Sir: Akathisia may be defined as the subjective feeling of muscle discomfort usually manifesting as a result of treatment with antipsychotic medication. Moreover, the subjective experience is often associated with objective symptomatology such as restless leg movements, walking to and fro, and inability to sit in one place for an extended period of time. This undesirable side effect frequently expresses itself as a formidable therapeutic challenge. While akathisia is most commonly expressed following the use of antipsychotic medication, often it may be observed resulting from the use of antidepressant therapy, in particular drugs of the selective serotonin reuptake inhibitor (SSRI) class expressing serotonin-2A (5-HT2A) stimulatory effects.1-6 Various reports have estimated the occurrence rate of this phenomenon of SSRI-induced akathisia to range from 9.8% to 45.1%.4,7,8
The subjective discomfort experienced by the patient with akathisia is frequently disabling and of significant severity to the extent that it may even lead to suicidal behavior.9-13 Furthermore, akathisia often results in treatment noncompliance following the inability to tolerate the psychotropic medication.14,15
Nefazodone is an antidepressant with both presynaptic serotonin and norepinephrine reuptake properties as well as postsynaptic 5-HT2A blockade characteristics.16 Considering its relatively unique receptor activity profile, we hypothesize that the medication will demonstrate beneficial effects in the reduction of akathisic symptomatology. To our knowledge, we present here the first reports of the utility of nefazodone in managing disabling akathisia following SSRI medication management. In these case reports, we demonstrate the marked and rapid improvement in akathisic symptomatology after a switch to treatment with nefazodone.
Case 1. Ms. A, a 40-year-old woman with no previous psychiatric or medical history, presented for the management of symptomatology consistent with a diagnosis of major depression (DSM-IV criteria). Treatment with paroxetine, 20 mg/day, was initiated. Following full remission of symptomatology after 1 month, treatment was maintained for a further 7 months, after which it was discontinued.
A year after discontinuation of paroxetine treatment, Ms. A presented with symptoms of moderate depression, accompanied by mild anxiety. Treatment with paroxetine was reinstated at the same dose. Two weeks after paroxetine reinitiation, a marked improvement in depressive symptomatology was observed; however, she presented with complaints of difficulty sitting in one place for any length of time, restless leg movements that precluded her attempts to fall asleep at night, and "inner restlessness," the nature of which she had never experienced. These subjective complaints were assessed as being classic symptomatology of akathisia. At this time, Ms. A was also taking atenolol, 25 mg/day, initiated several months previously for management of high blood pressure. Oxazepam, 30 mg/day, was prescribed for the management of these paroxetine-induced akathisic symptoms. However, in light of her inability to tolerate oxazepam due to persistent fatigue and resulting difficulty in functional ability, paroxetine was discontinued and replaced with nefazodone, 300 mg/day. With the initiation of nefazodone, Ms. A experienced a complete resolution of symptoms of akathisia as well as those of depression, and within a few days she returned to full baseline functioning and activities.
Case 2. Ms. B, a 40-year-old woman, was hospitalized for the first time in a psychiatric institution following complaints of a 2-week history of severe agitation, verbal aggression, and a subsequent decrease in ability to maintain her previous level of daily functioning. Associated with these symptoms was an inability to sit still for any period of time. These symptoms appeared a few days after the initiation of fluoxetine, 20 mg/day, prescribed for depressive ideation that had progressively worsened over several months. At the time of admission, she remained significantly dysphoric, with vegetative symptoms of depression including early morning awakening and diminished appetite. After admission, fluoxetine was discontinued, and nefazodone was initiated with titration up to 400 mg/day. Within a few days, the agitation and restlessness completely resolved. Two weeks after admission, Ms. B was discharged home. Three weeks after discharge, all depressive symptoms resolved, and she returned to full baseline function. It should be emphasized that following the initiation of nefazodone, the patient experienced a full remission of symptoms of akathisia.
While symptoms of akathisia are classically described as side effects of antipsychotic medications, disabling symptoms of akathisia may also be observed accompanying management with antidepressant medication of the tricyclic (TCA) and SSRI types. The precise pathophysiology of akathisia remains poorly understood; however, it has been suggested that akathisia results from inhibition of dopaminergic neurons in the ventral tegmental area (VTA) and by means of activity at the postsynaptic beta-adrenergic and serotonergic (5-HT2A) receptors.4 This hypothesis of akathisia with reference to the serotonergic system has come to light particularly since the introduction of TCA and SSRI medications into clinical practice. These medications lead to an increase of these catecholaminergic and serotonergic neurotransmitters in the synaptic space. Since akathisia is a syndrome related to a subjective experience of discomfort that may markedly disturb patients and may even lead to suicidal tendencies, a rapid method of management becomes considerably important.
The management of antidepressant-induced akathisia includes dose reduction and the addition of several various other medications such as beta-blockers, anticholinergics, antihistamines, and benzodiazepines.17 Alternate management options include the administration of other antidepressant medications with which medication-induced risk is minimal. Nefazodone, a relatively new antidepressant medication that is not accompanied by akathisic side effects, meets these demands. While nefazodone, like SSRIs, acts presynaptically by inhibiting serotonin reuptake and thus may potentially induce akathisia as described in a previous single case report,18 it appears that its predominant effect of postsynaptic 5-HT2A antagonism determines the final effect between these 2 opposing actions. This latter action is thought to result in augmentation of VTA dopaminergic activity, thus lessening the subsequent appearance of undesirable akathisia. This model of receptor activity is further supported by other 5-HT2A antagonists, including cyproheptadine19 and ritanserin.20
The 2 patients described above with disabling SSRI-induced akathisia both experienced rapid alleviation of the side effect following a switch to nefazodone. While it may be suggested that the abatement of akathisic symptoms was as a result of discontinuing the SSRI, we hypothesize, based on the relatively unique mechanism of nefazodone receptor activity, that it is the 5-HT2A antagonistic activity as described that resulted in this dramatic improvement.
The option of switching to nefazodone has a number of advantages. In addition to its primary anti-akathisia activity as suggested above, it reduces the need for dose reduction of the SSRI (which may be attempted to reduce akathisia) and thus lessens the risk of relapse. Furthermore, it reduces the number of medications the patients would require, i.e., no anti-akathisia medication would be needed, and thus would potentially improve compliance. Our observations thus suggest that should a patient develop akathisia while being treated with an SSRI, nefazodone is an appropriate alternative antidepressant medication, with an apparent low risk for akathisia. These 2 case reports provide only limited evidence of the benefits of nefazodone under these conditions; further studies are clearly warranted to test this hypothesis under double-blind conditions.
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Joseph Chelben, M.D.
Rael D. Strous, M.D.
Michal Lustig, M.D.
Yehuda Baruch, M.D.
Beer Yaakov Mental Health Center
Sackler School of Medicine, Tel Aviv University
Tel Aviv, Israel