Agitation from SSRIs

Nervousness and agitation in some patients early in treatment are characteristic side effects of the SSRIs. These too have been reported to be dose related. In the fluoxetine database, these side effects were more common with the 60-mg dose than with the 20-mg dose and were associated with some insomnia (G. L. Cooper 1988]. Although in general the various SSRIs differ little one from the other, there appear to be some differences in their propensity for producing nausea and nervousness. 

In general, the pattern of adverse reactions is similar among all the SSRIs and some of the other new antidepressants that block the reuptake of serotonin, especially venlafaxine. As a result, the FDA has required class label warnings for them in regard to suicidality and to the array of stimulant adverse reactions, from agitation and hostility to mania. 

Gerber and Lund (1998) reviewed the literature and located 127 case reports of SSRI-induced abnormal movements. These included akathisia (agitation with hyperactivity), tardive dyskinesia, parkinsonism, dystonia (muscle spasms), bruxism (tooth grinding), and related disorders. They found many additional case reports from the drug manufacturers, including 516 cases of parkinsonism and 76 cases of tardive dyskinesia. The term tardive dyskinesia is usually reserved for cases that are irreversible. 

Prozac and the other SSRIs, as well as any antidepressant that blocks the removal of serotonin from the synapse, can produce a well-documented, severe condition called the serotonin syndrome (Sternbach, 1991). This disorder includes the usual signs of overstimulation, such as euphoria and hypomania, agitation, confusion, and gastrointestinal upset, including diarrhea. However, the serotonin syndrome additionally involves overstimulation of the brain stem and spinal cord, producing fever and chills, severe incoordination, muscle spasms, and hyperactive reflexes. It bears some similarity to neuroleptic malignant syndrome, and like NMS it can also be lethal (chapter 4). 

Over the last decade there has been a debate as to whether SSRIs might increase the risk of suicide in certain individuals. Some patients can respond to SSRIs by becoming agitated and restless and developing symptoms that resemble akathisia. Case reports have suggested that adverse effects of this type could underlie an increased risk of self-harm and aggression. However, results from the placebo-controlled randomized trials carried out for regulatory purposes have not supported the proposal that SSRIs increase the risk of suicide of suicidal behavior. 

Another risk of antidepressants in vulnerable patients (particularly those with unrecognized bipolar depression) is switching, sometimes suddenly, from depression to hypomanic or manic excitement, or mixed, dysphoric-agitated, manic-depressive states. To some extent this effect is dose-related and is somewhat more likely in adults treated with tricyclic antidepressants than with SSRIs, bupropion, and perhaps with MAO inhibitors. Risk of mania with newer sedating antidepressants, including nefazodone and mirtazapine, also may be relatively low, but some risk of inducing mania can be expected with any treatment that elevates mood. 

Fewer adverse effects were reported among moclobemide-treated patients compared with selective serotonin reuptake inhibitor (SSRI)-treated patients. Since moclobemide does not induce orthostatic hypotension, does not possess anticholinergic properties, and is not cardiotoxic, it is very well suited among the MAOIs for the treatment of depression. Moclobemide has limited potential to elicit a hypertensive crisis, because the pressor effect of tyramine from food is only marginally potentiated compared with tranylcypromine. The pressor effect of tyramine is normalized within 3 days of cessation of treatment with moclobemide. The combination of SSRIs and moclobemide has good efficacy in cases of refractory depression, but there is controversy as to whether toxic side-effects such as serotonin syndrome can result from this combination. Currently, more studies are needed before this combination can be recommended. Acute overdose with MAOIs causes agitation, hallucinations, hyperpyrexia, hyperreflexia, convulsions, and death. The most dangerous MAOIs in overdose are the irreversible non-selective MAOIs. T2s-27... 

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