paroxetine were rated as having a significant increase in depressive symptoms during the withdrawal period on placebo (P < .001). Subjects who were taking fluoxetine did not experience this reemergence of depressive symptoms. Following restabilization on medication, there were no significant rating scale differences among the three drugs (Rosenbaum et al., 1998). Discontinuation symptoms are best managed by restarting the SSRI or serotonergic noradrenergic reuptake inhibitor (SNRI) and following a more gradual tapering of the medication (Hosenbocus and Chahal, 2011). In cases where SSRIs are unable to be tapered due to reemergence of symptoms, it is possible to overlap with a longer half-life SSRI such as fluoxetine. The first SSRI is tapered off slowly and then the fluoxetine can be discontinued.
SSRIs are of great interest to child and adolescent psychiatrists for several reasons:
1. Only one double-blind, placebo-controlled study conducted with prepubertal children and no such studies with adolescents have shown TCAs to be superior to placebo in treating MDD. In that study (Preskorn et al., 1987), however, subjects receiving IMI had their dose of IMI adjusted by laboratory personnel to achieve plasma levels within the therapeutic range.
2. There have been several reports of sudden death in at least eight children and adolescents being treated with tricyclics, leading to particular concern about their cardiotoxicity in younger patients. SSRIs have a significantly safer untoward-effect profile, including decreased lethality in overdose.
3. Although significant, the untoward effects of SSRIs are more tolerable than those of tricyclic and monoamine oxidase inhibitor (MAOI) antidepressants.
4. SSRIs may be administered once daily.
5. SSRIs appear to have potential in treating a spectrum of childhood psychiatric disorders in addition to depression, including OCD with and without comorbid Tourette disorder, attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, elective mutism, and eating disorders.
Fluoxetine was the first SSRI to be approved by the FDA, and there are more published reports of its use in children and adolescents than for the SSRIs that were introduced later. As additional clinical experience with the SSRIs in this age group has continued to accumulate, the SSRIs have displaced the TCAs as the agents of choice in treating children and adolescents diagnosed with depression, OCD, and other disorders where TCAs were used. Consensus guidelines on medication treatment of childhood MDD have been developed and recommend monotherapy with SSRI antidepressants as the first-line treatment (Hughes et al., 2007).
Fluoxetine Hydrochloride (Prozac, Sarafem)
Fluoxetine is an SSRI that is chemically unrelated to any current antidepressant. Fluoxetine’s antidepressant effect is thought to be related to its specific and selective inhibition of serotonin reuptake by central nervous system neurons. This action appears to take place at the serotonin reuptake pump, not at a neurotransmitter receptor site, and fluoxetine appears to have no significant pharmacological effect on norepinephrine or dopamine uptake (Bergstrom et al., 1988).
Fluoxetine binds to muscarinic, histaminergic, and alpha-1 adrenergic receptors significantly less than TCAs, which may account for the relative lack of anticholinergic, sedative, and cardiovascular effects of fluoxetine compared with TCAs.
The therapeutic serum levels of fluoxetine (FLX) and its major metabolite norfluoxetine (NORFLEX) in children and adolescents has recently been evaluated. Koelch and colleagues performed therapeutic drug monitoring of 71 youth aged 8 to 19 years who were being treated with fluoxetine in doses 10 to 60 mg. They found that the serum concentrations of the active moiety (FLX + NORFLEX) ranged from 21 to 613 ng/mL. They noted that there was very high interindividual variability in the serum concentrations of FLX at each dosage level. There was no relationship between serum concentration and clinical response. The only factor that affected serum concentration was smoking. These results are similar to therapeutic drug monitoring studies of fluoxetine in adults (Koelch et al., 2012).
Several studies, including some that were placebo controlled, have found fluoxetine’s therapeutic efficacy to be comparable to that of the tricyclics (IMI, amitriptyline, and doxepine) in treating adults with MDD (for reviews, see Benfield et al., 1986; Lader, 1988). Two meta-analyses of randomized controlled trials of antidepressants used to treat depression in children and adolescents concluded that fluoxetine is the only antidepressant that demonstrated efficacy in treating juvenile depression (Tsapakis et al., 2008; Usala et al., 2008).
Pharmacokinetics of Fluoxetine Hydrochloride
Peak plasma levels of fluoxetine at usual clinical doses occur after 6 to 8 hours. Food does not significantly affect the bioavailability of fluoxetine; hence, it may be administered with or without food. Fluoxetine is metabolized by the P450 2D6 system in the liver; active and inactive metabolites are excreted by the kidneys. About 95% of fluoxetine is bound to plasma proteins. The elimination half-life after chronic administration is 4 to 6 days for fluoxetine and 4 to 16 days for norfluoxetine, its active metabolite. It may take up to 4 to 5 weeks for steady-state plasma levels to be achieved, but once obtained they remain steady.
Sallee et al. (2000a) reported the death of a 9-year-old male attributed to genetic polymorphism of the CYP2D6 gene, revealed upon genetic testing of autopsy material, which resulted in impaired metabolism of fluoxetine. The case was complicated with multiple psychiatric diagnoses treated with polypharmacy, including high doses of fluoxetine, methylphenidate, and clonidine.
Contraindications for the Administration of Fluoxetine Hydrochloride
Known hypersensitivity to the drug is a contraindication.
Fluoxetine should not be administered to any patient who has received an MAOI within the preceding 2 weeks. Because of the long half-lives of fluoxetine and its metabolites, an MAOI should not be administered sooner than 5 weeks (35 days) after discontinuing fluoxetine. The manufacturer notes that it may be advisable to wait even longer before giving an MAOI if fluoxetine has been prescribed chronically or at high doses (PDR, 2000).
The drug should be administered with caution if impaired liver function is present; if prescribed, a lower dose or a decrease frequency of administration should be used.
Fluoxetine is secreted in breast milk, and hence nursing is not recommended while taking fluoxetine.
Interactions of Fluoxetine Hydrochloride with Other Drugs
The use of fluoxetine with other psychoactive drugs has not been systematically studied. However, because it is metabolized by the P450 2D6 enzyme system,
the potential exists for interactions with other drugs metabolized by this system, including TCAs and other SSRIs.
the potential exists for interactions with other drugs metabolized by this system, including TCAs and other SSRIs.
When used with TCAs, their plasma levels may be significantly increased.
Agitation, restlessness, and gastrointestinal symptoms have occurred when used concurrently with tryptophan.
Diazepam clearance was significantly prolonged in some patients who were administered both drugs.
Elevated plasma levels and toxicity have occurred in some patients receiving carbamazepine or phenytoin when fluoxetine was added to their drug regimes.
Untoward Effects of Fluoxetine Hydrochloride
Wernicke (1985) and Cooper (1988) have reviewed the safety and untoward effects of fluoxetine. The most frequent troublesome untoward effects are nausea, weight loss, anxiety, nervousness, insomnia, and excessive sweating. They are reported more frequently, and anticholinergic effects and sedation less frequently compared with the TCAs.
Many of the untoward effects may be described as behavioral activation. Riddle et al. (1990/1991) reported the behavioral side effects of fluoxetine in 24 children and adolescents of various diagnoses (age range, 8 to 16 years). Mean dose was 25.8 ± 9.0 mg/day for the 12 subjects (including the ADHD children) who developed fluoxetine-induced behavioral side effects, such as restlessness, hyperactivity, insomnia, an internal feeling of excitation, subtle impulsive behavioral changes, and suicidal ideation (King et al., 1991; Riddle et al., 1990/1991). Bangs et al. (1994) documented significant memory impairment in a 14-year-old who was receiving 20 mg/day of fluoxetine for treatment of MDD. Hypomania, mania, and transient psychosis have also been reported to occur in children and adolescents treated with fluoxetine (Boulos et al., 1992; Hersh et al., 1991; Jafri, 1991; Jerome, 1991; Rosenberg et al., 1992; Venkataraman et al., 1992).
Simeon et al. (1990) reported that those subjects receiving fluoxetine who were depressed experienced a small but significant weight loss compared with subjects receiving placebo. As many teenagers, especially females, refuse to take TCAs because of frequently associated weight gain, this could be a clinically advantageous characteristic of fluoxetine for some patients.
The effect of fluoxetine on aggression and or hostility-related events was examined in a meta-analysis (Tauscher-Wisniewski et al., 2007). Five studies were included in the analysis in which 376 children and adolescents were treated with fluoxetine compared with 255 treated with placebo. Aggression and/or hostilityrelated events were identified in 2.1% of youth treated with fluoxetine versus 3.1% of placebo-treated patients; this suggests that there is not an association between fluoxetine treatment and increased risk of aggression.
Indications for Fluoxetine Hydrochloride in Child and Adolescent Psychiatry
NOTE: Review the Black Box Warning at the beginning of the chapter or in the package insert before prescribing.
Fluoxetine is approved for use in children at least 8 years of age, adolescents, and adults for the treatment of MDD; children at least 7 years of age, adolescents, and adults for the treatment of OCD; and older adolescents and adults for treatment of bulimia nervosa, panic disorder, social anxiety disorder, and PMDD. Food does not seem to affect significantly the bioavailability of fluoxetine. It is recommended that once 20 mg/day is exceeded, particularly at higher doses, the medication be taken in divided portions twice daily, in the morning and at noon.
Fluoxetine Dosage Schedule
Children and adolescents ≤17 years: Fluoxetine has been approved for the treatment of MDD in children aged 8 years and older and for the treatment of OCD in children aged 7 years and older. The safety and efficacy of fluoxetine in younger children with these disorders has not been established. At the present time, the safety and efficacy of fluoxetine for children and younger adolescents diagnosed with other disorders remains to be elucidated. However, studies including patients in this age range are appearing in the literature with increasing frequency. Riddle et al. (1992) noted that 20 mg/day may be too high a dose for some children and suggested that an initial dose of 10 mg/day of fluoxetine is the most common starting dose given to children by most clinicians. Boulos et al. (1992) found that an initial dose of 20 mg of fluoxetine too often causes unacceptable untoward effects and suggested beginning with 5 to 10 mg daily the first week; they noted that some of the subjects (ranging from 16 to 24 years of age) experienced good antidepressant response on doses as low as 5 to 10 mg daily.
Treatment of Depression
Children <8 years: Not approved.
Children and adolescents ≥8 years through 17 years: An initial morning dose of 10 to 20 mg/day is recommended. Because of higher plasma levels in lower weight children, both the starting and target doses should be 10 mg daily. If there is no improvement after several weeks, increasing the dose to 20 mg daily may be considered. Older and heavier children may initially be prescribed 20 mg daily; there is evidence that this may frequently be the optimal dose (Altamura et al., 1988). The full antidepressant action may take 4 weeks or longer to develop.
Adolescents ≥ 18 years and adults: An initial morning dose of 20 mg is recommended, and this is usually the optimal dose. A dose increase may be considered after several weeks if there is inadequate clinical improvement. Such doses may be administered once or twice daily and should not exceed a maximum of 80 mg/day.
Treatment of OCD
Children <7 years: Not approved.
Children and adolescents ≥7 years through 17 years: In lower weight children, an initial morning dose of 10 mg/day is recommended; an increase to 20 mg may be considered after several weeks if there is inadequate clinical improvement. A dose range of 20 to 30 mg is recommended. In heavier children and adolescents, an initial dose of 10 mg is also recommended with an increase to 20 mg daily after 2 weeks. Further dose increases may be considered, if there is inadequate clinical improvement after several more weeks. A dose range of 20 to 60 mg/day is recommended.
Adolescents ≥18 years and adults: An initial morning dose of 20 mg is recommended. Full therapeutic effect may take 5 weeks or longer to develop. A dose increase may be considered after several weeks if there is inadequate clinical improvement. A dose range of 20 to 60 mg/day is recommended; the maximum dose should not exceed 80 mg/day. Full therapeutic effect in the treatment of OCD may take 5 weeks or longer to develop. If adequate clinical response does not occur after several weeks, the dosage may be increased gradually to a maximum of 80 mg/day.
Treatment of Bulimia Nervosa
Children and adolescents ≤ 17 years: Not approved. At the present time, the safety and efficacy of fluoxetine for children and younger adolescents remains to be elucidated.
Adolescents ≥18 years and adults: In clinical studies of fluoxetine in fixed doses of 20 or 60 mg/day versus placebo in subjects diagnosed with bulimia nervosa, only the 60-mg dose was significantly better than placebo; hence the recommended target dose is 60 mg/day administered in the morning. It is frequently helpful to begin at a lower dose and to reach the target dose by increments of dose over a period of several days.
Treatment of Panic Disorder
Children and adolescents ≤ 17 years old: Not recommended.
Adolescents ≥18 years and adults: An initial dose of 10 mg/day with an increase to 20 mg/day after 1 week is recommended. Further increase in dose may be considered, if no significant clinical improvement has occurred after several weeks. Doses over 60 mg/day have not been systematically evaluated.
Treatment of PMDD
The recommended daily dose is 20 mg.
Fluoxetine Hydrochloride Dose Forms Available
Eli Lilly, who manufactures all four forms of the medications, states that they are bioequivalent.
Tablets: 10, 20, and 60 mg (scored); Sarafem is available in 10- and 20-mg tablets.
Pulvules: 10, 20, and 40 mg
Weekly capsules (Prozac weekly capsules): 90 mg
Liquid: 20 mg/5 mL
Reports of Interest
Fluoxetine in the Treatment of Child and Adolescent MDD
Joshi et al. (1989) reported on their treatment with fluoxetine of 14 patients (8 males, 6 females) ranging in age from 9 to 15 years (average age, 11.25 years) who were diagnosed with major depression by DSM-III-R (American Psychiatric Association [APA], 1987) criteria and who had not responded adequately to TCAs, had serious untoward effects from tricyclics, or could not be treated with tricyclics for medical reasons. Ten (71.4%) of the subjects responded favorably within 6 weeks to fluoxetine 20 mg administered in the morning. Side effects were limited to transient nausea and hyperactivity in one patient each and did not require discontinuation of the drug.
Simeon et al. (1990) reported a 7-week, double-blind, placebo-controlled fluoxetine treatment study of 40 adolescents (22 females and 18 males), aged 13 to 18 years (mean age, 16 years), who met DSM-III criteria for major depression unipolar type and had baseline Hamilton Depression Scores (Ham-D) of at least 20. In addition, the Ham-D scores of all subjects improved <20% during a preceding 1-week, single-blind placebo treatment protocol. Fluoxetine was begun at 20 mg/day, increased to 40 mg/day after 4 to 7 days, and increased to 60 mg/day during the second week. Further dosage changes were individually titrated.
At baseline, no significant differences were found between the groups. Thirty subjects completed the study divided equally between medication and control groups. About two-thirds of patients in each group showed moderate to marked clinical global improvement with significant improvement by week 3. With the exception of disturbances of sleep, all symptoms showed slightly greater improvement in subjects treated with fluoxetine than in those receiving placebo, but differences were not significant. Patients taking fluoxetine, however, experienced a small but significantly greater weight loss than those receiving placebo. Untoward effects were usually mild and transient, and none necessitated discontinuation of medication. Those most frequently reported were headache, vomiting, insomnia, and tremor. There were no significant differences in the effects of fluoxetine and placebo on heart rate or blood pressure.
Thirty-two patients were successfully followed up 8 to 46 months later (mean, 24 months) at ages 15 to 22 years (mean, 18 years). No significant differences were found between the fluoxetine and placebo groups, or between responders and nonresponders to the initial clinical trial. Both groups showed further overall improvement; however, psychosocial functioning was still poor in more than one-third of the patients, and 50% of the patients’ parents felt their children still required professional help. The authors noted that 10 patients were still depressed and 7 of them were still in treatment. About half of the patients who did not respond to placebo or fluoxetine during the initial 8 weeks of treatment were thought to constitute a veryhigh-risk group and remained very disturbed at follow-up (Simeon et al., 1990).
Boulos et al. (1992) treated, with fluoxetine, 15 adolescents and young adults diagnosed with MDD who had responded unsatisfactorily to prior treatment with antidepressants, usually including tricyclics, for a minimum of 2 months at doses associated with clinical efficacy. Seven subjects were 18 years old or younger. Eleven patients completed at least 6 weeks of treatment. Of these, 64% showed at least a 50% improvement on the HDRS, and 73% achieved scores of “much” or “very much improved” on the Clinical Global Impressions Scale (CGIS). Optimal doses ranged from 5 to 40 mg daily, and several patients received other medications concurrently. Untoward effects included headache, vomiting and other gastrointestinal complaints, insomnia, tremor, sweating, dry mouth, and hair loss.
Emslie et al. (1997) reported an 8-week, double-blind, randomized (stratified for age, ≤12 years or ≥13 years, and sex), placebo-controlled study of 96 children and adolescents (52 males, 44 females; mean age, 12.35; range, 7 to 17 years), diagnosed by DSM-III-R (APA, 1987) criteria with nonpsychotic MDD. Following a 3-week evaluation period and a 1-week, single-blind, placebo run-in during which responders were dropped, the 96 remaining subjects were randomized to 8 weeks of treatment with placebo or fluoxetine; there were 48 in each group (24 subjects aged 12 years or younger and 24 subjects aged 13 years or older in each group). Overall effectiveness was rated on the Clinical Global Impressions-Improvement (CGI-I) subscale and the Children’s Depression Rating Scale-Revised (CDRS-R). In addition, the Brief Psychiatric Rating Scale-Children (BPRS-C) and the Children’s Global Assessment Scale (CGAS) were used. Subjects were given 20 mg of fluoxetine or placebo daily for the entire 8 weeks unless they were dropped from the protocol because of failure to improve or untoward effects. Fourteen patients (29%) on fluoxetine discontinued the protocol, seven for lack of efficacy, four for untoward effects (three developed manic symptoms and one developed a severe rash), and three for protocol violation. Twenty-two patients (46%) on placebo dropped out, 19 for lack of efficacy, 1 for an untoward effect, and 2 for protocol violations. Fluoxetine was statistically better than placebo on the CGI-I; using the intent-to-treat (ITT) sample, 27 (56%) of the fluoxetine group versus 16 (33%) of the placebo group were rated much or very much improved (P = .02). Using a last-observation-carried-forward (LOCF) analysis for all 96 subjects, there was a significant drug-by-time interaction in favor of fluoxetine (P = .01); there was no significant drug-by-age or -sex interaction, meaning that males and females in both age groups responded equally well. After week 5, the mean CDRS-R score for the fluoxetine group became significantly lower than that for the placebo group (P = .03). Comparing initial and exit outcome LOCF scores on the CDRS-R for both groups, fluoxetine (initial score, 58.5 ± 10.5; exit score, 38.4 ± 14.8) was significantly better than placebo (initial score, 57.6 ± 10.4; exit score, 47.1 ± 17.0; P = .002). Subjects initially had relatively severe and chronic symptoms of depression and, despite their overall improvement, after 8 weeks, only 15 (31%) of the fluoxetine group and 11 (23%) of the placebo group had CDRS-R scores <28, consistent with relatively complete remission of depressive symptoms. Scores on the BPRS-C and the CGAS improved for both groups and were not significantly different. The authors concluded that fluoxetine was significantly better than placebo in acute-phase treatment of children and adolescents diagnosed with severe, persistent MDD and encouraged further studies.
The Treatment for Adolescents with Depression Study (TADS) Team (2004) conducted a randomized controlled trial in 439 patients at 13 sites (age 12 to 17 years, mean age 14.6 years; 45.6% males and 73.8% White, 12.5% Black, and 8.9% Hispanic) with a primary diagnosis of MDD by DSM-IV criteria (APA, 1994), which compared the efficacy of fluoxetine (10 to 40 mg/day) versus cognitive-behavior therapy (CBT) versus fluoxetine (10 to 40 mg/day) plus CBT versus placebo (equivalent to 10 to 40 mg/day) over a 12-week period. Medication in the fluoxetine and placebo group was administered in a double-blind fashion;
fluoxetine was administered openly in the fluoxetine plus CBT group as CBT was administered unblindly.
fluoxetine was administered openly in the fluoxetine plus CBT group as CBT was administered unblindly.
The 439 subjects of the study were those remaining from an initial 2,804 screened by telephone after inclusion and exclusion criteria were satisfied and those not interested in participation or withdrawing consent were eliminated. Major outcome measures were the CDRS-R and the CGI-I Score. The Reynolds Adolescent Depression Scale total score and the Suicidal Ideation Questionnaire-Junior High School Version (SIQ-Jr) total score were used as secondary outcome measures. CBT was composed of a possible 15 skills-orientated 50- to 60-minute sessions based on the premise that depression is “caused by or maintained by depressive thought patterns and a lack of active, positively reinforced behavioral patterns.” The mean number of sessions completed was 11 in both groups with CBT. The mean fluoxetine dose in the fluoxetine-only group was 28.4 ± 8.6 mg/day and in the fluoxetine-plus-CBT group was 33.3 ± 10.8 mg/day; the mean placebo dose was 34.1 ± 9.5 mg/day.
Based on the improvement on the CDRS-R, combined treatment with fluoxetine and CTB was superior (P = 001) to treatment with placebo, but treatment with fluoxetine alone (P = .10) and CBT alone (P = .40) were not. Fluoxetine with CBT was superior to fluoxetine alone (P = .02) and to CBT alone (P = .001). Fluoxetine alone was also superior to placebo (P = .01).
On the CGI-I Scale, rates of positive response (a rating of 1 [very much improved] or 2 [much improved]) were fluoxetine plus CBT, 71% (95% CI, 62% to 80%); fluoxetine only, 60.6% (95% CI, 51% to 70%); CBT only, 43.2% (95% CI, 34% to 52%); and placebo 34.8% (95% CI, 26% to 44%).
After patients at high-risk for suicide were eliminated from the study because of exclusion criteria, 29% of the subjects had scores of >31, a level of suicidal thinking that requires prompt clinical attention on the SIQ-Jr at baseline; this decreased to 10.3% at 12 weeks and there was clinically significant improvement in suicidal thinking in all four groups. During the 12-week trial, 24 (5.5%) of the patients reported a suicide-related adverse event (worsening suicidal ideation or a suicide attempt) and 7 (1.6%) of patients attempted suicide but none was successful. Improvement in suicidality was greatest for the fluoxetine plus CBT group and least for the fluoxetine-only group. The authors concluded that fluoxetine is effective in the treatment of MDD and that the addition of CBT increases both clinical improvement and protection from suicidality (TADS, 2004).
The TADS study participants have been followed in a maintenance phase component from weeks 18 through 36 of the study (Stage III) and also in a naturalistic 1-year follow-up study after the end of 36 weeks of active treatment (Stage IV) (Kennard et al., 2009; March et al., 2009). In both of these studies, the remission rates were examined. Remission is defined as a return to a symptom-free state or a near symptom-free status. By 36 weeks, the estimated remission rates were as follows: combined treatment, 60%; Fluoxetine alone, 55%; CBT alone, 64%; and overall remission rate, 60% (Kennard et al., 2009). This is a significant improvement from previous reports of the TADS group remission rates of 23% after 12 weeks (Kennard et al., 2006). In the naturalistic study, TADS treatments were stopped at 36 weeks and participants received continued treatment in the community. They were assessed by the TADS researchers at 3, 6, 9, and 12 months after completion of the initial 36-week TADS study. Sixty-six percent of the original study group participated in at least one assessment and the benefits of active treatment continued during the naturalistic study period (March et al., 2009). These TADS follow-up studies suggest that the majority of adolescents with depression achieve remission and that their remission can be continued with long-term treatment (Kennard et al., 2009).
The Adolescent Depression and Psychotherapy Trial (ADAPT) study examined the effect of adding CBT to treatment with an SSRI (primarily fluoxetine). This
study was funded by the UK National Health System and was conducted in community clinic settings. In contrast to the TADS study, the authors included participants with active suicidal intent, self-harm, depressive psychosis, and/or conduct disorder. Subjects were aged 11 to 17 and had moderate to severe levels of depression.
study was funded by the UK National Health System and was conducted in community clinic settings. In contrast to the TADS study, the authors included participants with active suicidal intent, self-harm, depressive psychosis, and/or conduct disorder. Subjects were aged 11 to 17 and had moderate to severe levels of depression.
In the ADAPT study, 510 youth were screened for participation and of those 249 were eligible for the study. All participants were offered a brief initial intervention consisting of two sessions before they were referred to the study. Some participants declined to participate in the initial intervention and were enrolled in the study. Of those who participated in the intervention, 34 of 164 improved. Youth who did not respond to the brief intervention were randomized to SSRI alone (103) or SSRI plus CBT (105). The primary SSRI used in the study was fluoxetine, which was dosed at 10 mg daily for a week and then increased to 20 mg for 5 weeks. If no response was seen by 6 weeks, the dose was increased to 40 mg, and if no response was noted by 12 weeks, then the dose was increased to 60 mg. Participants who could not tolerate fluoxetine or in whom it was ineffective were given a different SSRI. Youth were followed for 28 weeks, and response was assessed at 12 and 28 weeks. Depressive symptoms decreased but no differences were detected between the two treatment arms. At the end of the 28-week study, 51% of those in the SSRI-alone group and 53% of those in the CBT-plus-SSRI group were much or very much improved (Goodyer et al., 2007).
The Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial was funded by the National Institute of Mental Health to provide empirical evidence to guide clinical practice when initial treatment for depression is unsuccessful. Participants aged 12 to 18 were recruited, who had not responded to an initial course of SSRI treatment. They were randomized into one of four treatments: (a) switch to a second, different SSRI (fluvoxamine, citalopram, or paroxetine); (b) switch to a different SSRI plus CBT; (c) switch to venlafaxine (150 to 225 mg); or (d) switch to venlafaxine + CBT. At the completion of 12 weeks of treatment, the groups who received CBT + medication had a response rate of 54.8%. The groups with a medication switch alone had a response rate of 48.2%. There was no difference in response rates between the study drugs fluoxetine, citalopram, paroxetine, or venlafaxine (Brent et al., 2008). In a continuation study, the TORDIA study participants were continued in their treatment arm if they had responded and nonresponders received open treatment which could consist of a switch to another antidepressant, augmentation, or addition of CBT or other psychotherapy. Of the individuals enrolled in the original study, 78.1% were followed for another 24 weeks. They found that treatment type did not have any statistical differences and that all groups had similar remission rates. At 24 weeks, 38.9% had achieved remission. Of those who had remitted, it was more likely to occur in subjects who had a clinical response by week 12 (61.6% vs. 18.3%). Factors which predicted remission were lower rates of depression, hopelessness, anxiety, suicidal ideation, family conflict, and absence of comorbid dysthymia. The relapse rate among subjects who had initially responded by week 12 was 19.6% by week 24 (Emslie et al., 2010). The study ended at 24 weeks, and subjects were discharged to community care and naturalistically assessed at weeks 48 and 72. By week 72, 61.1% of the youth in the study had reached remission. Treatment group did not influence remission rate or time to remission. The study did find that the group assigned to SSRIs had a more rapid decline in self-reported depressive symptoms and suicidal ideation than the group assigned to venlafaxine (Vitiello et al., 2011).
These three large studies build on earlier research on the use of fluoxetine and SSRIs in depressed youth and have advanced knowledge to guide treatment selections in depressed youth. The TADS, ADAPT, and TORDIA studies compare the effectiveness of different treatment methods instead of comparing a treatment against placebo. Taken together, they can give physicians confidence in the continued use of medications and therapy to treat depression in adolescents.
Fluoxetine in the Treatment of Children and Adolescents with OCD or OCD and Tourette Disorder
In an open clinical study, Riddle et al. (1990) treated, with fluoxetine, 10 children (5 males, 5 females) ranging in age from 8 to 15 years (average age, 12.2 years) diagnosed with OCD only or with both OCD and Tourette disorder. Dosage ranged from 10 to 40 mg/day, with 80% of the patients receiving 20 mg/day; duration of treatment ranged from 4 to 20 weeks. Four of the patients with Tourette disorder received concomitantly additional medication for treatment of their tics. Fifty percent were considered responders to fluoxetine and were rated much improved; response rates were similar in patients with OCD only and in those with both diagnoses. The most common untoward effect was behavioral agitation/activation, characterized by increased motor activity and pressured speech. It occurred in 40% of the patients and usually started within the first few days; symptoms were most severe during the first 2 to 3 weeks but remained until medication was discontinued. No significant changes in blood pressure, pulse, weight, laboratory tests, or ECG were observed (Riddle et al., 1990/1991).
Riddle et al. (1992) reported a randomized, 20-week, double-blind, placebocontrolled, fixed-dose study with crossover after 8 weeks of fluoxetine in treating 14 subjects (6 males and 8 females; age range, 8.6 to 15.6 years; mean, 11.8 ± 2.3 years) diagnosed with OCD by DSM-III-R criteria. Subjects received 20 mg of fluoxetine or placebo. For various reasons, 13 subjects completed the first 4 weeks, 11 subjects completed the first 8 weeks, and only 6 subjects satisfactorily completed the entire 20 weeks. A comparison of between-group differences at 8 weeks was made for 13 subjects; this number of subjects was made possible by carrying the 4-week data forward to 8 weeks for the 2 subjects who dropped out during that time. The seven subjects receiving fluoxetine showed significant decreases on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score (mean decrease, 44%; P = .003), obsessions score (mean decrease, 54%; P = .009), and compulsions score (mean decrease, 33%; P = .005), and on the Clinical Global Impressions for Obsessive-Compulsive Disorder (CGI-OCD) (mean decrease, 33%, P = .0004). The six subjects on placebo also showed reductions in their obsessive-compulsive symptomatology on the CY-BOCS of 27% and on the CGI-OCD of 12%, but these reductions were not significant. When the two groups were compared, the improvement of subjects on fluoxetine was significantly greater than that of those on placebo on the CGI-OCD (P = .01) but not on the CY-BOCS (P = .17). The most frequently reported untoward effects were insomnia, fatigue, motoric activation, and nausea. Preexisting chronic motor tics worsened in two subjects; however, fluoxetine was continued and the tics subsided to negligible levels over the subsequent 2 years. A subject with comorbid diagnoses of MDD, separation anxiety, and oppositional disorder developed suicidal ideation, which resolved after fluoxetine was discontinued. The authors noted that 20 mg/day may be too high a dose for some children and that an initial dose of 10 mg/day of fluoxetine was the most common starting dose given to children by most child and adolescent psychiatrists.
Of the six subjects initially on fluoxetine who crossed over to placebo at 8 weeks, three dropped out at week 12 because of worsening of symptoms, with a mean increase of 53% ± 37% in CY-BOCS scores. A fourth subject was worse at week 20 on the CY-BOCS, and the remaining two showed improvement (decrease) in their CY-BOCS scores. Although three of the four subjects who crossed over from placebo to fluoxetine had shown substantial reductions in their CY-BOCS scores during the placebo period, there was further reduction in these scores at 20 weeks. Overall, these results complement findings in adults and suggest that fluoxetine is both safe and effective in treating children and adolescents with OCD for 20 weeks (Riddle et al., 1992).
Geller and colleagues (2001) examined the effectiveness of fluoxetine in children and adolescents with OCD in a double-blind placebo-controlled study
(Geller et al., 2001). One hundred three patients were enrolled in the study and were randomized to receive either fluoxetine (71) or placebo (32). Patients were initially given a 10-mg dose of fluoxetine for the first 2 weeks of treatment and then 20 mg for the next 2 weeks. After 4 weeks, their fluoxetine dose was increased to 40 mg/day if their CGI-Severity score was unchanged or worse than baseline. Three weeks later, the dose could be increased another 20 mg if the CGI-Severity score was unchanged or worse. The maximum fluoxetine dose was 60 mg/day. If subjects had difficulty tolerating a higher dose of fluoxetine, the dosage could be reduced. Improvement was primarily measured with the CY-BOCS.
(Geller et al., 2001). One hundred three patients were enrolled in the study and were randomized to receive either fluoxetine (71) or placebo (32). Patients were initially given a 10-mg dose of fluoxetine for the first 2 weeks of treatment and then 20 mg for the next 2 weeks. After 4 weeks, their fluoxetine dose was increased to 40 mg/day if their CGI-Severity score was unchanged or worse than baseline. Three weeks later, the dose could be increased another 20 mg if the CGI-Severity score was unchanged or worse. The maximum fluoxetine dose was 60 mg/day. If subjects had difficulty tolerating a higher dose of fluoxetine, the dosage could be reduced. Improvement was primarily measured with the CY-BOCS.
The mean dose of fluoxetine in the treatment group was 24.6 mg. Sixteen (23%) had a final dose of 40 mg/day, and 15 (21%) had a final dose of 60 mg/day. Fluoxetine was associated with significantly greater improvement in CY-BOCS scores (P = 0.26), which indicate improvement in OCD symptoms. Patients with a 40% or greater reduction in their CY-BOCS scores were considered responders. By this criteria, 35 of 71 (49%) of the fluoxetine group and 8 of 32 (25%) of the placebo group were responders. CGI-Improvement scales in the fluoxetine treated group had 55% of patients rated as much or very much improved compared with 18.8% of the placebo group.
Fluoxetine was well tolerated. Discontinuation due to AEs occurred in 8.5% of the fluoxetine group and 6.3% of the placebo group. Discontinuation in the fluoxetine group occurred due to headache, hyperkinesia, abnormal liver function tests, manic reaction, nervousness, or somnolence. Placebo-treated patients discontinued because of hyperkinesia or nervousness. The authors conclude that fluoxetine 20 to 60 mg a day was effective and well tolerated for the treatment of OCD in the pediatric population.
Fluoxetine in the Treatment of Children and Adolescents with Anxiety Disorders
Birmaher et al. (1994) treated with fluoxetine 21 patients (age range, 11 to 17 years; mean, 14 years) diagnosed with overanxious disorder (OAD) only (N = 6); OAD, social phobia (SP), and separation anxiety disorder (SAD) (N = 5); or OAD and SP or SAD (N = 10), who had not responded to prior psychopharmacotherapy or psychotherapy. Subjects with a prior history of OCD, panic disorder, or current MDD were excluded. The mean fluoxetine dose after an average of 10 months (range, 1 to 31 months) on fluoxetine was 25.7 mg/day; the following distribution of doses was reported: 10 mg/day (1), 20 mg/day (15), 30 mg/day (1), 40 mg/day (2), and 60 mg/day (2).
Twenty subjects (95%) showed some improvement in anxiety, with 17 (81%) rated as moderately to markedly improved on the severity and improvement subscales of the CGIS (P = .0001). It is important to note that in most cases improvement did not begin until 6 to 8 weeks after initiation of fluoxetine. Although no subject fulfilled diagnostic criteria for MDD or dysthymia, 10 patients did have depressive symptoms. These symptoms also improved significantly (P = .0001); analysis suggested that the improvements in depressive symptoms and anxiety were independent. Only a few untoward effects, which were usually mild and transient, were reported: mild headache (one), nausea (three), insomnia (one), and stomachache (one). No significant changes in pulse, blood pressure, or ECG were found, and no subject experienced agitation, manic, or hypomanic symptoms, or suicidal ideation. These data suggest that fluoxetine may be a useful treatment for children and adolescents with anxiety disorders (Birmaher et al., 1994).
Fairbanks et al. (1997) treated with fluoxetine monotherapy on an open-label basis, 16 outpatients (8 males, 8 females; mean age, 13.0 ± 2.9 years; age range, 9 to 17 years) diagnosed by DSM-III-R (APA, 1987) criteria with mixed anxiety disorders and who were unresponsive to psychotherapy. Eleven subjects (69%) had a mean of 2.5 ± 1.5 coexisting anxiety disorders, including SAD (N = 11), SP (N = 10), GAD (N = 7), specific phobia (N = 6), and panic disorder (N = 5). Efficacy
was assessed by ratings on the CGAS, the modified Liebowitz Social Anxiety Scale, the modified social behavior scale, the CGIS, and a side-effects checklist. Fluoxetine was initiated at a dose of 5 mg/day and subsequently increased weekly by 5 or 10 mg/day for 6 to 9 weeks until clinical improvement occurred or to a maximum of 40 mg for subjects <12 years of age or 80 mg/day for subjects ≥12 years of age.
was assessed by ratings on the CGAS, the modified Liebowitz Social Anxiety Scale, the modified social behavior scale, the CGIS, and a side-effects checklist. Fluoxetine was initiated at a dose of 5 mg/day and subsequently increased weekly by 5 or 10 mg/day for 6 to 9 weeks until clinical improvement occurred or to a maximum of 40 mg for subjects <12 years of age or 80 mg/day for subjects ≥12 years of age.
The mean fluoxetine dose for all subjects was 35.0 ± 17.1 mg/day or 0.71 ± 0.28 mg/kg/day. The mean mg/kg/day dose was almost identical for subjects of all ages; subjects <12 years had lower optimal doses because they weighed less. Subjects with only one anxiety disorder responded to lower doses than subjects with two or more anxiety disorders. The CGIS ratings showed significant improvement in the severity of anxiety in ratings by psychiatrists, mothers, and subjects. Mean duration of time on medication until a rating of “improved,” “much improved,” or “completely recovered” on the CGIS was 5 weeks, with a range of 1 to 9 weeks. According to diagnoses, improvements on the CGIS were as follows: separation anxiety (N = 10): 6 much improved, 4 improved; SP (N = 10): 1 much improved, 7 improved; GAD (N = 6): 1 much improved, 4 improved; panic disorder with or without agoraphobia (N = 5): 1 much improved, 3 improved. Fluoxetine did not appear to aggravate the anxiety of any of the patients. The authors state that their outcome assessments found that SAD, SP, specific phobia, and panic disorder all responded favorably to fluoxetine but that GAD did not. The most common untoward effects were drowsiness, difficulty falling asleep or staying asleep, decreased appetite, nausea, abdominal pain, and a state of being easily excited or keyed up. None of the subjects was reported to have disinhibition, akathisia, suicidal or violent reactions, or hypomania. The authors concluded that fluoxetine is potentially effective in the short-term treatment of anxiety disorders (excluding GAD) in children and adolescents who do not have comorbid MDD, OCD, substance abuse, or medical complications and that further studies are needed.
Birmaher et al. (2003) conducted a 12-week, randomized, placebo-controlled, double-blind study to assess the efficacy and tolerability of fluoxetine in the outpatient treatment of 74 children and adolescents (age range 7 to 17 years; mean age 11.8 ± 2.8 years; 34 [45.9%] males and 40 [54.1%] females) diagnosed by DSM-IV (APA, 1994) criteria with GAD, SP, and/or SAD; most subjects were diagnosed with more than one anxiety disorder, and 24 (32%) were also diagnosed with other nonanxiety psychiatric disorders. Fluoxetine was initiated at a dose of 10 mg/day for the first week and, if tolerated, was increased to 20 mg/day for the remaining 11 weeks of the study. No other psychiatric medications were permitted for the duration of the study.
At the end of the study, on the CGI-I Scale, using an ITT analysis for all subjects, 61% (22/36) of subjects taking fluoxetine and 35% (13/37) of subjects taking placebo had scores of 1 (very marked improvement) or 2 (marked improvement) (P = .03) although the analysis for completers was even more positive for the fluoxetine group: 75% for fluoxetine versus 38.7% for the placebo group (P = .005). The authors noted that compared with SP subjects on placebo (N = 19), the subgroup with a diagnosis of SP on fluoxetine (N = 21) had significantly better outcomes on the CGI-I (12% vs. 76%, P = .001). Regarding AEs during the first 2 weeks, subjects on fluoxetine had significantly more AEs than those on placebo for abdominal pain and nausea, 46% versus 22%, P = .04; drowsiness and headaches 44% versus 14%, P = .004. For the entire duration of the study, only abdominal pain and nausea were significantly more frequent in the fluoxetine group: 44% versus 22%, P = .04. The authors also noted that during the study 11 patients (7 on fluoxetine and 4 on placebo, P = NS) experienced 20 incidents of excitement, giddiness, or disinhibition and 5 of these, all receiving fluoxetine, were dropped from the study as a result. Subjects were more severely
ill at intake (scores of >30) on the Screen for Child Anxiety-Related Emotional Disorders-Child (SCARED-C) and those with positive family histories for anxiety had a poorer clinical response to fluoxetine than subjects without such histories. The authors concluded that fluoxetine is clinically effective and safe for the acute treatment of anxiety in this age group. They suggested that an increase in dose is indicated for patients with no or only partial clinical response after 4 to 6 weeks of treatment. In addition, they noted that mild to moderate agitation/disinhibition may be successfully treated by lowering the dose of fluoxetine in many cases (Birmaher et al., 2003).
ill at intake (scores of >30) on the Screen for Child Anxiety-Related Emotional Disorders-Child (SCARED-C) and those with positive family histories for anxiety had a poorer clinical response to fluoxetine than subjects without such histories. The authors concluded that fluoxetine is clinically effective and safe for the acute treatment of anxiety in this age group. They suggested that an increase in dose is indicated for patients with no or only partial clinical response after 4 to 6 weeks of treatment. In addition, they noted that mild to moderate agitation/disinhibition may be successfully treated by lowering the dose of fluoxetine in many cases (Birmaher et al., 2003).
In a 1-year follow-up of the 74 subjects in Birmaher et al.’s (2003) 12-week acute, controlled study of fluoxetine, an open-label, l-year extension was conducted (Clark et al., 2005). Fifty-six completed the 1-year follow-up; of these, four were not included in the analysis as they received other medications as well. Of the 52 analyzed completers, 42 were assigned to fluoxetine (of this group, 22 had been on fluoxetine during the acute 12-week trial and 20 had been on placebo) and 10 received no medication (of these 4 had been on fluoxetine during the 12-week acute study and 6 had been on placebo). Those subjects on fluoxetine were rated as significantly more improved than those on no medication on the SCARED-Parent Report (P ≤ .01), the SCARED-C (P < .05); the Pediatric Anxiety Rating Scale-Parent Report (PARS-P), and the PARS-Rater Report (PARS-R) (P = .05). The PARS-Child Report (PARS-C) was not significantly different between the fluoxetine and the placebo groups. The group showing the greatest improvement in CGI-S was the group that was on placebo during the 12-week acute trial and on fluoxetine during the 1-year open-label extension period. The results suggest that fluoxetine continues to be of benefit for the treatment of anxiety in this group of subjects for up to 15 months (Clark et al., 2005).
Fluoxetine in the Treatment of Children and Adolescents with ADHD
Barrickman et al. (1991) reported on 19 children and adolescents (age range, 7 to 15 years) diagnosed with ADHD who were treated for 6 weeks in an open study with fluoxetine hydrochloride. Fourteen subjects had comorbid diagnoses of either conduct disorder (N = 6) or oppositional defiant disorder (N = 8). Most subjects had prior psychopharmacologic treatment that was unsatisfactory or had untoward effects on stimulants (e.g., tics) or antidepressants (e.g., sedation). Initial daily dose was 20 mg in the morning; subsequent doses were individually adjusted. Average daily dose was 27 mg (0.6 mg/kg) (range, 20 to 60 mg). Nine subjects took 20 mg/day, eight took 40 mg/day, and two took 60 mg/day. Most subjects improved within 1 week after a therapeutic dose was reached. Ratings were made on a large number of standardized instruments. Eleven subjects (58%) were rated “moderately improved” or “very much improved” after 6 weeks; eight had minimal improvement. Side effects were minimal and all remitted spontaneously or with dose reduction except mild sedation in one case. In particular, there were no reports of loss of appetite or significant changes in weight. Only one subject experienced nervousness, and none had insomnia or developed suicidal ideation.
All three children diagnosed with ADHD showed worsening of ADHD symptoms on fluoxetine in the Riddle et al. (1990/1991) study of behavioral side effects of fluoxetine discussed earlier.
Gammon and Brown (1993) reported the use of fluoxetine augmentation of methylphenidate in an 8-week open trial with 32 patients (9 to 17 years old) who were diagnosed with ADHD and one or more comorbid disorders—that is, dysthymia (78%), oppositional defiant disorder (59%), MDD (18%), anxiety disorders (18%), and conduct disorder (13%)—and who had inadequate therapeutic responses to methylphenidate alone. Addition of fluoxetine was begun with an initial dose of 2.5 or 5.0 mg/day for subjects <12 years of age and 12 years of age or older, respectively. Dose was titrated upward every 3 to 4 days in increments equal
to the initial dose, to a maximum of 20 mg/day. Optimal daily dose of fluoxetine at 8 weeks ranged from 2.5 to 20 mg. The majority of subjects (19, or 59%) required 20 mg/day; 6 subjects (18%) received 10 to 15 mg/day; 4 subjects (12.5%) received 5 to 7.5 mg/day; and 3 subjects (9%) had optimal fluoxetine doses of 2.5 mg/day. No significant or lasting untoward effects were reported.
to the initial dose, to a maximum of 20 mg/day. Optimal daily dose of fluoxetine at 8 weeks ranged from 2.5 to 20 mg. The majority of subjects (19, or 59%) required 20 mg/day; 6 subjects (18%) received 10 to 15 mg/day; 4 subjects (12.5%) received 5 to 7.5 mg/day; and 3 subjects (9%) had optimal fluoxetine doses of 2.5 mg/day. No significant or lasting untoward effects were reported.
After 8 weeks of combined drug treatment, all 32 subjects showed statistically significant improvements on assessments rating attention, behavior, and affect. These improvements were also rated clinically significant in 94% (30) of the subjects. Scores on the CGAS dramatically improved (P < .0001). Mean scores on the Children’s Depression Inventory declined from 22, which is in the clinical range for depressive symptoms, to 8, which is below that range (P < .0001). On the Conners Parents Rating Scale, group means improved on all six scales; on five scales improvement was significant (P < .001 to P < .0001). There was also a marked jump in student grade point average within one marking period. Parents reported substantial improvement in hyperactivity, impulsivity, anxiety, conduct, and learning problems. Augmentation with fluoxetine also produced significant further improvement in sustaining attention and concentration and helped to alleviate symptoms of anxiety, depression, irritability, and oppositionalism that had not responded adequately to methylphenidate alone. More seriously affected children showed the most significant improvements (Gammon and Brown, 1993).
Fluoxetine in the Treatment of Children Diagnosed with Bulimia Nervosa
Kotler and colleagues (2003) treated 10 subjects (age range of 12 to 18 years) who were diagnosed with bulimia nervosa in an open, 8-week study with fluoxetine 60-mg/day dose. They offered subjects a 4-week supportive psychosocial treatment phase preceding the 8-week medication trial. One subject improved significantly after therapy alone and did not receive medication. Five subjects elected to start the medication phase initially. Fluoxetine was initiated at 20 mg/day and titrated to 60 mg/day by day 7 and continued for the next 7 weeks. The subjects improved having average weekly binges decrease from 4.1 to 0. Average weekly purges decreased from 6.4 to 0.9. All patients improved their CGI-I scales with 20% rated as much improved, 50% improved, and 30% slightly improved (Kotler et al., 2003).
Fluoxetine in the Treatment of Children Diagnosed with Autism Spectrum Disorders
Given that youth with autism frequently often have repetitive behaviors similar to those seen in OCD, it is logical to believe that SSRIs could potentially help decrease compulsive symptoms in these children. One double-blind, placebo-controlled crossover study used fluoxetine in children with autism and examined its effect on global improvement. Hollander and colleagues enrolled 45 subjects with autism spectrum disorder (ASD). They defined ASD as meeting criteria for autism, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDDNOS) by Autism Diagnostic Interview. Subjects were randomized into two acute 8-week phases separated by a 4-week washout phase. Dosage began with 2.5 mg/day of liquid fluoxetine the first week and was then titrated up for the next 2 weeks up to a maximum dose of 0.8 mg/kg/day by the end of week 4. This dose was maintained for the remainder of the 8-week phases. AEs were monitored by use of the Fluoxetine Side Effects Checklist (FSEC). Clinical response was assessed by CY-BOCS and CGI-AD assessments. Thirty-nine subjects were included in data analysis ranging in age from 5 to 16 years. The dosage range of fluoxetine used was 2.4 to 20 mg. Their analysis showed that low-dose fluoxetine was superior to placebo in the treatment of repetitive behaviors by CY-BOCX compulsion scale. The effect size was in the moderate-to-large range (0.76). The improvement in CGI autism scores was only slightly superior to placebo in the fluoxetine group. The
fluoxetine group did not differ significantly from placebo in treatment-emergent side effects. They did not detect any increase in suicide subscale measures, and anxiety/nervousness on fluoxetine was less than on placebo. The authors attribute the lack of side-effect differences between placebo and fluoxetine groups to their low doses and slow titration schedule. This contrasts with other studies which have found that SSRI treatment in ASD children frequently has increased side effects of behavioral activation (hyperactivity and agitation), aggression, and suicidal ideation (West et al., 2009).
fluoxetine group did not differ significantly from placebo in treatment-emergent side effects. They did not detect any increase in suicide subscale measures, and anxiety/nervousness on fluoxetine was less than on placebo. The authors attribute the lack of side-effect differences between placebo and fluoxetine groups to their low doses and slow titration schedule. This contrasts with other studies which have found that SSRI treatment in ASD children frequently has increased side effects of behavioral activation (hyperactivity and agitation), aggression, and suicidal ideation (West et al., 2009).
Fluoxetine in the Treatment of Children Diagnosed with Selective (Elective) Mutism
Black and Uhde (1994) treated 15 subjects (age range of 6 to 11 years) who were diagnosed with elective mutism with fluoxetine in a double-blind, 12-week study. During a single-blind, 2-week placebo period preceding the study, a 16th subject who responded to placebo was dropped. Three boys and three girls (mean age, of 9.1 ± 2.3 years) were randomly assigned to fluoxetine. Three boys and six girls (mean age, of 8.1 ± 1.6 years) were assigned to placebo. Fluoxetine was given at a dose of 0.2 mg/kg/day for the first week, increased to 0.4 mg/kg for the second week, and further increased to 0.6 mg/kg for the final 10 weeks of the study. The mean maximum dose of fluoxetine was 0.60 to 0.62 mg/kg/day or 21.4 mg/day (range, 12 to 27 mg/day). The fluoxetine group improved more than the placebo group on 28 or 29 rating scales, but most of the differences were not significant. Both groups showed significant improvement from baseline over time in elective mutism, anxiety, and social anxiety as rated by parents, teachers, and clinicians. The fluoxetine group improved significantly more than the placebo group on parents’, but not on teachers’ or clinicians’, ratings of mutism and clinical global improvement. This was consistent with earlier findings that children with elective mutism show improvements in the home setting before school and clinic settings. The authors noted that, although statistically significant, the improvements were modest and that the subjects continued to show serious impairments in their functioning. Untoward effects were minimal (Black and Uhde, 1994).
Dummit et al. (1996) reported a 9-week, open-label study of fluoxetine in the treatment of 21 children (5 males, 16 females; mean age, 8.2 ± 2.6 years; range, 5 to 14 years) who met DSM-IV (APA, 1994) criteria for selective mutism and comorbid avoidant disorder or SP. Efficacy was assessed by ratings of the CGAS and the Liebowitz Social Anxiety Scale (LSAS). Subjects rated themselves on the social behavior scale, and parents rated their children on the same scale. Initially, fluoxetine was begun at a dose of 1.25 mg/day and gradually increased. As the authors found that none of the first 10 subjects improved on <20 mg/day and there were no problematic untoward effects at that dose, for subsequent subjects the initial dose was increased to 5 mg/day for the first week, 10 mg/day for the second week, and 20 mg/day for the third week. It was permissible to increase the dose to 40 mg/day for the sixth week and to 60 mg/day at the eighth week if clinically indicated. The mean optimal daily dose of fluoxetine was 28.1 mg/day or 1.1 mg/kg/day, and the dose ranged from 20 to 60 mg/day, with 15 subjects receiving 20 mg/day, 4 receiving 40 mg/day, and 2 requiring 60 mg/day. Overall scores on all indicators indicated significant improvement on all rating scales (P < .001 for clinicians’ and subjects’ self-ratings and P < .005 for parental ratings). After 9 weeks, 16 of 21 (76%) subjects were rated “improved” by their psychiatrist. Treatment outcome was inversely related to age, with 14 of 15 children <10 years improving to a clinically meaningful degree and only 2 of the 6 children ≥10 years old doing so. Four children developed excitement and behavioral disinhibition, which resulted in three of them discontinuing the medication and dose reduction in the fourth child. Most untoward effects were transient, and none was reported during the final week of treatment. The authors recommended a relatively low initial dose of
5 to 10 mg/day because of the possibility of behavioral activation and also noted that complete remission of the elective mutism often required more than 9 weeks of treatment, even in the marked treatment responders.
5 to 10 mg/day because of the possibility of behavioral activation and also noted that complete remission of the elective mutism often required more than 9 weeks of treatment, even in the marked treatment responders.
Sertraline Hydrochloride (Zoloft)
Sertraline hydrochloride is an SSRI that is chemically unrelated to other antidepressants currently in use. Its antidepressant effect is presumed to be related to its inhibition of neuronal serotonin uptake. Sertraline has also been approved for the treatment of OCD in patients 6 years of age and older, and for the treatment of panic disorder, social anxiety disorder, and PTSD in adults. It has only very weak effects on norepinephrine and dopamine reuptake. In vitro, sertraline has no significant affinity for alpha-1, alpha-2, or beta-adrenergic, cholinergic, gamma aminobutyric acid (GABA), dopaminergic, histaminergic, 5-HT1A, 5-HT1B, or 5-HT2 serotonergic, or benzodiazepine receptors. Chronic administration of sertraline is thought to down-regulate norepinephrine receptors.
Pharmacokinetics of Sertraline Hydrochloride
Peak plasma levels of sertraline hydrochloride are reached between 4.5 and 8.4 hours after ingestion. Food increases the availability of sertraline slightly and peak blood levels are higher and are reached more quickly. Dosage, however, does not require adjusting and sertraline may be taken with or without food. During the first pass, sertraline undergoes extensive N-demethylation in the liver to form N-desmethylsertraline, which has a half-life of 62 to 104 hours but is significantly less pharmacologically active than sertraline. Both drug and metabolite subsequently undergo oxidative deamination followed by reduction, hydroxylation, and glucuronide conjugation. The average termination half-life of plasma sertraline is about 26 hours. Steady-state plasma levels at a given dose occur within about 7 days. Drug and metabolites are excreted in about equal amounts in the feces and urine, although all unmetabolized sertraline (about 13%) is found in the urine.
Data provided by the manufacturer suggest that patients in the pediatric age range, 6 through 17 years old, metabolize sertraline with slightly greater efficacy than do adults. Nevertheless, because of their lower body weights, lower doses than that prescribed for adults may be advisable (PDR, 2000).
Alderman et al. (1998) explored single 50-mg-dose and steady-state (200 mg/day) pharmacokinetics of sertraline in 61 patients (age range, 6 to 17 years of age). The authors found that all pharmacokinetic parameters for serum sertraline and desmethylsertraline levels were similar for their patients and those reported for adults when corrected for weight. They conclude that the titration regime recommended for adults was suitable and safe.
In their study of 92 children and adolescents prescribed sertraline for the treatment of OCD, March et al. (1998) reported that trough plasma levels of sertraline and its active metabolite desmethylsertraline, normalized for body weight, did not correlate significantly with age, sex, or clinical response.
Axelson et al. (2002) reported that the pharmacokinetics of sertraline varied significantly in adolescents (mean age 15.1; range 13.1 to 17.9 years) according to dose. The mean steady-state half-life at 50 mg/day was 15.3 ± 3.5 hours compared with 20.4 ± 3.4 hours at a dose of 100 to 150 mg/day. Because of this, they recommended that sertraline should be administered twice daily if adolescents were receiving <200 mg daily. The authors also measured platelet serotonin reuptake inhibition. They found that after 2 weeks’ treatment with 50 mg/day of sertraline, platelet serotonin uptake was <70% in six of nine subjects and concluded that most adolescents need sertraline doses higher than 50 mg daily to achieve an adequate therapeutic response.
Alderman et al. (2006) reported the tolerability and efficacy of long-term sertraline use up to 200 mg/day in children and adolescents (Alderman et al., 2006). In this study, 16 children (6 to 12) and 27 adolescents (13 to 18) who were in a short-term study of sertraline safety and efficacy entered in a 24-week open-label phase with sertraline titrated to 200 mg/day. The mean daily dose at endpoint was 157 ± 49 mg. No significant age or gender effects or age-by-gender interactions were observed in sertraline values. Mean sertraline plasma concentrations normalized for dose and body weight did not differ significantly by age or gender. They had two patients (7%) discontinue due to AEs. Patients in the study had OCD or MDD, and both groups showed clinical improvement over 24 weeks of treatment. This study suggests that long-term treatment with sertraline in children and adolescents results in dose-normalized plasma concentration similar to that seen in adults.
Contraindications for the Administration of Sertraline Hydrochloride
Known hypersensitivity to sertraline hydrochloride is a contraindication.
Because of a possibility for serious, life-threatening reactions when administered simultaneously with an MAOI, the use of sertraline in combination with an MAOI is contraindicated. At least 14 days should elapse after stopping an MAOI before administering sertraline. Based on the half-life of sertraline, at least 14 days should elapse following its discontinuation before administering an MAOI.
Untoward Effects of Sertraline Hydrochloride
The most common side effects of sertraline in premarketing controlled studies included nausea, insomnia, diarrhea, ejaculatory delay, and somnolence. March et al. (1998) reported in a multicenter, 12-week, placebo-controlled trial of 187 children and adolescents (age range, 6 to 17 years) that 4 untoward effects occurred significantly more frequently in the subjects receiving sertraline: insomnia (37% vs. 13%; P <.001); nausea (17% vs. 7%, P = .05); agitation (13% vs. 2%, P = .005); and tremor (7% vs. 0%, P = .01). Additional untoward effects that occurred in at least 2% of the patients of the March et al. study and at least at twice the rate reported in patients on placebo were hyperkinesia, twitching, fever, malaise, purpura, weight loss, impaired concentration, manic reaction, emotional lability, abnormal thinking, and epistaxis (PDR, 2000). There is one case report of serotonin syndrome occurring in a 9-year-old boy following administration of a single 50-mg dose of sertraline (Phan et al., 2008).
Effects of Sertraline upon the Heart
Wilens et al. (1999) prospectively assessed cardiovascular functions (vital signs and ECG parameters) of the 187 children and adolescents diagnosed with OCD and treated with sertraline (N = 92) or placebo (N = 95) as discussed later in the report by March et al. (1998). Baseline data were contrasted with data from weeks 1, 4, and 12 of the study. There were no clinically significant differences in supine or standing heart rates or systolic or diastolic blood pressures between the two groups. There were no significant differences in PR, QRS, or QTc, and no significant new developments of sinus arrhythmias, nodal abnormalities, or intraventricular conduction abnormalities with the exception of two subjects on sertraline who developed a QTc interval of >440 msec (P = .05); no subject developed a QTc interval of >460 msec. The authors concluded that monotherapy with sertraline in doses of up to 200 mg/day in healthy children and adolescents was not associated with any symptomatic or asymptomatic clinically significant cardiovascular untoward effects but cautioned that the sample size precluded conclusions regarding small differences or rare events.
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