SSRIs-Related Behavioural Syndromes in Children and Adolescents

Dear Editor:

Selective Serotonin Reuptake Inhibitors (SSRIs) have become increasingly the mainstay of treatment for a wide array of depressive and anxiety disorders in Child and Adolescent Psychiatry (CAP) reflecting efficacy coupled with reasonable safety and tolerability- unlike its predecessors; tricyclic antidepressants (TCAs). Dire shortage of clinicians trained in Child and Adolescent psychotherapy renders SSRIs a default first-line treatment. FDA-approved SSRIs in CAP are sertraline, fluvoxamine, fluoxetine, and, escitalopram. Apart from expected somatic side-effect profile of SSRIs related to excess serotonin in the synaptic cleft stimulating post-synaptic 5HT2A, 5HT2c, and 5HT3 receptors, behavioural syndromes are now more frequently encountered in clinical practice that mandate special characterization.

Here, I delineate eight of these syndromes- mostly based on clinical experience, as there is dearth of pertinent data in literature notably regarding CAP. Its neurobiologic correlates are yet to be defined.

1. SSRI-Activation Syndrome (Reinblatt, dosReis, Walkup, & Riddle, 2009):

   • It is more in CAP populations;
   • It is commonplace;
   • Tends to occur early-on during course of treatment;
   • Mostly manifests as agitation, dysphoria or akathisia, but with no striking mood changes;
   • It is not indicative of latent bipolarity;
   • And responds to dose reduction or slower titration.
2. SSRI-Manic/Hypomanic Switch (Joseph, Youngstrom, & Soares, 2009):

   • It is less common than the activation syndrome;
   • It is usually of later onset;
   • Manifests striking mood changes, with hyperactivity;
   • Might continue symptomatic after stopping SSRI;
   • And indicative of bipolar (III) disorder;
   • Cycle acceleration is also possible;
   • Stopping culprit agent is mandatory or cautious use under umbrella of mood-stabilization.
3. SSRI-Discontinuation Syndrome (Hosenbocus, & Chahal, 2011):

   • It occurs with prolonged use (at least 1 month);
   • Follows abrupt cessation;
   • It takes place within 1–7 days of stopping of offending agent;
   • Notably manifest when higher doses employed;
   • More likely with short half-life agents;
   • It presents in form of dizziness, insomnia, electric shock-like sensations, nightmares, flu-like symptoms;
   • Paroxetine is notorious in this regard;
   • Gradual tapering, benzodiazepine coverage or switch to fluoxetine is all helpful avoiding stopping it “cold turkey”.
4. SSRI-Emotional Blunting (Reinblatt, & Riddle, 2006):

   • It shows as apathy or indifference;
   • Might be related to resultant secondary dopamine deficiency with boosting 5-HT tone;
   • Frontal lobe dysfunction has been postulated;
   • It is of insidious onset;
   • Seems to be dose-dependent (evident at high doses);
   • Agents boosting DA drive are helpful e.g. stimulants or bupropion.
5. SSRI-Unmasking Comorbidities:

   • It has been shown that effectively treating anxiety might reveal underling disruptive disorders or ADHD;
   • Conversely, anxiety/depression can masquerade as “counterfeit ADHD”;
   • It warrants treatment accordingly, with prioritized sequential approach based heavily on severity of symptomatology.
6. Serotonin Syndrome (Kant, & Liebelt, 2012):

   • It is likely especially if combined with other serotonergic agents or in the setting of overdosing;
   • Manifests as altered mental status (AMS), fever, gastro-intestinal (GIT) symptoms, hyperkinesias;
   • 5-HT2 antagonists e.g. cyprhepatidine, α -2 agonist; dexmedetomidine, and supportive measures are the mainstay of treatment, besides stopping the offending agent.
7. SSRI-related Suicidality:

   • Activation of suicidal ideations- paradoxical suicide is noted where mood symptoms improvement lag behind regaining of energy levels;
   • FDA black box for those below 25 years- in 2004, based on data from 23 trials comprising 4300 patients, FDA issued this black-box warning of increased risk of suicidal thinking, feeling, and behaviour associated with antidepressants use in young population (Naguy, 2016);
   • 2-fold increase compared to placebo; (4% vs. 2% respectively);
   • And more when it is used for depressive than for anxiety or OCD disorders;
   • Still, benefit of use clearly outweighs this theoretical risk as demonstrated by American College of Neuropsychopharmacology (Mann et al. 2006);
   • AACAP developed practice parameters as regards frequency of close monitoring when intiating SSRIs in the first 12 weeks.
8. SSRI-Withdrawal Mania/hypomania (Goldstein et al., 1999):

   • It is self-limited, paradoxical phenomenon;
   • Has been reported in mood disorders (uni or bipolar);
   • Might be related to nor-adrenergic (NE) overactivity and overriding cholinergic tone.

   This list is not all-inclusive. It is ever-expanding as clinical data accrues. It merely sheds some light on oft-times under-recognized SSRIs behavioural syndromes. It beehoves clinicians be vigilant and mindful of these syndromes that might be a source of diagnostic confusion with syndromic relapse/recurrence and inform subsequent treatment directions accordingly. Hence, there is a pressing need to dissect the neurobiology of these syndromes and better define them as clinical entities