Major depression comorbid with panic disorder has a more severe clinical picture and adverse course than either disorder alone, and both conditions are associated with abnormalities in the serotonin system. Therefore, we hypothesized that central serotonergic function in the patients with comorbid panic disorder would be more disturbed than in major depression alone. Concentrations of cerebrospinal fluid (CSF) monoamine metabolites of serotonin, norepinephrine, and dopamine were assayed by high-pressure liquid chromatography, and compared in female subjects with DSM-IV-diagnosed major depressive disorder and a lifetime diagnosis of panic disorder (MDD+PD, n=13), major depressive disorder and no lifetime panic disorder (MDD-, n=35), and a healthy volunteer (HV, n=15) group. All subjects were free of antidepressant medication for at least 14 d prior to the lumbar puncture procedure. CSF 5-hydroxylindoleacetic acid (5-HIAA) was higher in the MDD+PD group (124.0+/-43.0 nmol/l) compared with the MDD- group (100.1+/-28.8 nmol/l, p=0.03) and the HV group (93.3+/-33.6 nmol/l, p=0.02). The MDD- group and HV group did not differ in CSF 5-HIAA. There were no group differences in the CSF metabolites of norepinephrine and dopamine, 3-methoxy-4-hydroxyphenylglycol and homovanillic acid respectively. Higher CSF 5-HIAA in women with comorbid major depressive disorder and lifetime panic disorder is indicative of greater serotonin release, increased serotonin metabolism, and/or decreased 5-HIAA clearance in this group. This difference in pathophysiology is potentially related to the greater morbidity and poorer treatment response of this group.