Elsevier

Biological Psychiatry

Volume 46, Issue 10, 15 November 1999, Pages 1364-1374
Biological Psychiatry

Priority Communications
Baseline cerebral hypermetabolism associated with carbamazepine response, and hypometabolism with nimodipine response in mood disorders

https://doi.org/10.1016/S0006-3223(99)00210-3Get rights and content

Abstract

Background: Positron emission tomography (PET) studies have reported baseline (medication free) differences between mood disorder patients and healthy control subjects, but relatively little is known about relationships between baseline PET scans and treatment responses. Carbamazepine (CBZ) and to a more limited extent nimodipine (NIMO) seem useful in mood disorders. We explored whether baseline regional cerebral glucose metabolism (rCMRglu) could discriminate CBZ and NIMO responders from nonresponders and healthy control subjects.

Methods: In refractory mood disorder patients, we examined relationships between responses to these drugs, assessed by Clinical Global Impression-Improvement scores, and baseline rCMRglu, determined with fluorine-18 deoxyglucose and PET.

Results: CBZ responders had baseline left insular hypermetabolism compared to healthy control subjects and nonresponders, whereas nonresponders had widespread (including left insular) hypometabolism. Degree of CBZ response correlated with baseline paralimbic (including insula) and prefrontal hypermetabolism. In responders but not nonresponders, CBZ decreased widespread metabolism, with the degree of decrease in left insula correlating with response. In contrast, NIMO responders but not nonresponders had baseline widespread (including left insular) hypometabolism. Left prefrontal and left insular baseline hypometabolism, but not metabolic changes with treatment correlated with degree of NIMO response.

Conclusions: These data suggest that baseline anterior paralimbic and prefrontal hypermetabolism may be associated with CBZ response, and hypometabolism with NIMO response. Based on these preliminary data, further exploration of relationships between baseline PET scans and treatment responses is indicated. Biol Psychiatry 1999;46:1364–1374

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.

References (25)

  • P.J. Pazzaglia et al.

    Nimodipine increases CSF somatostatin in affectively ill patients

    Neuropsychopharmacology

    (1995)
  • P.J. Pazzaglia et al.

    Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation

    Psychiatry Res

    (1993)
  • R.M. Post et al.

    Correlates of antimanic response to carbamazepine

    Psychiatry Res

    (1987)
  • W.E. Bunney et al.

    Methods for reliable longitudinal observation of behavior

    Arch Gen Psychiatry

    (1963)
  • R.M. Cohen et al.

    Functional localization of sustained attentionComparison to sensory stimulation in the absence of instruction

    Neuropsychiatr Neuropsychol Behav Neurol

    (1988)
  • J. Endicott et al.

    A diagnostic interviewThe schedule for affective disorders and schizophrenia

    Arch Gen Psychiatry

    (1978)
  • K.J. Friston et al.

    The relationship between global and local changes in PET scans

    J Cereb Blood Flow Metab

    (1990)
  • K.J. Friston et al.

    Comparing functional (PET) imagesthe assessment of significant change

    J Cereb Blood Flow Metab

    (1991)
  • K.J. Friston et al.

    Plastic transformation of PET images

    J Comput Assist Tomogr

    (1991)
  • K.J. Friston et al.

    Localisation in PET imagesDirect fitting of the intercommissural (AC-PC) line

    J Cereb Blood Flow Metab

    (1989)
  • K.J. Friston et al.

    Assessing the significance of focal activations using their spatial extents

    Hum Brain Mapp

    (1994)
  • P.J. Goodnick

    Predictors of Treatment Response in Mood Disorders

    (1995)
  • Cited by (69)

    • Interregional cerebral metabolic associativity during a continuous performance task (Part I): Healthy adults

      2008, Psychiatry Research - Neuroimaging
      Citation 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.

    View all citing articles on Scopus
    View full text