Efavirenz is a non-nucleoside reverse transcriptase inhibitor that is used in the treatment of the HIV-1 variant. Adverse central nervous system side effects such as headache, dizziness, insomnia, fatigue, severe depression and suicidal ideation are noted in patients receiving efavirenz. In this study, the effects of efavirenz on changes in behaviour and on some pro- and anti-inflammatory cytokines in Wistar rats were studied to assess whether efavirenz causes depressive symptoms via the cytokine network and, if so, whether antidepressant therapy known to attenuate the effects of pro-inflammatory cytokines could prevent these changes. The efavirenz-treated rats displayed spatial memory deficits in the Morris water maze. These rats also appeared to be more susceptible to stress than the other groups as seen by an increase in the latency to emerge in the home cage emergence test following the stress of the Morris water maze. The concentrations of pro-inflammatory cytokines interleukin-1 beta and tumour necrosis factor-alpha were also significantly higher in the efavirenz group. The antidepressant paroxetine reduced the susceptibility to stress and prevented such an increase in pro-inflammatory cytokines. It is concluded that efavirenz induces depressive-like behaviour in the rat and a susceptibility to stress, which are accompanied by an increase in pro-inflammatory cytokines. These symptoms are partially alleviated by chronic treatment with paroxetine. Copyright (C) 2005 S. Karger AG, Basel.