Pathophysiological significance of cerebral perfusion abnormalities in major depression-trait or state marker?

European Neuropsychopharmacology 7 (1997) 225–233

Pathophysiological significance of cerebral perfusion abnormalities in major depression-trait or state marker? a, b Omer Bonne *, Yodphat Krausz a

b

Department of Psychiatry, Hadassah University Hospital, Jerusalem, Israel Department of Nuclear Medicine, Hadassah University Hospital, Jerusalem, Israel Received 4 July 1996; revised 30 January 1997; accepted 30 January 1997

Abstract Considerable data support the existence of impaired regional cerebral blood flow in major depression. However, it is unclear whether the impairment in brain function in major depression is a ‘‘state’’ marker, reversible upon remission, or an enduring trait phenomenon. We have studied brain technetium-99m hexamethylpropyleneamineoxime (Tc-99m HMPAO) uptake ratios in healthy subjects of various ages, in depressed patients before and after electroconvulsive therapy (ECT) and in healthy subjects before and after administration of fluoxetine. Analysis of our findings, presented along with research data of other groups, strongly suggests that reduced cerebral perfusion in major depression is reversible by successful treatment. Furthermore, since fluoxetine had little effect on cerebral perfusion in healthy subjects, and ECT had little effect on cerebral perfusion in depressed patients who did not respond to treatment, we contend that increases in perfusion represent remission rather than treatment effect. Therefore, reduced perfusion in major depression appears to be a state marker and not a trait abnormality.  1997 Elsevier Science B.V. Keywords: Brain imaging; Cerebral blood flow; Depression; HMPAO; SPECT

1. Introduction The potential contribution of functional brain imaging to the understanding of mental illness was initially demonstrated by the finding of a relative decrease in blood flow in the frontal lobes of schizophrenic patients by Ingvar and Franzen (1974), a finding that has been both replicated and disputed since (see Woods et al. (1991) for review). Curiously, this report went relatively unnoticed for several years and it was only in the early 1980s that interest in this imaging modality was renewed. The development of positron emission tomography (PET), capable of providing high resolution images of brain metabolism and neurochemistry, further bolstered functional imaging research. A close correlation was illustrated between the various indices of brain metabolism, in particular, glucose metabolism, oxygen consumption and cerebral blood flow across *Corresponding author. Tel.: 972-2-776348. 0924-977X / 97 / $17.00  1997 Elsevier Science B.V. All rights reserved PII S0924-977X( 97 )00410-0

most physiological conditions (Lebrun-Grandie et al., 1983; Sokoloff, 1981; Ginsberg et al., 1988; Raichle et al., 1976). The great research potential of PET, however, is limited by its high purchase costs and operating expenses. The introduction of single photon emission computed tomography (SPECT) enabled three-dimensional assessment of cerebral blood flow (CBF) at a moderate cost. SPECT scanning currently employs diffusible (Xenon133) and static (iodine- or technetium-bound) radiopharmaceuticals. Diffusible radiopharmaceuticals freely traverse the blood–brain barrier and do not chemically interact with brain parenchyma, and enable an absolute quantification of blood flow. However, the low gamma ray energy and diffusibility of xenon-133 makes it difficult to obtain reliable data from subcortical structures. The static (lipophilic) radiopharmaceuticals readily traverse the blood–brain barrier and, upon reaching the brain, become trapped within parenchymal cells, losing their lipophilic properties. A good correlation has been demonstrated

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between the early distribution of static radiopharmaceuticals and CBF measurements obtained by xenon-133 and labeled microsphere techniques (Kuhl et al., 1982; Neirinckx et al., 1987). However, quantification is not routinely employed with static radiotracers and data analysis involves the generation of a ratio between radiotracer uptake in distinct brain regions.

2. Cerebral blood flow in depression Most studies comparing global cerebral blood flow between depressed subjects and healthy controls report decreased values. This has been demonstrated in techniques utilizing the radiotracer Xenon-133 (Mathew et al., 1980; Rush et al., 1982; Sackeim et al., 1990; Lesser et al., 1994), I-123 SPECT (O’Connell et al., 1989; Kanaya and Yonekawa, 1990), Tc-99m HMPAO SPECT (Austin et al., 1992; Mayberg et al., 1994) and Au-195 (Schlegel et al., 1989). Similar finding have been reported from PET studies (Baxter et al., 1985, 1989; Martinot et al., 1990; Biver et al., 1994). However, several investigators, particularly those employing two-dimensional CBF measurements, have not observed global flow deficits (Silfverskiold and Risberg, 1989; Goldstein et al., 1985; Gur et al., 1984) and negative results have also been described from PET data (Buchsbaum et al., 1986; Bench et al., 1993). Regional decreases in cerebral perfusion have also been reported, localized mostly to frontal and prefrontal cortices [Sackeim et al. (1990); Schlegel et al. (1989) using twodimensional rCBF measurement; Kanaya and Yonekawa (1990) using I-123 SPECT and Ebert et al. (1991) using Tc-99m HMPAO SPECT]. CBF reductions were also found in the temporal lobes [Sackeim et al. (1990); Schlegel et al. (1989) using two-dimensional rCBF measurement; Yazici et al. (1992); Austin et al. (1992); Mayberg et al. (1994) using Tc-99m HMPAO SPECT] and basal ganglia [O’Connell et al. (1989) using I-123 SPECT; Austin et al. (1992); Mayberg et al. (1994) using Tc-99m HMPAO SPECT]. Regional decreases in analogous locations have also been reported from PET research (Buchsbaum et al., 1984; Baxter et al., 1989; Cohen et al., 1989; Hurwitz et al., 1990; Bench et al., 1992; Biver et al., 1994). Several studies note lateral asymmetries in depressed patients. The deficits reported in blood flow (Kanaya and Yonekawa, 1990; Ebert et al., 1991; Yazici et al., 1992) and metabolism (Baxter et al., 1989; Martinot et al., 1990) are often more pronounced in the left hemisphere This is in agreement with the association between depression and left anterior cortical and subcortical injury reported by Robinson and Starkstein (1989). Attempts made to correlate CBF with the severity of depression, as determined by rating scales such as the Hamilton Rating Scale for Depression (HAM-D; Hamilton, 1960), mostly show an inverse correlation (O’Connell et

al., 1989; Schlegel et al., 1989; Sackeim et al., 1990; Kanaya and Yonekawa, 1990; Volk et al., 1992), although a lack of correlation (Silfverskiold and Risberg, 1989) has also been reported. A sufficient number of reports denote reductions in cerebral blood flow and metabolism to support an hypothesis associating depression with reduced brain perfusion. Conflicting results, particularly regarding the precise location of reduced blood flow, have been reported even within each imaging technique (and are notably prominent in two-dimensional xenon RCBF studies), deeming it unlikely that the choice of imaging method could account for these discrepancies. The reason for the inconsistencies may be better accounted for by variation in patient characteristics between studies, due to the diverse presentations of depression. Research conducted by our group (using Tc-99m HMPAO SPECT) has focused upon patients with severe depressive illness who are resistant to antidepressant medication (Bonne et al., 1996b). This is a rather welldefined group, which is of interest in both clinical and research contexts. Twenty unmedicated inpatients, 15 female and 5 male, aged 5969.8 years, who met DSMIII-R (APA, 1987) criteria for major depressive disorder (MDD; 11 unipolar, 9 bipolar) participated in the study. All had scores of at least 18 (mean 25.965.2) on the 21 item HAM-D and had not responded to at least one full course of antidepressant medication at adequate dosage. A group of 21 physically healthy volunteers, 11 male and 10 female, aged 54.768.8 years served as controls for the depressed patients. All control subjects were free of psychopathology as were all of their first degree relatives. Semi-quantitative analysis was performed by applying preformed templates to transaxial SPECT slices, parallel to the orbito-meatal line (OML, Fig. 1). Three templates were employed, based on a standardized brain atlas (Talairach et al., 1988), delineating anatomical structures at 4, 6 and 7

Fig. 1. Mid sagittal section of the brain illustrating the levels of the three transaxial brain slices relative to the OML.

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Fig. 2. Illustration of the regions of interest within the 3 templates, delineating the regions in which increases in cerebral blood flow after electroconvulsive therapy reached statistical significance. F5frontal lobe, ST5superior temporal lobe; MT5middle temporal lobe; O5occipital lobe; ACG5anterior cingulate gyrus; PCG5posterior cingulate gyrus; BG5basal ganglia; TH5thalamus; P5parietal lobe; PrO5parieto-occipital cortex and SCG5superior cingulate gyrus.

cm above the OML (Fig. 2). The average number of counts for each region of interest (ROI) was normalized to the mean cerebellar uptake. As a check, uptake was also normalized to the mean whole brain uptake. Data were analyzed by analysis of covariance (ANCOVA) with diagnosis (control / depressed) as the grouping factor, ROI as the repeated measures factor and age as the covariate. Main effect of group was significant in the left hemisphere in the transaxial slices that were 4 and 6 cm above the OML, and neared significance in the right hemisphere at 4 cm above the OML, indicating a lower overall CBF in these slices in depressed compared to normal subjects. Statistically significant interactions between group and ROI emerged in the left hemisphere in the transaxial slices that were 4 and 6 cm above the OML, indicating that the pattern of uptake ratios among ROIs is significantly different between groups in these regions. No main or interaction effect, other than ROI, was observed in the transaxial slice that was 7 cm above the OML. Comparisons of HMPAO uptake ratios in individual ROIs between depressed and control subjects (corrected for age) reveal reduced uptake in the depressed patients in all ROIs but one. A significant regional difference was found bilaterally in the temporal lobe, in the left anterior cingulate and right occipital and basal ganglia regions in the transaxial slice, 4 cm above the OML. At 6 cm above the OML, differences in uptake ratios reached statistical significance in the occipital, anterior cingulate and posterior cingulate bilaterally and in the right parietal lobe. At 7 cm above the OML, a significant regional difference was reached bilaterally in the superior cingulate and in the right superior frontal lobe. Group differences in laterality were sought by applying ANCOVA, with diagnosis as the grouping factor and the ratio between the respective left and right ROIs as the repeated measures factor. A main effect of group was obtained at 4 cm above the OML.

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Correlation analysis between HAM-D values and HMPAO uptake ratios revealed several ROIs in which statistically significant inverse correlations (or a trend in this direction) were observed. A degree of overlap is seen between regions that distinguish depressed from control subjects and those correlated to depression severity (i.e. temporal and occipital regions at 4 cm above the OML, particularly in the right hemisphere). This pattern was less evident in the higher slices, although some matching regions were found. Correlation between HAM-D values and uptake ratios is better demonstrated in a group consisting of a mixed depressed–remitted population, and will be presented below. It should be noted that differences between groups delineated in our study were far more conclusive before age was added as a covariate in the analysis. A similar impression regarding the pivotal effect of age on CBF in depressed patients and control subjects was recently presented by Devous et al. (1993), who found that diagnostic subtype-dependent age effects on rCBF precluded comparisons of mean values within or across regions for subject groups. The pivotal effect of aging on cerebral perfusion is emphasized by a further study which we conducted (Krausz et al., submitted). Twenty seven healthy subjects were divided into a ‘‘younger’’ (,47; n514) and an ‘‘older’’ (.50; n513) group. Analysis was performed by the same methodology as previously described. CBF ratios, normalized to cerebellum, were significantly lower in the ‘‘older’’ group in all hemispheres. At 4 cm above the OML, perfusion was lower in the temporal and occipital regions and basal ganglia on the left, while on the right, decreases were prominent in the frontal and occipital regions. Perfusion deficits were observed in fronto-parietal regions at 6 cm above the OML and the occipito-parietal regions at 7 cm above the OML. Since the CBF values analyzed are ratios rather than absolute flow values, findings of this study suggest a relative cerebellar ‘‘sparing’’ from the trend of reduced cerebral blood flow in the elderly. While the finding of reduced CBF in depression seems robust, it further remains to be explored whether these abnormalities in perfusion are dependent upon the patient’s clinical state and, therefore, are partially or wholly reversible upon remission, or reflect a more enduring pattern, which may even precede onset of the depressive episode and persist into remission.

3. Primary depression, secondary depression and mood Data reviewed thus far has addressed primary ‘‘functional’’ depression, i.e. the presence of major depression without the existence of any organic (physiological) impairment, with which the mental state is associated.

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Complementary approaches in the study of major depression are to focus upon organic disease that is often accompanied by depression, or to examine the neuroanatomic regions involved in experiencing normal sadness in healthy subjects. This can indicate whether the whole spectrum of human emotion, ranging from normal transient sadness to the clinical state of depression, is universally related to a single neuronal network or may involve different cerebral structures with or without overlap. Research on secondary depression has demonstrated that regions displaying reduced perfusion in primary depression are for the most part impaired in secondary depression as well (see Krausz et al., 1996, for review). This has been demonstrated in the prefrontal region, mainly in the left side but, at times, bilaterally, in depression associated with stroke or other brain lesions (Robinson et al., 1988; Starkstein et al., 1991), Parkinson’s disease (Mayberg and Starkstein, 1991; Jagust et al., 1992; Ring et al., 1994), Huntington’s chorea (Mayberg and Starkstein, 1991) and AIDS (Renshaw et al., 1992). A few recent studies have attempted to capture functional brain responses associated with the induction of mood and emotion in normal subjects. Brain regions involved in conditions of evoked sadness are mainly similar to those mentioned in the study of depression (e.g. prefrontal and limbic structures), although findings are generally bilateral rather than centering on the left hemisphere. Furthermore, increased rather than decreased cerebral activity has been noted in states of transient sadness, in the orbito-frontal cortex bilaterally (Pardo et al., 1993) and in the cingulate, medial prefrontal and mesial temporal cortices, bilaterally (George et al., 1995). To summarize, similar brain regions exhibited changes in blood flow and metabolism in all conditions of altered mood, regardless of etiology. The discrepancy between the excitatory or inhibitory nature of these changes is still to be elucidated.

4. Longitudinal studies of cerebral blood flow and metabolism in depression Only a few studies have sought to find an association between treatment effect and / or remission from depression and changes in CBF or cerebral metabolic rate (CMR). Such studies are of pivotal importance in determining whether the abnormalities in brain function evinced in depression are limited to the period of compromised mood or persist after recovery. Furthermore, since numerous psychopharmacological and other approaches to the treatment of depression are currently employed, the effect of treatment on brain physiology has to be teased apart from that of a change in mental status. Increased CMR in the anterolateral prefrontal cortex after remission has been reported in 12 depressed patients who responded to pharmacological treatment (Baxter et al., 1989) and increases in CBF have been observed in patients

remitted from depression, whether or not they have been medicated (Kanaya and Yonekawa, 1990). Normalization of left–right asymmetries, but not of hypofrontality and global hypometabolism, has been reported by PET study after successful pharmacological treatment in a small group of patients (Martinot et al., 1990). As with most findings reported with functional imaging, no change in CMR despite clinical improvement from depression has also been reported (Hurwitz et al., 1990). Three recent studies have examined CBF and CMR in depressed patients before and after treatment by sleep deprivation [Ebert et al. (1991); Volk et al. (1992) using HMPAO and Wu et al. (1992) using CMR]. In all three studies, changes were limited to responders, defined according to a (modest) decrease in HAM-D symptom severity. Results, however, are not uniform. Volk et al. (1992) report CBF increases in the left temporal and right parietal lobes, whereas Wu et al. (1992); Ebert et al. (1991) describe CMR and CBF decreases in the cingulate cortex and limbic systems, respectively. Several studies have examined the effect of electroconvulsive therapy (ECT) on CBF and CMR in depressed patients. Most have addressed immediate and acute effects of ECT (i.e. from 30 min to 24 h post treatment) and disclose reductions in rCBF (Silfverskiold et al., 1986; Rosenberg et al., 1988; Prohovnik et al., 1986) and CMR (Ackerman et al., 1986; Guze et al., 1991; Volkow et al., 1988). Concerning the long-term effects of ECT, a significant reduction in CBF, measured by the Xe-133 rCBF technique, was observed in remitted patients 0–3 months after ECT (Silfverskiold et al., 1986), with return to baseline 4–12 months after ECT (Silfverskiold et al., 1986; Silfverskiold and Risberg, 1989). Another Xe-133 study (Nobler et al., 1994) found response to ECT to be associated with decreased global and regional CBF, whereas non-response was associated with increased flow. In contrast to the above Xe-133 studies, a recent preliminary Tc-99m HMPAO report (Vasile, Bradely, Bloomingdale and Schildkraut. CBF after ECT for depression. American Psychiatric Association Annual Meeting, May 1994 Philadelphia, PA.) assessing CBF in 8 depressed patients before and after completion of, and response to, a full course of ECT, revealed increased flow in the left frontal cortex after treatment. Of particular interest is a recent PET study comparing cerebral activity in depressed patients with Parkinson’s disease before and after treatment with antidepressants (Mayberg, 1995). Bilateral increases in glucose metabolism were seen after treatment (and response) in the inferior and dorsolateral prefrontal cortices. This finding lends additional support to the notion that control of mood and emotion, even in instances of physical illness, is largely mediated by the same neural systems. Using SPECT imaging of Tc-99m HMPAO uptake, we examined CBF in 20 medication-free patients (15 female, 5 male; age 5969.8 years) with severe MDD, 2–4 days

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before and 5–8 days after a course of treatment with ECT (Bonne et al., 1996a). Depressed subjects and imaging procedures are identical to those presented above. Differences between pre- and post ECT Tc-99m HMPAO uptake ratios for the group of subjects as a whole (n520) were observed only in the transaxial brain slice at 6 cm above the OML, with increased perfusion after treatment in the anterior and posterior cingulate gyri of the left hemisphere ( p50.04 and 0.03, respectively) and in the posterior cingulate gyrus of the right hemisphere ( p5 0.002). The data were then analyzed separately for responders (n511) and non-responders (n59) to ECT, defined according to a priori criteria. Fig. 2 shows the significance levels of pre- versus post ECT differences in Tc-99m HMPAO uptake ratios of the responders in each of the three transaxial slices. Increases, which survived Bonferroni correction for multiple testing, were observed in a number of brain regions. A visual representation of the increases in CBF in a depressed patient who responded to ECT is shown Fig. 3. The most robust increases were noted in the cingulate gyrus, which is part of the paralimbic cortex. This finding is compatible with the paralimbic hypoperfusion observed in unipolar depression by Mayberg et al. (1994). The paralimbic cortex has been implicated as having an important role in mood and emotional changes observed in depressed patients after various brain lesions (Starkstein et al., 1987). In subjects who had not responded to ECT, a reduction in Tc-99m HMPAO uptake ratios was observed in 30 of the 34 brain regions in all 3 brain slices, although differences did not reach statistical significance. Significant inverse correlations, most of which survived Bonferroni correction for multiple testing, were obtained between HAM-D scores and Tc-99m HMPAO uptake

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ratios after ECT in many brain regions, as well as globally in all three brain slices. This finding replicates previous reports and would appear to be a relatively robust observation in MDD. Before ECT, statistical significance was reached in fewer regions (results presented above), resulting perhaps from the considerably lesser variance in HAM-D scores in a uniformly depressed subject sample. A numerical measure of the changes in HAM-D scores and Tc-99m HMPAO uptake ratios was obtained by subtraction of the respective post ECT values from the pre ECT ones. Correlations between the change in HAM-D score and the change in Tc-99m HMPAO uptake ratios were computed. The degree of improvement (numerical decrease) in HAMD was inversely correlated with the extent of increase in Tc-99m HMPAO uptake in many regions, globally over the left hemisphere in all three brain slices and within the right hemisphere in the 7 cm slice. Results compiled thus far from treatment / response studies are inconsistent. Although one may be tempted to attribute the discrepancies in findings to the different imaging techniques employed, it should be borne in mind that findings in studies examining major depression are much more uniform despite similar technical disparities. Nevertheless, the majority of studies do report changes in brain function after remission or response to treatment, and brain regions involved in these changes are mostly similar. However, the nature of changes in brain perfusion or metabolism differs, with several studies showing increases in these indices after remission whereas others note decreases. The reason for these discrepancies is unclear, but may be related (among other reasons) to the effect of the treatment modality on brain function. We therefore conducted the following preliminary study, examining the effect of fluoxetine on healthy subjects. Twelve healthy volunteers (7 male, 5 female, aged 23–63 years) were scanned by Tc-99m HMPAO and administered a comprehensive psychometric testing battery before and after 4 weeks of treatment with fluoxetine (20 mg per day). The imaging procedure and data analysis were performed as described above. Results showed that fluoxetine administration does not have a discernible effect on mood in normal subjects (Gelfin et al., submitted). Similarly, cerebral blood flow was minimally affected by fluoxetine administration (Bonne et al., 1996b). These results support the contention that reduced CBF in depression and increase following remission represents reversal of a state marker and is not a direct effect of antidepressant treatment on CBF.

5. Prediction of response: preliminary findings

Fig. 3. Two sagittal (left of midline) brain sections of a patient from our cohort before and after treatment with ECT.

We analyzed pre-treatment rCBF ratios in responders and non-responders to ECT, in an attempt to determine whether pre-treatment perfusion measures could in any way predict response or non-response to this treatment.

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Table 1 Results of stepwise logistic regression at the transaxial brain slices 4 and 6 cm above the OML Variable

Degree of freedom

Parameter estimate

Wald statistic

Chi-square ( p)

4 cm above OML

Intercept Left posterior cingulate Left basal ganglia

1 1 1

8.00 214.59 5.76

3.08 6.04 3.20

0.07 0.01 0.07

6 cm above OML

Intercept Left posterior cingulate Right posterior cingulate

1 1 1

13.45 38.43 250.28

4.69 3.23 4.05

0.03 0.07 0.04

Currently, the choice of antidepressant medication in the treatment of depression is based more upon side effect profile than upon likelihood of response. Regarding ECT, its employment is scheduled after non-response to medication and, again, outcome is estimated by probabilities and not by specific patient characteristics. Stepwise logistic regression was employed, with significance level entry and significance level stay of 0.1, with ROIs from both hemispheres in each transaxial slice analyzed conjunctly, and with age and sex entered into the regression as well (Table 1). Pretreatment uptake ratios of the left posterior cingulate and left basal ganglia of the brain slice 4 cm above the OML predicted in 80% of the cases whether patients would or would not respond to treatment (sensitivity, 91%; specificity, 67%; false positive, 23%; false negative, 14%). When the model was applied to the transaxial slice 6 cm above the OML, uptake ratios of the posterior cingulate gyri bilaterally predicted response or non-response in 85% of the cases (sensitivity, 91%; specificity, 78%; false positive, 16%; false negative, 12%). In the transaxial slice 7 cm above the OML, pre-treatment perfusion rates in responders and non-responders were not highly predictive of response status. These results are preliminary and must be replicated, but offer a means to provide, based upon individual patient characteristics rather than statistical probabilities, the proper therapeutic modality to patients suffering from major depression.

6. Discussion As presented, considerable data support the existence of a cerebral impairment in major depression. It is unclear, however, whether the emergence of this impairment coincides with the onset of the depressive episode and will cease once remission is achieved, i.e. is a ‘‘state’’ related property, or has existed prior to the evolution of depression and is therefore a ‘‘trait’’ phenomenon. It may also be possible that although the impairment has not existed prior to the advent of depression, it may persist after clinical remission and thus will not fit into either state or trait categorization. Furthermore, it is unknown whether the functional abnormalities noted in the studies reviewed are

pathophysiologically involved in the evolution of depression or are an additional expression of an as yet unknown etiological factor of the disease. The paucity of data concerning treatment / response / remission effects currently precludes an answer to these issues. The results of our ECT study support the hypothesis that the reductions in brain function observed in major depression are state-related and reversible. This is in contrast to the two comparable Xe-133 ECT studies (Silfverskiold et al., 1986; Nobler et al., 1994), which report reductions in CBF after response to treatment. Among these two studies, Silfverskiold et al. (1986) found no difference in CBF between depressed patients and control subjects, but the group of Nobler et al. reported what may be the strongest evidence supporting reduced CBF in major depression (Sackeim et al., 1990), making their findings all the more intriguing. It would therefore appear that the Nobler et al. (1994) study, while not precisely fitting into the ‘‘state’’ or ‘‘trait’’ dichotomy, is more in the line of the latter approach. However, should the finding of a reduction in CBF after remission hold true and, as depression is a recurring illness, one would expect to find lower CBF in subjects that have suffered from numerous episodes of depression compared to those who have only undergone one or a few episodes, but this has not been demonstrated in that cohort (Sackeim, pers. comm.). An absence of correlation between Xe-133 and Tc-99m HMPAO data was observed by Rubin et al. (1992), who found no abnormality in obsessive compulsive disorder (OCD) patients when employing Xe-133, while HMPAO located abnormalities. Results obtained with Tc-99m HMPAO were consistent with those previously reported from PET studies of OCD (Baxter, 1990). The reason for the discrepancy between Xe-133 and Tc99m HMPAO may be related to superior resolution of the latter, with its ability to identify sub-cortical processes or metabolic mechanisms involved in Tc-99m HMPAO uptake by brain parenchymal cells (Kung, 1990) or to as yet ill-defined mechanisms. The difference in findings between our HMPAO-SPECT studies and those of Silfverskiold et al. (1986); Nobler et al. (1994) employing Xenon-133 may be understood on this basis. We assume that the changes in CBF observed in remitted patients after ECT in our study reflect in some

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measure both the change in mental state and the effects of repeated induced seizures. Therefore, it may be expected that in those patients who have not responded to treatment (or were partial responders but did not meet response criteria), the effect of induced seizures would be more prominent. We believe that the direct effect of ECT on cerebral perfusion may be similar to that of epileptic seizures, and that CBF at a certain period following termination of the ECT course may resemble that of the interictal state. As mentioned above, decreases in CBF were observed in the time period shortly following ECT (Ackerman et al., 1986; Rosenberg et al., 1988). In patients suffering from epilepsy (and for the most part not displaying structural brain pathology), functional imaging studies that have been conducted both shortly following the ictus and interictally have consistently shown hypoperfusion (Lancet, editorial, 1989; Devous et al., 1990; Duncan, 1992; Chugani, 1992). This applies particularly to partial seizures (Lee et al., 1988; Duncan et al., 1992), but has been noted in generalized and secondary generalized seizures as well (Devous et al., 1990; Launes et al., 1992). The effects of ECT and alleviation from depression on CBF would therefore act in opposite directions. This assumption is supported by the findings of our ECT study. The increased CBF in responders has already been sufficiently expounded, but we would like to emphasize the widespread reductions in CBF in the subjects who did not respond to the treatment. The fact that the reductions in perfusion did not reach statistical significance can be attributed first to the small number of subjects in this category (n59) and to the fact that, due to the strict response criteria employed in the study, in at least some of these subjects improvement in mood did occur, although it fell short of the 60% reduction in HAM-D score required to classify them as responders. The findings of our group and others, reviewed above, strongly suggest that major depression is characterized by abnormalities of cerebral perfusion. These abnormalities characterize both primary ‘‘functional’’ depression as well as depressive states secondary to various diseases. Moreover, perfusion deficits are reversed following remission of the depressed state induced by a variety of treatment modalities. Therefore, reduced brain perfusion appears to be a state marker of the depressed condition. Since the causation of MDD is clearly multifactorial, elucidation of the role played by cerebral perfusion would open the way for other pathogenetic factors to be evaluated under circumstances that are considerably more favorable than those that are presently operative.

Acknowledgments The authors would like to thank Professor Bernard Lerer, Head of the Biological Psychiatry Laboratory at the Department of Psychiatry, Hadassah - Hebrew University

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Medical Center, for his continuous support and guidance in these and all on-going projects.

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