Recent concern that treatment with antidepressant (AD) drugs can, under certain circumstances, increase suicidality has created a difficult problem for clinicians treating depressive patients. The controversy has focused on three aspects of pharmacotherapy: (i) administration of AD drugs to juveniles (children and adolescents), (2) use of selective serotonin reuptake inhibitors (SSRIs), especially paroxetine, and (3) effects during the early course of AD treatment. Substantial evidence can be presented for both sides of the debate, and our goal is not to attempt to resolve this issue. Rather, our goal is to propose a mechan- istic animal model to explain how, under certain conditions, ADs may exacerbate rather than ameliorate the depressive state. Both clinical and preclinical evidence suggests that the principle noradrenergic cell group in the brain, the locus coeruleus (LC), is over-active in depressives and, in particular, in people who die from suicide. Effective AD treatments - that is, chronic administration of AD drugs and electroconvulsive shock - exert the opposite influence to decrease LC activity. Here we propose that treatment with SSRIs, especially in juveniles and early in treatment, can actually produce an increase in LC activity (rather than the normal """"""""therapeutic"""""""" decrease) which may promote depressive symptoms and adverse events including suicidality. If indeed this unwanted effect on LC does occur with SSRIs given to juveniles, then countermeasures (i.e., co- medication) should prevent this from occurring. The proposed research will test our animal model by comparing the effects of short-term and long-term administration of AD drugs on the activity of LC neurons in young rats as compared to mature, adult rats. First, effects of a range of doses of an SSRI (paroxetine), a dual serotonin-norepinephrine reuptake inhibitor (venlafaxine), and a """"""""standard"""""""" tricyclic (desipramine), administered continuously via osmotic minipump, will be compared in juvenile (45 days old) and mature adult (5 months old) rats. Second, the possibility that low and/or fluctuating blood levels of ADs may promote LC hyperactivity will be examined by measuring LC activity in animals that have been given an AD orally once-per-day, in a manner mimicking a patient taking medication as a pill. Third, a potential therapeutic countermeasure for SSRI-induced increase in suicidality will be explored by co-administering an SSRI with drugs (clonidine, alprazolam) having the potential to block LC hyperactivity. In parallel with measurement of LC activity, we will also measure effects on swim-test activity of rats. Swim-test activity has been widely used to (a) detect effects of AD drugs and (b) indicate the presence of a depressive condition, so measurement of swim-test activity of the rats will be used to confirm antidepressant action and, most importantly, to test for indication of increased depression in young rats during the early stages of treatment with drugs suspected to exacerbate depression-related symptoms.
