Priority CommunicationsBaseline cerebral hypermetabolism associated with carbamazepine response, and hypometabolism with nimodipine response in mood disorders
Introduction
In spite of the dramatic advances in clinical diagnosis, neuroscience, and psychopharmacology of mood disorders in the last three decades, effective targeting of therapies in individual patients remains problematic (Goodnick 1995). Functional brain imaging studies have largely focussed on baseline differences between mood disorder patients and healthy control subjects, with decreased prefrontal activity in depression being the most consistent finding, although decreased subcortical activity and other (at times varying) findings have also been reported (Ketter et al 1996). Heterogeneity of such findings could be due to methodological, diagnostic, mood state, medication, and possibly even treatment response differences. Preliminary evidence suggests that baseline functional brain imaging may yield markers for treatment responses. Thus, sleep deprivation responders but not nonresponders have limbic hyperactivity that resolves in concert with clinical improvement after sleep deprivation (Wu et al 1992). Baseline decreases in prefrontal and anterior paralimbic metabolism have been observed in unipolar outpatients who were subsequently venlafaxine or bupropion responders but not in nonresponders (Little et al 1996). Increased baseline rostral cingulate metabolism has been reported in unipolar inpatients who were responders to selective serotonin reuptake inhibitors, tricyclic antidepressants or bupropion, whereas nonresponders had decreased metabolism in this region (Mayberg et al 1997).
Carbamazepine (CBZ) and to a more limited extent nimodipine (NIMO) seem useful in the treatment of mood disorders. These agents have important biochemical differences. CBZ decreases calcium entry into neurons by an N-methyl-d-aspartate receptor mediated effect (Hough et al 1996), and NIMO by anl-type calcium channel mediated effect (Towart and Kazda 1979). CBZ but not NIMO inhibits sodium entry into neurons by blocking type II sodium channels (Willow et al 1984). CBZ decreases (Rubinow et al 1985) and NIMO increases (Pazzaglia et al 1995) somatostatin. These medications may even have different therapeutic efficacy spectra, with CBZ helping in dysphoric manic, rapid cycling, and lithium resistant mood disorders (Post et al 1987), and NIMO providing modest benefit in ultradian (within a day) cycling and recurrent brief depressive disorders (Pazzaglia et al 1993). This paper outlines our preliminary studies that suggest that for CBZ and NIMO baseline (medication free) cerebral glucose metabolism (CMRglu) may discriminate between responders, nonresponders, and healthy control subjects.
Section snippets
Subjects, medications, and mood ratings
We studied inpatients with treatment-refractory DSM-III major affective disorders. Medical and neurological histories and physical examinations were obtained to rule out medical illnesses in patients and in age and gender matched healthy control subjects. Life course of illness was plotted for each patient (Squillace et al 1984). Patient diagnoses and absence of mental illness in healthy control subjects were confirmed by the Schedule for Affective Disorders and Schizophrenia (Endicott and
Carbamazepine study
Seven of 26 (27%) patients were CBZ responders, with CGI-I ratings of much or very much improved. Responders were significantly younger (32.3 ± 9.1 years vs. 42.0 ± 10.3,t = 2.20, df = 24, p < .04) than nonresponders, but these groups did not differ significantly in gender (5/7 female vs. 10/19), diagnosis (7/7 bipolar vs. 13/19), baseline Hamilton depression ratings (18.7 ± 5.9 vs. 18.1 ± 9.8), CBZ doses (886 ± 323 mg/day vs. 795 ± 248), or plasma levels (8.3 ± 2.7 μg/mL vs. 8.0 ± 2.0).
Discussion
We found that a pattern of baseline anterior paralimbic and prefrontal hypermetabolism was associated with CBZ response. With treatment, CBZ responders had a significant 7.0% decrease in global and widespread (including anterior paralimbic and prefrontal) significant decreases in absolute and normalized regional metabolism, whereas nonresponders had a nonsignificant 1.0% decrease in global and no significant changes in absolute or normalized regional metabolism. The degree of clinical
Acknowledgements
Mark W. Willis is supported by the Stanley Foundation.
Presented in part at the 148th Annual Meeting of the American Psychiatric Association, May 20–25, 1995, Miami, Florida.
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2008, Psychiatry Research - NeuroimagingCitation Excerpt :To be compatible with our studies regarding treatment prediction (Ketter et al., 1999), characterization of baseline metabolism (Ketter et al., 2001; Kimbrell et al., 2002), co-morbid anxiety features (Osuch et al., 2000), and relative metabolic and perfusion coupling (Dunn et al., 2002), identical image processing methods were used. Scans were visually inspected for artifacts and stereotactically normalized using a histogram equalization-based non-linear transformation as described previously (Ketter et al., 1999; Willis et al., 2002) into a standard space corresponding to the human brain atlas of Talairach and Tournoux (1988). These images were then smoothed with a Gaussian low-pass filter of 10 mm in-plane and 6 mm axial FWHM (in order to minimize noise and improve between-subject spatial alignment) for a final resolution of approximately 12 mm isotropically.