Familial Pure Depressive Disease Research Articles

Glucose metabolism in the amygdala in depression: Relationship to diagnostic subtype and plasma cortisol levels

In a previous positron emission tomography (PET) study of major depression, we demonstrated that cerebral blood flow was increased in the left amygdala in unipolar depressives with familial pure depressive disease (FPDD) relative to healthy controls [J. Neurosci. 12 (1992) 3628.]. These measures were obtained from relatively low-resolution PET images using a stereotaxic method based upon skull X-ray landmarks. The current experiments aimed to replicate and extend these results using higher-resolution glucose metabolism images and magnetic resonance imaging (MRI)-based region-of-interest (ROI) analysis. The specificity of this finding to FPDD was also investigated by assessing depressed samples with bipolar disorder (BD-D) and depression spectrum disease (DSD). Finally, the relationship between amygdala metabolism and plasma cortisol levels obtained during the scanning procedure was assessed. Glucose metabolism was measured using PET and 18F-fluorodeoxyglucose ( 18FDG) in healthy control ( n=12), FPDD ( n=12), DSD ( n=9) and BD-D ( n=7) samples in the amygdala and the adjacent hippocampus. The left amygdala metabolism differed across groups ( P<.001), being increased in both the FPDD and BD-D groups relative to the control group. The left amygdala metabolism was positively correlated with stressed plasma cortisol levels in both the unipolar ( r=.69; P<.005) and the bipolar depressives ( r=0.68; .1< P<.05). In contrast, neither significant main effects of diagnosis nor significant relationships with plasma cortisol were evident in post hoc analyses of metabolism in the right amygdala or the hippocampus. Preliminary assessment of BD subjects imaged during remission suggested that amygdala metabolism is also elevated in remitted subjects who are not taking mood-stabilizing drugs, but within the normal range in subjects taking mood stabilizers. These data confirm our previous finding that neurophysiological activity is abnormally increased in FPDD, and extend it to BD-D. These abnormalities were not accounted for by spilling in of radioactivity from the adjacent hippocampus. The correlation between left amygdala metabolism and stressed plasma cortisol levels may conceivably reflect either the effect of amygdala activity on corticotropin-releasing hormone (CRH) secretion or the effect of cortisol on amygdala function.

Brain imaging of affective disorders and schizophrenia.

We review recent findings in human brain imaging, for example, which brain areas are used during perception of colors, moving objects, human faces, facial expressions, sadness and happiness etc. One study used fluorine-18-labeled deoxyglucose positron emission tomography (PET) in patients with unipolar depression and bipolar depression, and found hypometabolism in the left anterolateral prefrontal cortex. Another study reported increased regional cerebral blood flow in the amygdala in familial pure depressive disease. Using 11C-glucose PET, we reported that the glutamic acid pool was reduced in cortical areas of the brain in patients with major depression. We also found that the thalamic and cingulate areas were hyperactive in drug-naive (never medicated) acute schizophrenics, while the associative frontal, parietal, temporal gyri were hypoactive in drug-naive chronic schizophrenics. Brain biochemical disturbances of schizophrenic patients involved glutamic acid, N-acetyl aspartic acid, phosphatidylcholine and sphingomyelin which are important chemical substances in the working brain. The areas of the thalamus and the cingulate which become hyperactive in acute schizophrenic patients are important brain areas for perception and communication. The association areas of the cortex which become disturbed in chronic schizophrenia are essential brain areas in human creativity (language, concepts, formation of cultures and societies) and exist only in human beings.

All roads lead to depression: clinically homogeneous, etiologically heterogeneous

Manias, and particularly depressions, are syndromes not diseases. Considerable data support the fact that depressions, though similar clinically, are of heterogenous etiologies. We can separate depressions generally into those that are endogenous/psychotic and those that occur in the context of marked emotional instability. Familial pure depressive disease is a specific example of the former, depression spectrum diseases a specific example of the latter. These are separable on the basis of personality, clinical, follow-up, familial and treatment variables.

Depression spectrum disease with and without depression in first-degree relatives

Family history was assessed in 211 outpatients with unipolar major depression and diagnoses were rendered according to Winokur et al. (Winokur et al. (1978) J. Nerv. Ment. Dis. 166, 764–768) family history typology. The subclassification of Depression Spectrum Disease with Alcoholism and Depression (DSDA + D) was applied to those patients reporting at least one first-degree relative suffering from alcoholism and another first-degree relative suffering from depression ( n = 103), while Depression Spectrum Disease with Alcoholism (DSDA) was applied to those patients with at least one first-degree relative suffering from alcoholism, but none suffering from depression ( n = 108). These two groups were compared on demographic, clinical and biological characteristics. They were also compared with 162 patients who reported the presence of depression and absence of alcoholism in first-degree relatives, designated as Familial Pure Depressive Disease (FPDD) by the Winokur et al. (1978) classification. Results revealed that the DSDA + D group was younger, had an earlier age at onset of depression and experienced more episodes of depression than did the DSDA group. No differences were found between the two groups on biological measures. The FPDD group was more similar to the DSDA + D group than the DSDA group in terms of age at onset and number of depressives episodes. However, the FPDD group had a longer length of illness than either of the DSD groups. These data suggest that the DSD group should be more narrowly defined (excluding those with a positive family history of depression) in future clinical research studies.

Familial subtypes of unipolar depression: A prospective study of familial pure depressive disease compared to depression spectrum disease

In a large multicenter effort, major depressives were systematically studied at index admission and prospectively followed up for 5 years. Primary unipolar depressives with a family history of alcoholism (depression spectrum disease) differ from depressives with a family history of depression only (familial pure depressive disease) in having more familial anxiety and somatization disorder, more divorce, more suicide attempts, more negative life events, and needed more time to recover from the index episode. In the 5-year follow-up they are more likely to develop alcoholism and drug abuse. Depressive spectrum disease patients are more likely to meet systematic criteria for neurotic depression. The data suggest that major depression is a syndrome that is heterogeneous, and may be a final common pathway of more than one familial illnesses.

A functional anatomical study of unipolar depression

The functional neuroanatomy of unipolar major depression was investigated using positron emission tomography to measure differences in regional cerebral blood flow (BF). A relatively homogeneous subject group was obtained using criteria for familial pure depressive disease (FPDD), which are based upon family history as well as upon symptoms and course. Because of the absence of certain knowledge about the pathophysiology of mood disorders and their underlying functional neuroanatomy, we used data obtained from the subtraction of composite images from one-half of depressed and control subjects to identify candidate regions of interest. The major cortical region defined in this manner was statistically tested on a second set of subjects. Using this strategy, we found increased BF in an area that extended from the left ventrolateral prefrontal cortex onto the medial prefrontal cortical surface. Based upon the connectivity between these portions of the prefrontal cortex and the amygdala and evidence that the amygdala is involved in emotional modulation, activity was measured in the left amygdala and found to be significantly increased in the depressed group. A separate group of subjects with FPDD who were currently asymptomatic were also imaged to determine whether these findings represented abnormalities associated with the depressed state, or with a trait difference that might underlie the tendency to become depressed. Only the depressed group had increased activity in the left prefrontal cortex, suggesting that this abnormality represents a state marker of FPDD. Both the depressed and the remitted groups demonstrated increased activity in the left amygdala, though this difference achieved significance only in the depressed group. This suggests that the abnormality involving the left amygdala may represent a trait marker of FPDD, though further assessment in a larger sample size is necessary to establish this. These data along with other evidence suggest that a circuit involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus is involved in the functional neuroanatomy of depression.

Alpha 2 adrenergic receptor subtypes in depression: A candidate gene study

Alpha 2 adrenergic receptors play an important role in regulating the neuronal release of norepinephrine through presynaptic feedback inhibition in the locus ceruleus. Therefore, alpha 2 adrenergic autoreceptors may underlie some aspects of the pathogenesis and symptomatic expression of depressive illness. We studied two brain-expressed alpha 2 adrenergic receptor genes as genetic markers in linkage analyses in 17 multiplex pedigrees of unipolar depression. Neither of the genes was supportive of linkage to depression. Lod scores of less than -2 were found in both familial pure depressive disease pedigrees and in depression spectrum disease pedigrees. Therefore, we conclude that depression in our pedigrees is not related to mutations in the two alpha 2 adrenergic receptor genes tested.

Evidence for possible linkage between genetic markers and affective disorders

Studies of the underlying components of affective disorders are particularly difficult because of the confounding effects of both genetic and environmental factors. Linkage analysis is a useful tool in delineating the etiology of affective disorders, as it is unlikely that linkage between behavioral traits and blood group polymorphisms could result from environmental effects. The present study used the robust Haseman and Elston sibpair method to analyze linkage between 24 genetic markers and affective disorder in 34 nuclear families from 25 pedigrees (195 people). The probands were ascertained as part of the ongoing NIMH Collaborative Depression Study. Indications of linkage between familial pure depressive disease and MNS and depression spectrum disease and ORM were found, as had been previously suggested. There was also suggestive evidence for linkage between the latter and GC. Results are discussed in terms of methodological differences with previous studies.

Prognostic validity of the familial subtypes of depression.

We examined the prognostic validity of Winokur's familial subtypes of depression in 184 in-patients with primary unipolar major depression. Patients with familial pure depressive disease had a more favorable hospital course and reported less symptoms during a 6-month follow-up evaluation than patients with depressive spectrum disease or sporadic depressive disease. Consistent with previous studies of the validity of the familial subtypes, the use of stringent thresholds to diagnose the patient's relatives increased the validity of classification.

Validity of familial subtypes of primary unipolar depression. Clinical, demographic, and psychosocial correlates.

We examined the psychosocial, demographic, and clinical correlates of familial subtypes of primary unipolar depression. Our findings supported the hypothesis that depression spectrum disease is a variant of neurotic depression, whereas familial pure depressive disease overlaps with endogenous depression. Patients with depressive spectrum disease experienced more life events, had more marital separations and divorces, had poorer social support, more frequently made a nonserious suicide attempt, and had a less characteristic endogenous symptom profile than patients with familial pure depressive disease. Consistent with our previous report on the relationship between dexamethasone suppression test results and familial subtyping, the broadness of the criteria used to diagnose the patients' first-degree relatives affected the strength of the association between the familial subtypes and the dependent variables.

Tritiated imipramine binding distinguishes among subtypes of depression.

We studied 45 depressed patients and 20 healthy controls in order to determine if tritiated imipramine binding distinguished among subtypes of primary major depressive disorder. Mean (+/- standard deviation) values for maximal concentration of tritiated imipramine binding sites on platelet membranes were significantly lower in patients with bipolar and familial pure depressive disease (754 +/- 149 and 870 +/- 241 femtomoles [fmole]/mg of protein, respectively) than in patients with depressive spectrum and sporadic depressive disease (1,236 +/- 241 and 1,188 +/- 325 fmole/mg of protein, respectively), neither of which differed from healthy controls (1,238 +/- 201 fmole/mg of protein). Multiple linear regression analysis revealed that these differences could not be attributed to differences in age, sex, Hamilton Rating Scale score, presence of psychotic features, hospitalization status, or medication history. This association of a biological finding with distinct clinically defined subtypes of depression may lead to a classification of affective disorders useful in further research.

The familial classification of primary unipolar depression: Biological validation of distinct subtypes

FUNDAMENTAL PROBLEM in the study of affective disorders has been isolating relatively homogeneous groups of depressed patients. This type of separation is essential to studies of both the etiology and treatment of depression. The bipolar-unipolar and primary-secondary distinctions have proven to be useful classifications in this regard. However, even with these distinctions, the majority of depressed patients remain classified in the heterogeneous group of primary unipolar depression. Winokur’s* has demonstrated that primary unipolar depression can be reliably subclassified on the basis of family history. According to Winokur’s scheme, depressive spectrum disease (DSD) refers to those patients with unipolar depression who have a first-degree family member with alcoholism and/or antisocial personality. There may or may not be a family history of depression in these patients. Familial pure depressive disease (FPDD) applies to patients with a family history only of depression. Those patients without a family history of depression, alcoholism, or antisocial personality are considered to have sporadic depressive disease (SDD). In a hospital population, these subtypes accounted for 16%, 26%, and 45%, respectively, of the unipolar depressives. The remaining 13% could not be classified according to this scheme because either the family history was unknown or because there was a history of mania in a first-degree relative.’

The thyrotropin-releasing hormone and dexamethasone suppression tests in the familial classification of depression

Eighty-eight depressed patients who had received a dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) test were divided into four subgroups based on family history of psychiatric illness. Nonsuppression on the DST was found in 46% of familial pure depressive disease (FPDD) patients, 38% of sporadic depressive disease (SDD) patients, 38% of depressive spectrum disease (DSD) patients, and 50% of mixed depressive disease patients (patients with both a first degree relative with alcoholism and one with depression). A blunted thyroid-stimulating hormone response to TRH was found in 50% of FPDD patients, 56% of SDD patients, 47% of DSD patients, and 56% of mixed depressive disease patients. Neither the DST nor TRH test was found to distinguish significantly among the four familial subgroups of depression.

Differentiation of Depressive Subtypes by Insulin Insensitivity in the Recovered Phase

The glucose response to a standard insulin tolerance test (ITT) has been reported to be blunted in the acute phase of heterogeneous depressive disorders and to be normal in the recovered phase. We studied the glucose response to ITT in the recovered phase depression in patients who had previously been subclassified according to familial and clinical characteristics. All patients with depressive spectrum disease had an adequate glucose response to the ITT, whereas only 40% of patients with familial pure depressive disease and 56% of patients with bipolar illness had an adequate hypoglycemic response. There was also a trend toward a decrease in insulin sensitivity in patients who had been nonsuppressors to dexamethasone when depressed. These findings suggest that the glucose response to ITT may be a useful tool in differentiating among the heterogeneous depressive disorders.

Subtypes of unipolar depression distinguished by the dexamethasone suppression test

The dexamethasone suppression test (DST) was administered to 54 primary unipolar depressed patients and 19 non-depressed hospitalized inpatients. Abnormal DST were found in 23 depressed patients (43%) in contrast to 2 (11%) non-depressed patients ( P <0.05). With the endogenously depressed group, 69% of patients categorized as familial pure depressive disease (FPDD) in contrast to 13% of depressive spectum disease (DSD) patients had abnormal DST results ( P <0.02). The DSD group had significantly fewer abnormal DST results than all other subtypes of unipolar depression ( P <0.05). The distinction revealed between DSD patients and other endogenously depressed patients may be due to biological factors or due to the heterogeneous nature of the DSD subtype group.

Plasma GABA in affective illness: A preliminary investigation

Plasma levels of γ-aminobutyric acid (GABA) were determined in 34 clinically symptomatic patients with diagnosis of affective disorder and in 20 normal controls. Lowest levels were found in patients with familial pure depressive disease and in depression spectrum disease, while levels of patients with sporadic depressive disease, though significantly lower than control, were not as low. Plasma GABA levels in secondary depression and in bipolar depression were similar to control. Bipolar manic patients had plasma GABA levels that were significantly higher than control values.

Dexamethasone Suppression Test and Subtypes of Depression

To the Editor.— In reference to the Schlesser et al article, Hypothalamic-Pituitary-Adrenal Axis Activity in Depressive Illness: Its Relationship to Classification (Archives1980;37:737-743), the conclusions drawn by the authors do not appear to be valid based on the methodology used in their study. Carroll et al 1 have shown that most patients with endogenomorphic depression did not show escape from dexamethasone suppression of cortisol until late afternoon (4Pm) or evening (12Am) on the day following dexamethasone administration. This point was also brought up by Brown and Shuey in their article, Response to Dexamethasone and Subtype of Depression, which appeared in the same issue of theArchives(1980;37:747-751). The methodology used by Schlesser et al (ie, measuring only the 8Amcortisol levels after dexamethasone administration) could have missed a substantial proportion of patients with familial pure depressive disease (FPDD), sporadic depressive disease (SDD), or depressive spectrum disease (DSD),

Neuroendocrine studies in affective disorders: Part 2. Plasma thyroid-stinulating hornone response to thyrotropin-releasing hormone in affective disorders: Effect of ECT

The plasma thyroid-stimulating hormone response to thyrotropin-releasing hormone in controls and patients with affective disorders has been studied. The results of the investigation do not suggest any abnormality of this response in monopolar or unipolar depressed patients or bipolar patients undergoing a manic phase of their illness. No significant difference in this response could be detected between ‘sporadic depressive disease’ patients and ‘familial pure depressive disease’ patients, and age- and sex-matched controls. The neuroendocrine response was essentially unchanged after treatment by ECT.

Hypothalamic-pituitary-adrenal axis activity in depressive illness. Its relationship to classification.

Serum cortisol response to the 1-mg overnight dexamethasone suppression test was studied in 221 depressed patients and 109 nondepressed psychiatric controls. Nonsuppression distinguished patients with primary unipolar depression (65/146) from patients with secondary unipolar depression (0/42) and nondepressed controls (0/109). Furthermore, nonsuppression distinguished the three familial subtypes of primary unipolar depressive illness: familial pure depressive disease (FPDD; 38/50 patients), sporadic depressive disease (SDD; 24/55 patients), and depression spectrum disease (3/41 patients). Moderate elevations in baseline serum cortisol levels were found in FPDD, SDD, and bipolar depression. Medication did not affect the results. The data suggest that the depressive syndrome is composed of separate illnesses, each of which has a distinctive pattern of hypothalamic-pituitary-adrenal axis activity during the depressed state as well as a specific clinical and familial psychiatric history.

Familial (genetic) subtypes of pure depressive disease

The author reviewed data from five studies and found that depressed patients with a history of depression in a parent or child have more sibships containing depression than depressed patients without this family history. Thus, there is a clustering of depressions in certain families. Sporadic pure depressive disease (PDD), where no depressive illness exists in a first-degree family member of a depressed proband, is associated with a later age of onset than familial PDD, where depressive illness does exist in a first-degree relationship. The possibility exists that familial PDD and sporadic PDD are autonomous illnesses. The presence of a family history of depression may be predictive to some extent of a good response to adequate tricyclic medication or ECT.