Do Antidepressants Induce Psychosis in Children and Adolescents? A Naturalistic Study in Ambulatory Pediatric Population

Abstract

Objective:

The aim of the present study was to examine if selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) induce psychotic symptoms in children and adolescent outpatients. We secondarily aimed to assess the occurrence of adverse events (AE), with particular interest in psychiatric adverse events (PAE), timing of their onset, and the effectiveness of antidepressants in children and adolescents.

Methods:

We retrospectively evaluated the computerized medical records of children and adolescents treated with antidepressants (SSRIs or SNRIs) for depressive disorders, anxiety disorders, and obsessive–compulsive disorders. AE and Clinical Global Impressions scores were recorded.

Results:

Sixty-nine children and adolescents aged 13.3 ± 3.0 years were included. None of the patients treated presented with acute psychotic symptoms (delusions, hallucinations, and disorganized thinking or behavior). Duration of treatment extended over 13.4 ± 11.8 months. PAE occurred in 39% of cases. Of these, 16% included suicidality (ideations or attempts), and 3% included nonpsychotic hypomanic symptoms. Significant clinical improvement was achieved in 41% of patients.

Conclusions:

In contrast to the clinical impression of some clinicians, antidepressant treatment in pediatric ambulatory population was not associated with emergence of psychotic symptoms.

Introduction

Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), are among the most commonly prescribed psychopharmacologic drugs, widely used to treat depressive disorders, anxiety disorders, and obsessive–compulsive disorder (OCD) among children and adolescents (Zito et al. 2003; Jonas et al. 2013; Olfson et al. 2015).

Antidepressants may worsen emotional, cognitive, or behavioral symptoms and cause physical adverse events (AE) in pediatric population. The most common AE experienced in 10% or more of children and adolescents on antidepressant treatment include nausea, diarrhea, abdominal pain, restlessness, insomnia, headache, and sexual dysfunction (Kaufman et al. 1997; Scharko 2004; Dopheide 2006; Safer and Zito 2006). However, the most concerning AE in adolescents is increased risk of suicidal ideation and behavior with the use of SSRIs compared with placebo (RR 1.58; 95% CI 1.02–2.45) (Hetrick et al. 2012). Furthermore, a meta-analysis of nine randomized controlled trials (RCTs) in children and adolescents showed that antidepressant-related activation (hyperactivity, impulsivity, insomnia, or disinhibition) tended to be associated with antidepressant treatment compared with placebo (OR 1.86, 95% CI 0.98–3.53, p = 0.054) (Strawn et al. 2015).

While AE are routinely monitored in clinical trials, little is known about SSRI-/SNRI-induced psychosis and/or mania in children and adolescents with no history of bipolar disorder (BD). Mania with psychosis often begins with mild insomnia, nervousness, anxiety, and/or hyperactivity and progresses toward more severe agitation, aggression, and mania.

Most relevant data are drawn from research on adult patients. There have been a few case reports of adult patients with and without preexisting history of psychosis, developing psychotic symptoms on antidepressant medications with disappearance of symptoms upon discontinuation (Popli et al. 1997; Preda et al. 2001; Cancelli et al. 2004; Capaldi and Carr 2010).

Another study assessed plasma-free catecholamine metabolites (homovanillic acid [HVA] and methoxyhydroxyphenethylene glycol [MHPG]) that are often elevated in acute psychosis in 39 patients with antidepressant-induced psychotic and/or manic symptoms. The authors found that plasma HVA levels in patients who became psychotic or manic following SSRIs were similar to those of patients with a psychotic/manic relapse secondary to discontinuation of antipsychotic treatment. They concluded that “these laboratory finding further support the clinical experience indicating that SSRI antidepressants can exacerbate mania and psychosis in vulnerable individuals” (Fortunati et al. 2002).

However, less research has been done in children and adolescents, and most relevant reports are single or small-sample case studies. One such report described a 14-year-old boy with OCD treated with a high dose of citalopram (60 mg/day) who developed psychotic symptoms, including thought insertion and delusions. Two days after dose reduction (to 40 mg/day), the psychotic symptoms disappeared (Lamps 2002). In a retrospective chart review, 8 of 82 (10%) children and adolescents treated with SSRIs for either depressive disorders or OCD were reported to develop psychotic symptoms (Wilens et al. 2003). However, no details are provided in this study about the types of psychotic symptoms observed, and the psychotic symptoms are not distinguished from manic symptoms (Wilens et al. 2003).

In addition, there have been few studies regarding antidepressant-induced mania (AIM) in children and adolescents. The rates of AIM were reported to be 7% to 10% in nonbipolar children and as high as 67% in children with bipolar affective disorder (Martin et al. 2004). In a review comparing 29 single case studies and RCTs, it was determined that youth are genetically loaded for BD, have a family history of BD, and are more likely to develop manic symptoms as a result of antidepressant treatment than are typical patients. Of all the studies, 21% of patients who developed AIM had a family history of BD (Goldsmith et al. 2011). Pooled data from RCTs and case reports found a 2% mean rate of AIM in children and adolescents without a family history of BD, with the highest incidence of mania occurring with fluoxetine (6%); for placebo, the incidence was 0%–2% (Cheung et al. 2005). It was suggested that mania emerges more frequently in patients at risk for BD because the antidepressant unmasks BD that was already latent within them. Specifically in pediatric patients with BD, SSRI treatment increases the chance of manic symptom development threefold compared with patients who did not receive SSRIs (Goldsmith et al. 2011).

The aim of the present study was to assess the rate of occurrence of AE induced by SSRI/SNRI treatment in children and adolescents, with special attention paid to the development of psychotic symptoms. We further evaluated the emergence of other psychiatric adverse events (PAE), including mania, hypomania, suicidality, acceleration-related symptoms, sleep disturbances, and mood changes, as well as physical AE.

Methods

Participants

A retrospective analysis of the computerized medical charts of 657 patients treated in the Child and Adolescent Psychiatry Outpatient Clinic of a major hospital in central Israel was conducted, covering a 4-year period between January 2010 and October 2014. From this pool of patients, we identified 167 who were exposed to an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, or sertraline) or SNRI (venlafaxine) antidepressant for the treatment of depressive disorders, OCD, anxiety disorders, posttraumatic stress disorder (PTSD), and somatization disorders.

Older patients (age >18 years) and patients with intellectual disability, autistic spectrum disorders (ASDs), and genetic disorders (e.g., velocardiofacial syndrome and Williams syndrome) were excluded as neurobiological and AE profiles may be different among these groups. Patients concurrently treated with antipsychotics or with a psychiatric history of BD or psychosis were excluded to obtain a more rigorous review of behavioral changes related solely to antidepressant treatment. In addition, patients with a recorded nonadherence to treatment were excluded. Patients receiving concomitant treatment with stimulants for attention-deficit/hyperactivity disorders (ADHD) were included in the study.

All participants underwent a clinical evaluation performed by two senior psychiatrists, and all diagnoses were established according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria (American Psychiatric Association 1994).

The Sheba Medical Center Review Board approved the protocol of this chart review design, and the need for informed consent was waived due to the retrospective nature of the study, namely, review of electronic medical records.

Assessment

Demographic and clinical data

The following demographic and clinical data were collected: (1) age and gender, (2) physical illness, (3) family history of psychiatric disorders in first-degree relatives, (4) prior medication treatment, (5) adjunctive treatment with another medication along with antidepressants, (6) type and dosage of SSRI/SNRI administered, and (7) suicidality, defined as emergence of suicidal ideations, a specific plan to commit suicide or any suicidal attempt.

Adverse events

Each medical record included spontaneous reports of AE by the patients or their parents. All detailed electronic charts were systemically evaluated, collecting data from all visits, to determine if an AE had occurred, and if so, the nature of the event, its clinical implications, and the antidepressant and dose with which the AE occurred. We further observed the timing of the appearance of each AE in relation to the beginning of treatment or dose increase. AE that occurred within the first 3 months after initiation of treatment or a dose increase were referred to as early onset AE. This time point was chosen based on a previous study that demonstrated that the median time for onset of PAE in SSRI-treated children was within the first 91 days of treatment (Wilens et al. 2003). Events that were reported at a later time point within the first year of treatment were considered late onset. The major AE in SSRI/SNRI treatment reports were organized into two major categories. The first is PAE, which is further divided into acceleration (which refers to irritability, restlessness, lability, aggression, agitation, crying spells, and oppositional and impulse control difficulty), mood disturbances (anxiety, depressed mood, dysphoria, diminished functioning, decreased motivation, and indifference), aggravation of OCD, hypomania; psychotic symptoms, sleep disturbances, fatigue and insomnia, and suicidality. The second group includes the physical AE. Data on emergent visits to the clinic due to suicidal ideations or attempts in addition to consultation phone calls were also retrieved from the charts.

Clinical improvement

The Clinical Global Impressions (CGI) scales, CGI-Severity (CGI-S) and CGI-Improvement (CGI-I), were completed retrospectively to determine the severity of the psychiatric disorders at the time of initiation of antidepressant treatment and the alterations following the treatment (Guy 1976). The CGI-S scale measures the illness severity on a seven-point scale ranging from 1 = normal, not at all ill, to 7 = among the most extremely ill. The CGI-S scale was completed at two time points: at baseline upon prescribing the antidepressant and at the last follow-up visit or, alternatively, upon switching to another antidepressant or discontinuation of antidepressant treatment. The CGI-I estimates improvement or worsening of psychiatric symptoms compared to baseline. The improvement is rated on a seven-point scale ranging from 1 = very much improved since the initiation of treatment to 7 = very much worse. Significant clinical improvement is considered as CGI-I = 1 or 2 (very much improved or much improved, respectively). The CGI-I score was completed at the last visit or upon switching to another antidepressant or discontinuation of antidepressant treatment. The ratings were conducted independently by two trained clinicians based on well-documented notes in the electronic records. The completion of the CGI retrospectively based on chart reports has been successfully used by us in a previous pediatric study (Green et al. 2012) as well by others (Hedges et al. 2009). As antidepressants target multiple symptoms and were prescribed for a wide range of diagnoses that may overlap, both CGI-S and CGI-I were used to evaluate the alterations in the severity of the primary psychiatric diagnosis of each patient. In cases when there were two main psychiatric diagnoses that were simultaneously being treated (e.g., OCD and depressive disorders), each diagnosis was assessed separately.

Statistical analysis

Statistical analysis was conducted using SPSS software version 21 (IBM, Chicago, IL). A paired sample t-test was performed to test the differences between baseline and follow-up CGI-S scores for each of the tested diagnoses (depressive disorders, anxiety disorders, and OCD). Pearson's χ² tests were conducted to assess differences in categorical variables, and unpaired Student's t-tests were performed to determine differences in continuous variables. A two-tailed p-value of 0.05 was considered as the significance threshold. Data are expressed as mean ± SD or rates.

Results

In the present study, 69 children (32 boys and 37 girls) aged 13.3 ± 2.95 (range 6.1–17.8) years fulfilling the inclusion criteria were identified and included in the analyses. The mean treatment duration extended over 13.4 ± 11.8 (range 1–48) months. Demographic and clinical characteristics of the study sample are shown in Table 1.

Table 1.

Demographic and Clinical Characteristics of the Children and Adolescents Treated with Antidepressants (N = 69)

Characteristics	Mean ± SD (range)	n (%)
Age (years)	13.31 ± 2.95 (6.17–17.82)
Duration of follow-up (months)	13.4 ± 11.8 (1–48)
Sex
Male		32 (46)
Female		37 (54)
Psychiatric disorders^a
Anxiety disorders		36 (52)
Depressive disorders		26 (38)
Obsessive–compulsive and related disorders		17 (25)
Attention-deficit/hyperactivity disorders		26 (38)
Learning disorders		8 (12)
Tic disorders		4 (6)
Posttraumatic stress disorder		2 (3)
Elimination disorders		3 (4)
Disruptive, impulse control, and conduct disorders		7 (10)
Somatic symptom and related disorders		4 (6)
Eating disorders		3 (4)
Personality disorders		9 (13)
SSRI/SNRI medications (mg/day)^b
Fluoxetine	23.07 ± 12.23 (10–60)	53 (60)
Citalopram	17.69 ± 11.68 (10–40)	13 (15)
Sertraline	98.86 ± 62.42 (25–200)	11 (13)
Venlafaxine	77.08 ± 32.72 (37.5–150)	9 (10)
Concomitant medications
Stimulants		25 (36)
Methylphenidate		23 (33)
Amphetamines		2 (3)
Anxiolytics		5 (7)
Antihistamines		6 (9)
Melatonin		2 (3)
Clonidine		1 (1)
Isotretinoin		1 (1)
Minocycline		1 (1)
Corticosteroids		1 (1)
Levothyroxine		1 (1)
Desmopressin		1 (1)
Oxybutynin		1 (1)
Glycopyrulate		1 (1)
Psychiatric history in first-degree family members^c		27
Suicidality
Previous suicidal attempt		12 (17)
Suicidal ideations		6 (9)
Specific plan to commit suicide		4 (6)

Some of the patients suffered from more than one psychiatric disorder.

Some of the patients underwent more than one treatment trial with antidepressants.

In some families members, none had any psychiatric history.

SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin–norepinephrine reuptake inhibitor.

Primary indications for antidepressant treatment were anxiety disorders (n = 36, 52%) [generalized anxiety disorder (n = 15), anxiety disorder unspecified (n = 7), selective mutism (n = 3), social phobia (n = 4), and separation anxiety disorder (n = 2)], depressive disorders (n = 26, 38%) [major depressive disorder (n = 6), dysthymia (n = 6), and mood disorder not otherwise specified (n = 13)], and OCD (n = 17, 25%). In four cases, there was an overlap in the indication for SSRI treatment. Overall, there were 86 SSRI/SNRI treatment trials comprising fluoxetine (n = 53), citalopram (n = 13), sertraline (n = 11), and venlafaxine (n = 9). Seventeen patients (25%) were exposed to multiple antidepressant trials. Patients had a high degree of comorbidity, including ADHD (n = 26, 38%), personality disorders (n = 9, 13%), learning disorders (n = 8, 12%), tic disorders (n = 4, 6%), PTSD (n = 2, 3%), elimination disorders (n = 3, 4%), disruptive, impulse control, and conduct disorders (n = 7, 10%), somatization disorders (n = 4, 6%), and eating disorders (n = 3, 4%). Concomitant psychotropic medications included stimulants (n = 25, 36%), clonidine (n = 1, 1%), anxiolytics (n = 5, 7%), antihistamines (n = 6, 9%), and melatonin (n = 2, 3%) targeting sleep disturbances. Twenty-seven patients had first-degree relatives (n = 40) diagnosed with psychiatric disorders, including depressive disorders (n = 14), BDs (n = 3), anxiety disorders (n = 9), ADHD (n = 7), OCD (n = 2), eating disorders (n = 2), ASD (n = 2), and personality disorder (n = 1). Some of the family members had more than one psychiatric disorder.

Adverse events

Antidepressant treatment-related AE are shown in Table 2. Overall, 42 patients (61%) presented with any AE. None of the patients presented with acute psychotic symptoms (delusions, hallucinations, and disorganized thinking or behavior). Twenty-six patients (38%) experienced PAE grouped into psychotic symptoms, mania and hypomania, suicidality, acceleration, sleep, and mood domains. Acceleration-related AE were most common, reported in 15 patients (22%), and comprising irritability (n = 7, 10%), restlessness (n = 10, 14%), emotional lability (n = 2, 3%), aggressive behavior (n = 3, 4%), agitation (n = 3, 4%), crying spells (n = 2, 3%), oppositional behavior (n = 2, 3%), and impulse control difficulty (n = 2, 3%). Two patients (3%) developed hypomanic symptoms, including psychomotor agitation, decreased need for sleep, heightened euphoric mood, impulse control difficulty, and poor judgment. In one of these cases, drug discontinuation for a week coupled with initiation of a mood stabilizer was followed by symptom improvement. The second case did not necessitate drug discontinuation as hypomanic symptoms disappeared following dose reduction of fluoxetine from 20 to 10 mg/day.

Table 2.

Adverse Events Reported in the Children and Adolescents Treated with Antidepressants (N = 69)

Adverse event	n (%)	Days after initiation of treatment or dose increase (mean ± SD)
Any adverse event	42 (61)	87.8 ± 101.5
Psychiatric adverse events	26 (38)	74.1 ± 82.9
Psychotic symptoms	0
Delusions	0
Hallucinations	0
Negative symptoms	0
Hypomania	2 (3)	107.0 ± 34.0
Mania	0
Suicidality	11 (16)	70.7 ± 69.5
Suicidal ideations
Aggravation of ideations	5 (7)	82 ± 103.7
Emergence of ideations	0
Suicidal attempts	6 (9)	64.1 ± 44.7
Drug overdose	6 (9)	81.0 ± 37.8
Cuts	2 (3)	13.5 ± 3.5
Self-injurious behavior
Aggravation of self-mutilation	1 (1)	20.0
Emergence of self-mutilation	0
Acceleration	15 (22)	83.1 ± 77.0
Irritability	7 (10)	73.4 ± 61.6
Emotional lability	2 (3)	42.0 ± 5.6
Crying spells	2 (3)	30.0 ± 22.6
Aggressive behavior	3 (4)	161.0 ± 187.5
Restlessness	10 (14)	61.6 ± 28.9
Agitation	3 (4)	106.3 ± 117.7
Oppositional behavior	2 (3)	40.5 ± 37.5
Impulse control difficulty	2 (3)	86.5 ± 44.5
Mood/anxiety symptoms	9 (13)	87.5 ± 52.4
Anxiety (aggravated)	2 (3)	126.5 ± 12.2
Depressed	0
Dysphoric	3 (4)	118.6 ± 72.2
Diminished functioning level	4 (6)	90.5 ± 80.5
Decreased motivation	4 (6)	70 ± 32.1
Apathy	1 (1)	76.0
Sleep disturbances	8 (12)	38.2 ± 17.8
Insomnia	7 (10)	36.4 ± 18.5
Nightmares	2 (3)	68.0 ± 24.0
Sedation	11 (16)	40.8 ± 28.3
Fatigue	7 (10)	59.6 ± 140.2
Obsessive/compulsive symptoms	3 (4)	54.3 ± 24.5
Aggravation of obsessive/compulsive symptoms	3 (4)	54.3 ± 24.5
Physical	21 (30)	166.6 ± 171.5
Gastrointestinal	9 (13)	139.7 ± 146.0
Nausea	3 (4)	32.0 ± 29.8
Decreased appetite	3 (4)	97.3 ± 82.5
Weight loss	2 (3)	128.5 ± 86.9
Weight gain	2 (3)	336 ± 192.3
Increased appetite	0
Thirst	0
Diarrhea	0
Constipation	0
Other	1 (1)	270
Other physical	12 (17)	166.6 ± 171.5
Headache	2 (3)	59.5 ± 23.3
Abdominal pain	3 (4)	126.6 ± 83.5
Chest pain	2 (3)	283 ± 189.5
Dizziness	1 (1)	10.0
Orthostatism	1 (1)	46.0
Palpitations	1 (1)	243.0
Exertional dyspnea	2 (3)	330.0 ± 123.0
Skin itching	1 (1)	74.0
Skin rash	1 (1)	35.0
Increased libido	1 (1)	570.0
Decreased libido	0
Neurological	1 (1)	96 ± 99
Tics
Emergence of tics	1 (1)	26.0
Slurred speech
Aggravation of slurred speech	1 (1)	166.0

Aggravation of suicidal ideation presented in five patients (7%), all of whom had a history of suicidal ideations. Six patients (8%) committed suicidal attempts, two of whom committed two suicidal gestures during the study period. Of the eight total attempts, six were done by drug overdose and two by self-cutting with intention to die. From all, one patient attempted the first suicidal gesture in his life, and another patient, with a history of self-cutting with no thoughts of death, committed suicidal attempt by drug overdose. The first patient, who had been under treatment with fluoxetine 20 mg/day for 81 days, made an impulsive suicide attempt by drug overdose using 6 tablets of acetaminophen, 3 tablets of fluoxetine, and 3 tablets of zinc. The patient was hospitalized overnight for observation. A different patient with a history of self-mutilation with no intention to die also made a suicide attempt by drug overdose while on SSRI treatment. The suicide attempt occurred 100 days after beginning of treatment with citalopram and 24 days after dose increase from 10 to 15 mg/day. The patient acted impulsively, taking 15 fluoxetine tablets. The patient was then hospitalized in a psychiatric ward, and citalopram was discontinued and sertraline was initiated.

Eight patients (12%) developed sleep disturbances, namely, insomnia (n = 7, 10%) and nightmares (n = 2, 3%). Sedation occurred in eleven patients (16%), and fatigue occurred in seven patients (10%). Mood changes, documented as mood alteration from pretreatment level and necessitated dose augmentation, were recorded in nine patients (13%). In somatic domain AE, gastrointestinal-related symptoms were the most frequently experienced physical AE (n = 9, 13%).

The mean time for onset of any AE from initiation of treatment or dose increase was 87.8 ± 101.5 days. Overall, any PAE were reported in 74.1 ± 82.9 days from initiation of treatment or dose increase. Late-onset AE (appearing 3 months or more after initiation of treatment or dose increase) included hypomania, aggressive behavior, restlessness, agitation, aggravation of anxiety, and dysphoric mood. The latest somatic symptoms to occur were weight gain (336 ± 192.3 days), cardiovascular AE, including chest pain (283 ± 189.5 days), exertional dyspnea (330.0 ± 123.0 days), and palpitations (243.0 days).

We did not find any significant effects for any of the demographic or clinical variables tested (age, sex, family history of psychiatric disorders, concomitant stimulant medications, and the patients’ main diagnosis) on the rates of PAE or physical AE in all domains (χ² tests, p ≥ 0.2 for all).

Clinical improvement

Based on the CGI-S scores, we found significant improvement from baseline to follow-up in severity of depressive disorders (5.31 ± 0.96 vs. 4.29 ± 1.83, respectively, t = 3.25, df = 34, p = 0.003), OCD (4.85 ± 1.04 vs. 3.33 ± 1.52, respectively, t = 3.86, df = 20, p = 0.001), and anxiety disorders (4.55 ± 0.74 vs. 2.97 ± 1.58, respectively, t = 6.3, df = 34, p = 0.0001).

Looking into the CGI-I scores, significant clinical improvement (much improved = 2 or very much improved = 1 on the CGI-I scale) at follow-up was found in 11 patients (31%) with depressive disorders, 9 patients (43%) with OCD, and 17 patients (49%) with anxiety disorders.

Discussion

Major findings

In our sample of 69 children and adolescents treated with antidepressants, none experienced induction of psychotic symptoms. However, two patients (3%) developed hypomania-like symptoms, including elevated mood, decreased need for sleep, and poor judgment.

Overall, 42 patients (61%) presented with any AE, a rate that is consistent with the literature (Goodyer et al. 2007). Suicidal behavior presented in 11 patients (16%). None of the patients expressed emergence of new suicidal ideations. However, aggravation of suicidal ideation presented in 7% of patients, while 9% committed suicidal attempts during the study period. The highest clinical improvement rate was achieved in patients treated with antidepressants for anxiety disorders (49%), whereas 43% of patients treated for OCD achieved significant clinical improvement and 31% of patients in the depressive trial.

SSRI-induced psychosis

The risk factors of precipitating psychosis following the use of SSRIs are not clearly known but may be attributed to several factors. First, patients with a history of BDs may be associated with a greater susceptibility. In a retrospective study of 82 children with a history of BD, new-onset psychosis was reported in 12% of subjects (Faedda et al. 2004). However, evidence is lacking regarding the rates of SSRI-induced psychotic symptoms among children and adolescents with no history of affective disorders. Adults may show a greater vulnerability to psychosis induction with the use of antidepressants. In a retrospective review of 533 adults, it was found that 8.1% of psychiatric hospital admissions over a 14-month period could be attributed to AIM and/or psychosis. Most cases (61%) were known to have a history of psychosis (Preda et al. 2001). In addition, concomitant substance use, such as cannabinoid or stimulant use, may be involved in psychotic induction (Goldsmith et al. 2011). In our study of children and adolescents with no history of psychosis or affective disorders, none of the patients developed psychotic symptoms, data that may be helpful for physicians to consider when hesitating to prescribe SSRIs to this population.

The findings from treatment trials with SSRI medications of youngsters with attenuated psychotic syndrome also support our findings regarding the safety of antidepressants in terms of risk of inducing psychotic symptoms. These studies show that in comparison to atypical antipsychotics, SSRI medications seem to be more effective in reducing the rates of conversion of individuals with attenuated psychotic syndrome to a full-blown psychotic disorder (Cornblatt et al. 2007).

SSRI-induced mania or hypomania

In our study, two patients (3%) presented with hypomanic symptoms demonstrating elevated mood, reduced need for sleep, impulse control difficulty, and poor judgment. According to the literature, susceptibility to manic conversion with the use of antidepressants is higher in patients treated with tricyclic antidepressants (11.7%) compared with SSRIs (3.7%) and placebo (4.2%) in patients with bipolar depression. In contrast, switch rates among unipolar depressive patients are lower (1%) (Peet 1994). Compared with adults, children and adolescents who are treated with antidepressants are reportedly at higher risk for developing hypomania and mania (Martin et al. 2004). In children with a history of BD, manic conversion rate was observed in 44% of patients treated with antidepressants in one study (Faedda et al. 2004), but another study revealed a much lower switch rate of SSRI-related mania (5.4%), with peripubertal (10–14 years old) children being particularly susceptible (Martin et al. 2004). In the TADS study, mania occurrence was the same in both the fluoxetine-alone group and the placebo group (1%). However, 3% of patients on fluoxetine alone or fluoxetine plus cognitive behavioral therapy (CBT) experienced irritability and hypomania versus 1% of patients on placebo (Emslie et al. 2006).

Other SSRI-related PAE

One of the most disturbing AE of SSRIs is the occurrence of PAE comprising a collection of mood and behavioral symptoms. It is suggested that 25%–45% of children and adolescents treated for depressive disorders or OCD with fluoxetine or sertraline exhibit behavioral side effects, such as restlessness, excitation, sedation, disinhibition, or self-injurious behavior (Bailly 2008). In the TADS study, PAE were more common in patients receiving fluoxetine alone (23%) than in those receiving fluoxetine with CBT (15%) (Emslie et al. 2006). The higher rate of occurrence of PAE in our study (38%) may be related to the retrospective nature of our study and large variability in the duration of follow-up. As such, some of the reported PAE (e.g., irritability) may stem from exacerbation of the diagnosed psychiatric condition (e.g., depression) and thus are not real AE. Furthermore, in our study, as supported by the literature, most of the nonsuicidal, nonhypomanic PEA were managed in the clinic setting by either augmentation of the antidepressant type or dose reduction (Gualtieri and Johnson 2006).

Notably, SSRI-induced acceleration (referring to the activation cluster, including irritability, hyperactivity, impulsivity, and disinhibition) is distinct from treatment-emergent mania or hypomania (Walkup and Labellarte 2001). The average rate of SSRI-induced activation is 10.7% (range 8%–17%) for children and 2.1% (range 2%–5%) for adolescents, while rates for placebo are 3.4% and 1.9%, respectively. In these trials, insomnia was not included (Safer and Zito 2006). Occurrence of acceleration cluster AE may be a predictor of upcoming mania or psychosis. Another study found that behavioral disinhibition occurred in 7.5% of 263 pediatric inpatients and was associated particularly with the use of SSRIs (Carlson el al. 2003).

SSRI-related suicidal behavior

In recent years, SSRI-induced suicidal behavior in children and adolescents has received considerable attention in clinical trials. All antidepressants hold a black box warning issued by the FDA for increased suicidal thoughts or behaviors in patients younger than 25 years (FDA 2007). The FDA decision was based on RCT data suggesting an increased risk of suicidality up to 4% for all antidepressants, including SSRIs compared with placebo (2%) (Hammad et al. 2006). Pooled analysis of 17 RCTs of new-generation antidepressants for child and adolescent psychiatric disorders (N = 3229) revealed a risk ratio of 1.58 for suicidal events (behavior or ideation), as evaluated by the Columbia Classification Algorithm of Suicide Assessment, by 58% for those on antidepressants compared with placebo. There was no evidence that the effect of new-generation antidepressants on suicide-related outcomes was modified by drug class (Hetrick et al. 2012).

In our study, five patients (7%) exhibited aggravation of suicidal ideation, but none of the patients expressed emergence of new-onset suicidal ideations. Six patients (8%) committed eight suicidal attempts, with no complete suicide in any attempt. The relatively high rate of suicidality in our sample is consistent with population-based studies presenting 12%–23% reporting suicidal ideation and 4%–8% of adolescents (aged 13–18 years) attempting suicide. Particularly, patients with a history of suicidal attempts, as well as those with comorbidities, are at increased risk for suicidal ideation (Hetrick et al. 2007).

Timing of AE

We had the opportunity to retrospectively follow back patients on a long-term period. In our study, suicidal attempts by self-cutting were the earliest AE to arise within the first 2 weeks of treatment, possibly due to impulsivity. Emotional lability, crying spells, and oppositional behavior were reported to occur within the first 3 weeks of treatment. Mood and anxiety AE appeared 87.5 ± 52.4 days following initiation of treatment. Similar to previous reports in pediatric population, amotivational syndrome (characterized by apathy, lack of motivation, lack of appropriate concern, and sometimes disinhibition) occurred during the first 6 months of antidepressant treatment (Garland 2001). The AE that was last to emerge was weight gain (336 ± 192.3 days following initiation of treatment). This is in line with previous reports on antidepressant-induced weight gain in children and adolescents (Jerrell 2010; Cockerill et al. 2014).

Limitations

The major limitations of this study are its retrospective nature and the use of data from computerized medical records of visits. It was difficult to ascertain whether the emergence of AE was related to the initiation of an SSRI drug therapy or inherent in the disorder course. Furthermore, we did not use a cutoff time frame from initiation of treatment to a maximal latency period, instead aiming to find all AE that occurred following drug initiation or dose augmentation. In the present naturalistic study, we could not be confident of medication adherence, although patients with recorded nonadherence were excluded from the study. The AE were not methodically assessed as prespecified outcomes; rather, the events were collected from spontaneous reports of the patients and their parents. However, the child psychiatrist was aware of common SSRI-related AE, such as psychotic or manic symptoms, acceleration, mood changes, suicidality, sleep, and somatic symptoms. Additionally, assessment of the improvement was conducted retrospectively by the CGI-S and CGI-I based on a chart review of each visit.

Conclusions and Clinical Significance

In our study, we found that SSRI/SNRI treatment in nonpsychotic and nonbipolar pediatric ambulatory population did not induce psychotic symptoms and appears to be safe in this regard. However, it is of note that our sample size was too small to detect rare AE of antidepressants, including emergence of psychosis.

Footnotes

Disclosure

No competing financial interests exist.

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