Only one-quarter of our bipolar outpatients show an adequate clinical prophylactic response in double-blind, randomized, one- year trials of either lithium or carbamazepine monotherapy. Even with the combination of lithium and carbamazepine, only 50% of these outpatients respond. With the additional use of valproate, 37% of the initial cohort of patients still remain unresponsive. It is from this large pool of highly treatment-refractory patients that the Branch seeks to better understand the differential pathophysiological mechanisms in recurrent unipolar and bipolar affective disorders and develop new therapeutic modalities. A recently completed study is a double-blind, randomized trail of six weeks of treatment with an agent that enhances inhibitory GABAergic function (gabapentin, GPN), versus one that decreases excitatory glutamatergic function (lamotrigine, LTG), versus placebo, with patients crossing over to the other drug treatments in order to ascertain differential clinical response. This study, involving 45 patients, found significant benefit of LTG (53% response rate) over GPN (27%) and placebo (22%) (Frye et al, 2000). Correlates of lamotrigine response included male gender, bipolarity, fewer prior clinical trails, and hospitalizations for depression (Obrocea et al, 2002). Preliminary evidence suggests that a baseline pattern of hypo-perfusion on 0-15 PET was associated with clinical response. In relationship to the assessment of possible predictors of clinical response, preliminary evidence indicates that depressed patients with global hypermetabolism on PET, especially in the left insula, are more likely to be responsive to carbamazepine (N=26), while those with the more classic pattern of frontal and left insular hypometabolism are more likely to be responsive to the dihydropyridine L-type calcium channel blocker nimodipine (Ketter et al, 1999). We have found that nimodipine increases somatostatin in cerebrospinal fluid (CSF) and those with lower CSF somatostatin at baseline are more likely to respond clinically. The major treatment initiative in the Branch is now the use of repeated transcranial magnetic stimulation (rTMS) of the brain for the treatment of depression. Two of the first six patients responded in a pilot study of 20 Hz stimulation at 80% of motor threshold of left frontal cortex (George et al, 1995). A double-blind, randomized, crossover trial indicated significant antidepressant effects of active rTMS for two weeks compared with the sham (George et al, 1998). The next study assessed the differential responsivity to low-frequency (1 Hz) versus higher frequency (20 Hz) rTMS vs. sham stimulation over left frontal cortex at 80% of motor threshold. These data in 15 subjects suggest differential clinical and metabolic responses within the same patient to these different frequencies. Moreover, those with a pattern of baseline hypometabolism tend to respond to the 20 Hz stimulation, while those with baseline patterns of hypermetabolism are more likely to respond to the 1 Hz stimulation (Kimbrell et al, 1998). As the incidence and magnitude of clinical responsivity was not adequate for many patients, a fourth study using higher intensities (100% of motor threshold) was completed. This study replicated the findings of differential responsivity within individual patients and revealed that 20 Hz stimulation increased 0-15 blood flow while 1 Hz rTMS decreased it (Speer et al, 2000). A further controlled study in normal volunteers has confirmed that 1 Hz rTMS over frontal contex induces relative decrements in bilateral frontal and striatal metabolism on PET. The current rTMS study involves higher intensities of rTMS stimulation (110% MT) for a longer time (3 weeks) and continues to reveal moderate responsiveness compared to sham. Thus, a number of promising and mechanistically novel treatment approaches have been prioneered in the Branch and continued effort will be aimed at defining optimal parameters for rTMS response and the elucidation of clinical and neurobiological markers of differential clinical responsivity.