____________________________________________________________________________ Anxiety Disorders
with clonazepam or fluvoxamine, and symptoms subsided only with paroxetine reinstatement. In a third patient, clonazepam had little benefit, paroxetine reinstatement was refused, and symptoms persisted unchanged over one year [249]. Following SSRI/SNRI cessation, the rates of withdrawal syn- drome range from 17.2% to as high as 78% (with venlafaxine). Among SSRI/SNRIs, venlafaxine XR may have the worst withdrawal syndrome. In addition to serotonergic withdrawal symptoms, palinopsia (persistent visual images) and sensory disturbances are frequently reported. These symptoms are described as sensations affecting the brain and head that feel like electrical shocks or the sensation of the brain shivering. This sensory disturbance, often accompanied by dizziness, headache, and disorientation, is distressing to patients and has been reported to persist for months after venlafaxine XR cessation [244; 250]. Other unexpected withdrawal symptoms that may emerge include gait difficulties, delirium, suicidal ideation, and hypomania or mania. The onset of withdrawal is usually one to four days post-venlafaxine XR cessation; dose reduction can also trigger withdrawal [251]. The etiology and treatment of these highly distressing sensory symptoms are unknown. However, contribution from norad- renergic dysregulation is suggested theoretically and by reports of positive treatment response to noradrenergic agents. Abrupt cessation of venlafaxine XR 37.5 mg led to a sensation that “felt like the brain was shaking inside the skull,” with anhedo- nia, anxiety, tinnitus, headache, nausea, and increased noise sensitivity. A trial of the norepinephrine transporter inhibitor atomoxetine 40 mg/day led to immediate improvement in “brain shivers” two to three hours from the first dose [250]. Post-venlafaxine XR electric shock-like sensations and dizziness were greatly reduced by low-dose clonidine (0.05 mg twice/day), a central α -2 adrenergic agonist. The positive response suggests an underlying noradrenergic rebound mechanism [244]. Interdose withdrawal symptoms have been reported with venlafaxine XR, probably resulting from the “ultrarapid metabolizer” genetic variant of 2D6, the hepatic cytochrome P450 isoenzyme that metabolizes venlafaxine. Occurring in 3% to 5% of white individuals, this polymorphism accelerates venlafaxine elimination, causing interdose withdrawal [251]. Antidepressant Lethality in Overdose In some patients with anxiety disorder, and especially those with depressive comorbidity, consideration of overdose fatal- ity is necessary when deciding on therapy options. Lethality rates from intentional overdose involving single medication ingestions of agents commonly prescribed for depression and anxiety were calculated from data obtained during the period 2000–2014 [252]. TCAs remain the most lethal antidepres- sants, with fatality rates from 31–142 per 10,000 ingestions. Amitriptyline is associated with the greatest lethality in over- dose and alone accounted for 37% of all deaths from antide- pressants [252]. Lithium, bupropion, venlafaxine, quetiapine, and valproic acid had rates of 6.9–12.0 per 10,000 ingestions, while citalopram and fluvoxamine had rates of 3.9–4.1 per
The National Collaborating Centre for Mental Health asserts that all patients prescribed antidepressants should be informed that, although the drugs are not associated with tolerance and craving, discontinuation/withdrawal symptoms may occur on stopping or missing doses or, occasionally, on reducing the dose of the drug. (https://www.nice.org.uk/guidance/cg113. Last accessed April 27, 2025.) Level of Evidence : Expert Opinion/Consensus Statement A 2015 meta-analysis found SSRI withdrawal symptoms can occur with any SSRI but are exceedingly more frequent with paroxetine [248]. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger, and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthe- sias, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Symp- toms do not greatly differ between patients with anxiety versus mood disorders. The authors concluded that the typical SSRI withdrawal syndrome begins within a few days of cessation and lasts two to three weeks [248]. Variations include late onset and protracted duration up to one-year follow-up. Several cases of persistent postwithdrawal disorders induced by paroxetine have been described. Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [248]. Patient characteristics that predict increased vulnerability are not known. Recognition of withdrawal symptoms requires careful exploration, as they can be misidentified as signs of impending relapse. Even when withdrawal symptoms are recognized, clinical management is hindered by the lack of research. SSRI cessation may trigger complex phenomena related or unrelated to the onset of withdrawal, such as hypomania, mania, and persistent postwithdrawal disorders. Iatrogenic comorbidity describes the lasting effects from treatment well beyond their time of administration, such as mood instabil- ity and high reactivity to environmental stimuli in persistent postwithdrawal disorders [248]. Among 20 patients with remitted panic disorder with agora- phobia followed over one year after SSRI cessation, nine expe- rienced SSRI withdrawal syndrome that subsided within one month [249]. Exceptions were three patients taking paroxetine, who experienced worsened mood, fatigue, and emotional labil- ity with trouble sleeping, irritability, and hyperactivity. One patient prescribed clonazepam after three months of symptom persistence improved considerably but was later unable to discontinue clonazepam. A second patient did not improve
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