_______________________________________________________________________ Depression and Suicide
burden of sexual side effects from antidepressants and other medications [183]. Among antidepressants, prevalence rates of sexual side effects are highest with venlafaxine and SSRIs; moderate with TCAs and MAOIs; low with bupropion, trazo- done, nefazodone, mirtazapine, agomelatine, and vilazodone; and lowest with the reversible MAOI moclobemide [184; 185]. Compared to spontaneous patient reporting, systematic inquiry increases the rate of identifying sexual side effects by ≥60% [185]. Management of sexual side effects in men includes the use of phosphodiesterase-5 inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil as first-line treatment or switching to bupropion [186]. In women, sexual side effect management considers symptoms, age, and potential hormonal contribution when peri- or post-menopausal. Increased Suicidality Several papers documenting an increased risk of suicidal thoughts and behavior with antidepressants, primarily SSRIs, have been published over the past decade. A review of the literature found that antidepressant use, including SSRIs, carried a small short-term risk of inducing suicidal thoughts and suicide attempts in persons younger than 25 years of age, with persons 30 to 40 years of age having a lower risk than those younger than 25 years. This risk should be balanced against the well-known beneficial effects of antidepressants that include reduced suicidal ideation and behavior, particularly in the long term. Clinical decision making should weigh the benefits and potential risks and strive to keep the potential risks of antidepressant treatment to a minimum [187; 188]. Discontinuation Symptoms Antidepressant discontinuation (more appropriately termed withdrawal) symptoms are described by the FINISH mnemonic (flu-like symptoms, insomnia, nausea, imbalance, sensory dis- turbances, hyperarousal), may be experienced by up to 40% of patients when antidepressants are stopped abruptly, and may occur with any antidepressant [158; 189; 190; 191]. SSRI withdrawal symptoms are far more frequent with paroxetine. 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, paresthesia, intensified suicidal ideation, aggression, derealization, depersonaliza- tion, and visual/auditory hallucinations. Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [192]. SSRI withdrawal syndrome is least likely with fluoxetine and vortioxetine [158]. Symptoms usually begin within five days of treatment cessation or occasionally during taper or after missed doses [193; 194]. Symptoms are usually mild and self-limiting but may also be severe and prolonged, particularly following abrupt withdrawal.
Some symptoms occur more frequently with specific drugs, such as dizziness and electric shock-like sensations with SSRIs and sweating and headache with TCAs [189; 195]. Risk factors include taking antidepressants longer than eight weeks, devel- opment of anxiety symptoms during antidepressant initiation (particularly with SSRIs), use of other medications with CNS activity (e.g., antihypertensives, antihistamines, antipsychotics), and a history of previous discontinuation symptoms [195; 196]. Outpatients who discontinued escitalopram and developed a withdrawal syndrome (56%) had significantly higher mean escitalopram doses and higher plasma concentrations reflect- ing delayed clearance of escitalopram, than patients without withdrawal. Escitalopram treatment duration, age, and sex were unrelated to withdrawal risk [197]. Symptoms may be severe enough to interfere with daily func- tioning, and although a four-week taper is usually suggested, some patients may require longer periods, particularly with paroxetine and venlafaxine [198]. Treatment is pragmatic. If symptoms are mild, reassure the patient that this is a common occurrence and that the symptoms will pass in a few days. If symptoms are severe, reintroduce the original antidepressant or a replacement from the same class with a longer half-life, and taper gradually while monitoring for symptoms. Patients should be emphatically informed that the possible or actual emergence of discontinuation symptoms is not a manifesta- tion of addiction to the antidepressant [68]. SSRI withdrawal can also be approached by switching to a course of fluoxetine, such as 10 mg for several weeks, which is slowly tapered and discontinued [22]. Extended-release venlafaxine has the most severe withdrawal syndrome of any antidepressant. In addition to serotonergic withdrawal symptoms, persistent visual images and sensory disturbances are frequently reported. Electrical shock-like sensations in the brain or the sensation of the brain shiver- ing has also been described. This sensory disturbance, often accompanied by dizziness, headache, and disorientation, is distressing to patients and may persist for months after cessa- tion of the drug [199; 200]. Other unexpected symptoms that may emerge include gait difficulties, delirium, suicidal ideation, hypomania, or mania. The usual onset of withdrawal is one to four days post-cessation or with dose reduction [201]. The origin and treatment of these highly distressing sen- sory symptoms are unknown, but case reports describe positive response to noradrenergic agents. Abrupt cessation of extended-release venlafaxine 37.5 mg led to sensations that “felt like the brain was shaking inside the skull,” with anhedo- nia, anxiety, tinnitus, headache, nausea, and increased noise sensitivity. A trial of atomoxetine (40 mg/day), a norepineph- rine transporter inhibitor, led to immediate improvement in “brain shivers” two to three hours from the first dose [199]. Post-cessation electric shock-like sensations and dizziness were greatly reduced by low-dose clonidine (0.05 mg twice-daily). These positive responses suggest an underlying noradrenergic rebound mechanism [200].
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