Neuron Numbers and Volume of the Amygdala in Subjects Diagnosed with Bipolar Disorder or Schizophrenia Sabina Berretta, Harry Pantazopoulos, and Nicholas Lange Background: Growing evidence supports a pivotal role for the amygdala in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). However, the occurrence of morphologic changes in the amygdala is currently controversial. Methods: Total number and numeric density of neurons, neuronal somata size, and volume of the lateral (LN), basal (BN), accessory basal (ABN), and cortical (CO) nuclei of the amygdala were measured in 12 normal control, 10 BD, and 16 SZ subjects. Results: In BD subjects, reductions of total numbers (41.1%; p = .01) and numeric densities of neurons (14.5%, p = .01), as well as volume (29.0%; p = .01), were detected in LN. Density of neurons was also decreased in ABN of the same subjects (20.8%; p = .0005). These changes were not related to antipsychotics or lithium salt exposure. In SZ subjects, a decrease of total numbers of neurons was detected in LN (23.6%; p = .04). This effect was no longer significant once exposure to antipsychotics was taken into account. Conclusions: These findings offer structural evidence for an involvement of the amygdala in BD. Consequent loss of amygdalar function may account for abnormalities in emotion processing typical of BD subjects. In contrast, changes in SZ were limited and may have been induced by pharmacologic treatment. Key Words: Amygdala, bipolar disorder, light microscopy, post- mortem, schizophrenia, stereology I n recent years, a growing number of investigations on the pathogenesis of major psychoses have been focused on the amygdala, a nuclear complex located within the temporal lobe. The amygdala is thought to play an important role in assigning emotional and motivational valence to sensory inputs, in social communication, and in the processing of representation of the disposition and intentionality of others (e.g., 1,2–5). Stimulation of the human amygdala has been reported to evoke a variety of emotions, as well as highly complex hallucina- tions (5,6). In bipolar disorder (BD), altered amygdala functions are suggested by in vivo imaging reports of increased metabolic activity in the amygdala (7–11). Underlying these functional abnormalities are morphologic changes, detected by a number of structural imaging studies (12). Results from these studies are contradictory, however, showing either a decrease (13–18) or an increase (19 –21) of amygdala volume in BD subjects. A postmor- tem study in which the volume of the whole amygdala was assessed detected no changes in BD (22). Functional and clinical investigations also strongly support the involvement of the amygdala in schizophrenia (SZ) (e.g., 23,24 –28). Postmortem evidence for neurochemical and gene expression abnormalities in the amygdala of subjects with SZ is consistent with this idea (29 –35). No significant structural changes were detected in a postmortem study (36), however, and results from imaging investigations remain controversial (e.g., 37,38 – 40). Our postmortem investigations were designed to test the hypothesis that structural abnormalities in the amygdala of SZ and BD, that is, decreases of volume and total neuron numbers, may be selective for specific nuclei. We further postulated that BD and SZ may differentially affect these nuclei, with greater changes in BD and distinct distribution patterns. Total number, numeric density, and somata size of neurons, as well as nuclear volume, were measured in the lateral (LN), basal (BN), accessory basal (ABN), and cortical (CO) amygdalar nuclei (Figure 1A–1D) of normal control donors and donors diagnosed with BD or SZ. Methods and Materials Human Subjects Postmortem tissue blocks containing the whole amygdala from 16 SZ, 10 BD, and 12 healthy control donors (one hemi- sphere/subject), matched by age, gender, and postmortem time interval (PMI), were obtained from the Harvard Brain Tissue Resource Center, Belmont, Massachusetts (Supplemental Table 1). All subjects were Caucasian. Diagnoses were made by retrospective review of medical records and an extensive questionnaire con- cerning social and medical history provided by family members of the donor. In combination, these records provided informa- tion on each subject starting from the onset of the disease or earlier. Two psychiatrists reviewed all records and applied the criteria of Feighner et al. (41) for the diagnosis of SZ and DSM-III-R for the diagnosis of BD. The cohort used for this study did not include subjects with neuropathologic or clinical evi- dence for gross or macroscopic brain changes consistent with Alzheimer’s disease, cerebrovascular accident, ethanol and drug abuse, or lacking sufficient medical records. Tissue Processing Tissue blocks were dissected from fresh brains and post- fixed in .1 mol/mL phosphate buffer (PB; pH 7.4) containing 4% paraformaldehyde and .1 mol/mL Na azide at 4°C for 3 From the Translational Neuroscience Laboratory (SB, HP), McLean Hospital, Belmont; Department of Psychiatry (SB, NL), Harvard Medical School; Department of Biostatistics (NL), Harvard School of Public Health, Bos- ton; Neurostatistics Laboratory (NL), McLean Hospital, Belmont, Massa- chusetts. Address reprint requests to Sabina Berretta, M.D., McLean Hospital, 115 Mill Street, Belmont MA 02478; E-mail: s.berretta@mclean.harvard.edu. Received November 12, 2006; revised March 8, 2007; accepted April 3, 2007. BIOL PSYCHIATRY 2007;62:884 – 893 0006-3223/07/$32.00 doi:10.1016/j.biopsych.2007.04.023 © 2007 Society of Biological Psychiatry