Decreased dopamine beta-hydroxylase activity in unipolar geriatric delusional depression

Decreased Dopamine Beta-Hydroxylase Activity in Unipolar Geriatric Delusional Depression Barnett S. Meyers, George S. Alexopoulos, Tatsu Kakuma, Fughik Tirumalasetti, Michelle Gabriele, Stephanie Alpert, Charles Bowden, and Herbert Y. Meltzer Background: Decreased dopamine beta-hydroxylase (DBH) activity has been reported in unipolar psychotic depression. DBH comparisons between elderly delusional and nondelusional depressives and controls and determination of whether pretreatment group differences persist have not been reported. Our objective was to compare DBH activity in elderly delusional major depressives with that of nondelusional depressives and normal control subjects before and after hospital treatment. Methods: Enzyme activity was assessed after hospital admission. A subsample had predischarge assessments. Treatment was not controlled but accounted for in analyses. Electroconvulsive therapy subjects were medicationfree for posttreatment assays. Results: Baseline and predischarge DBH assays were lower in subjects with delusional depression than in either comparison group. Despite high intraindividual correlation, treatment was associated with significant increases in activity in the clinical groups. Conclusions: Patients with late-life delusional depression have lower DBH activity before and after hospital treatment than age-matched nondelusional patients or normal controls. Biol Psychiatry 1999;45:448 – 452 © 1999 Society of Biological Psychiatry Key Words: Dopamine beta-hydroxylase, delusional depression, geriatric, treatment

Introduction

D

opamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, is of interest to studies of psychiatric disorders because peripheral and

From the Department of Psychiatry (BSM, GSA) and Department of Biostatistics (TK), Cornell University Medical College, Ithaca, New York; Department of Medicine, Medical College of Pennsylvania, Philadelphia, Pennsylvania (FT); The New York Hospital–Cornell Medical Center, Westchester Division, White Plains, New York (MG); Department of Psychiatry, New York University, New York, New York (SA); Division of Biological Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas (CB); and Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee (HYM). Address reprint requests to Barnett S. Meyers, MD, The New York Hospital– Cornell Medical Center, Westchester Division, 21 Bloomingdale Road, White Plains, NY 10605. Received July 28, 1997; revised January 28, 1998; accepted February 5, 1998.

© 1999 Society of Biological Psychiatry

cerebral spinal fluid DBH activity are significantly correlated in drug-free patients (Lerner et al 1978). Furthermore, DBH deficiency syndromes are associated with increased levels of dopamine relative to norepinephrine (Robertson et al 1991). An early study of serum DBH activity in unipolar depression, bipolar disorder, schizophrenia, and normal controls found no significant group differences (Meltzer et al 1976); however, serum DBH activity was significantly lower in patients with psychotic major depression compared to controls and patients with nonpsychotic depression. The possible relationship between DBH activity and the delusional form of psychotic depression is particularly relevant to geriatric depression because delusions have been identified in over 40% of elderly patients hospitalized for major depression (Post 1962; Meyers and Greenberg 1986). Furthermore, elderly patients are at low risk for developing bipolar depression and provide a sample that is well suited for studying a biological association that may occur only in unipolar depression (Rihmer et al 1984; Mod et al 1986). Although serum DBH is largely under genetic control (Robertson et al 1991), reports suggesting that treatment with psychopharmacologic medications can affect the activity of this enzyme (Damase-Michel et al 1991; Sofuoglu et al 1995) raise the question whether low levels in psychotic depression are present after somatic treatment. The present study was conducted to test the hypothesis that geriatric patients with unipolar delusional depression have lower serum DBH activity than comparably aged unipolar nonpsychotic depressives and normal controls. A second hypothesis postulated that group differences in DBH activity are present both before and after somatic treatment.

Methods and Materials Subjects The subjects were $60 years of age and recruited from a geriatric acute inpatient service at an academic medical center. To be eligible for inclusion, patients had to meet DSM-III-R criteria (American Psychiatric Association 1987) for major depression with a severity score of at least 22 on the 17-item 0006-3223/99/$19.00 PII S0006-3223(98)00085-7

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Hamilton Depression Rating Scale (HDRS) (Hamilton 1960). Classification as delusional required the presence of a fixed belief maintained despite reality testing confrontation in an interview with the senior investigator (BSM) and a clear history that the belief was absent prior to the depressive episode. Patients with bizarre or mood-incongruent delusions and those for whom a clearly defined delusional idea could not be demonstrated were excluded (n 5 2). Paranoid delusions were considered mood congruent if a patient attributed persecutory ideas to a real or imagined misdeed. Because the study focused on delusional depression, patients with hallucinations without concurrent organized delusional ideas were excluded (n 5 1). Other exclusion criteria included Parkinson’s disease, severe or unstable medical illnesses (e.g., uncontrolled diabetes mellitus, congestive heart failure), or use of medications known to affect catecholaminergic function other than neuroleptics of antidepressants. Patients were also excluded if a history of cognitive impairment preceded the depressive episode or if they failed to achieve a Mini-Mental State Examination (Folstein et al 1975) score of $24 within 2 weeks of completing a course of electroconvulsive therapy (ECT). Controls were selected from community-residing elderly volunteers who did not meet current or lifetime criteria for an Axis I psychiatric disorder. Controls were not taking psychotropic medications or other agents known to affect catacholaminergic functioning.

Procedures Assessments and assays for serum DBH activity were obtained within 5 days of hospitalization after obtaining informed consent and prior to the institution of ECT in patients who received this treatment. There was no placebo washout before baseline assays. A subgroup of subjects recruited later in the study had additional assessments, including both baseline and predischarge HDRS scores and DBH assays. Treatment was selected on a “doctor’s choice” basis. In subjects treated with ECT, posttreatment DBH assays were obtained within 3 days of the last treatment and prior to post-ECT pharmacotherapy. Patients treated with pharmacotherapy were receiving medication at the time of posttreatment assays. Serum was obtained before breakfast after lying for 20 min in a supine position. Blood was collected in plastic syringes and spun for 10 min in a refrigerated centrifuge after 15 min of standing. Serum was frozen at 280°C for periods between 3 and 9 months until express mailing for analysis. Assays were done in duplicate and averaged for each subject. Enzyme stability during storage was not assessed. DBH activity was analyzed at different laboratories (Dr. Meltzer’s and Dr. Bowden’s) during the study period. Both used a modification of the Nagatsu and Udenfriend (1972) photometric method with a DBH Unit defined as the number of micromoles octopamine formed per/milliliter of serum per minute (Matuzas et al 1982; Bowden et al 1988). Two noncorrelational approaches were used to determine the comparability of values from the two laboratories. Split sample analyses across laboratories were not carried out. Mean DBH values for the total sample and for the three clinical groups of interest were compared across laboratories using Student’s t test. Analysis of

Figure 1. Baseline DBH values in three groups. variance (ANOVA) was also used. The average DBH activity (all p values exceeded .49) and the variances of assays carried out in the two laboratories (F(20,35) 5 1.21, p 5 .60) were highly comparable. DBH values determined by the two laboratories were then added into the total data set for analyses.

Statistical Analyses ANOVA was applied to compare DBH activity between the three experimental groups at baseline and after hospital treatment. Pair-wise comparisons were carried out for appropriate contrasts using Student’s t test. Pearson’s correlation coefficient was used to examine intraindividual variation in DBH activity and to determine relationships between changes in DBH activity with treatment and improvement on HDRS scores. Group values are described as means 6 standard deviations.

Results Baseline DBH Activity Baseline characteristics of 15 delusional, 20 nondelusional, and 22 control subjects compared for DBH (see Figure 1) are described in Table 1. Data from a delusional outlier with a DBH value 3.36 standard deviations above the mean for this group were not included. Two of the delusional depressives (13.3%) had concurrent hallucina-

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Changes Associated with Treatment

Table 1. Characteristics of 57 Subjects with Baseline Comparisons

Age (years) Range Age of onset (years) Range Gender (F/M) DBH units

Delusional (n 5 15)

Nondelusional (n 5 20)

Controls (n 5 22)

75.7 6 7.0 62–92 67.5 6 16.2 35–92 10/5 34.3 6 19.1

75.3 6 6.9 62–90 58.0 6 19.09 27– 81 14/6 55.2 6 36.7

72.3 6 7.3 63– 88 — — 10/12 58.0 6 24.4

ANCOVA revealed a significant group effect (F 5 3.49, df 5 2,54, p 5 .04). Pair-wise t tests showed that delusional depressives had lower activity than both controls (t 5 2.50, df 5 35, p 5 .02) and nondelusional depressives (t 5 2.16, df 5 33, p 5 .04), with controls and nondelusional patients having highly comparable activity (t 5 0.32, df 5 43, p .75).

tions. ANOVA revealed a significant group effect (F 5 3.49, df 5 2,54, p 5 .04). Pair-wise t tests showed that delusional depressives had lower activity than both controls (t 5 2.50, df 5 35, p 5 .02) and nondelusional depressives (t 5 2.16, df 5 33 p 5 .04). DBH activity in controls and nondelusional patients were highly comparable (t 5 .32, df 5 43, p 5 .75). Although delusional depressives had a somewhat later age of onset, this difference was not statistically significant. Neither age (r 5 .10, p 5 .45) nor age of onset (r 5 .19, p 5 .40) were significantly correlated with baseline DBH activity.

Posttreatment DBH Activity Twenty-seven patient-subjects had assessments after a minimum of 3 weeks of hospital treatment. None of the initially delusional depressives had psychotic symptoms at the posttreatment assessment. Baseline values were not available in 6 subjects with postdischarge assays. Distribution of DBH activity between the 14 delusional depressives and 13 nondelusional depressives with posttreatment assays and controls differed significantly (F 5 3.32, df 5 2,46, p 5 .05). Pair-wise t tests revealed lower DBH activity in subjects who had been delusional initially than either the nondelusional depressives (t 5 2.40, df 5 25, p 5 .02) or controls (t 5 2.09, df 5 34, p 5 .04) Nondelusional subjects and controls had comparable activity (t 5 0.60, df 5 33, p 5 .55). Twelve of the 14 (85.7%) delusional subjects and 8 of 13 (61.5%) without delusions had received ECT. None of the patients treated with ECT had received concurrent antidepressants or neuroleptics. All of the delusional subjects treated with medication had received combination pharmacotherapy, and nondelusional patients had received ongoing antidepressants only. Antidepressant therapies included nortriptyline, serotonin reuptake inhibitors, and combinations of the two classes. Controlling for pharmacotherapy versus ECT did not affect the between-group differences in posttreatment DBH activity.

Table 2 describes HDRS scores and DBH activity in the subsample of 21 subjects who had both baseline and posttreatment DBH assays. Although within individuals pre- and posttreatment DBH values were highly correlated (r 5 .78, p 5 .0001), DBH activity increased significantly after treatment (mean increase 5 10.01 6 19.39, t 5 2.37, df 5 20, p 5 .03). Changes in DBH activity in delusional and nondelusional subjects were highly comparable. Nine of the 10 delusional subjects and 8 of the 11 without delusions who had repeated assays received ECT. Although ANOVA failed to reveal an effect for type of treatment on DBH change, there was a trend (t 5 2.05, df 5 15, p 5 .058) for an association between ECT and increases in DBH. Treatment was associated with highly significant decreases in HDRS scores in the patient sample (F 5 42.01, df 5 1,19, p 5 .0001), with no interaction by clinical subgroup. Decreases in HDRS scores were not correlated with change in DBH activity (r 5 .04, n 5 21, p 5 .87). Pretreatment DBH was not related to change in HDRS scores (F 5 0.88, df 5 2,19, p 5 .43).

Discussion Serum DBH activity in patients with late-life delusional depression was significantly lower than that of similarly aged patients with nondelusional major depression at hospital admission and after a course of somatic treatment. Activity in controls was comparable to that in nondelusional depressives and higher than in delusional subjects. The high intraindividual correlation of pre- and posttreatment assays (r 5 .78, p 5 .0001) and the persistence of lower DBH in psychotically depressed subjects are consistent with a genetic contribution to DBH activity and high intraindividual stability described previously (Weinshilboum 1979); however, the significant increase in DBH activity occurring during hospitalization indicates that somatic treatment of an acute depressive episode can influence enzyme activity. Table 2. HDRS Scores and DBH Assays in 21 Subjects with Baseline and Predischarge Assessments

Age (years) Baseline HDRS Predischarge HDRS Baseline DBH units Predischarge DBH units

Delusional (n 5 10)

Nondelusional (n 5 11)

76.6 6 8.8 30.3 6 6.9 12.0 6 10.9 35.6 6 19.3 46.4 6 23.0

76.0 6 5.6 28.6 6 8.0 12.8 6 7.6 54.7 6 35.7 64.0 6 30.3

ANOVA for change in HDRS score with treatment: F 5 42.01, df 5 1,19, p 5 .0001, with no significant interaction by clinical group (F 5 0.22, df 5 1,19, p 5 .64). ANOVA for change in DBH with treatment: F 5 5.35, df 5 1,19, p , .032, with no interaction by group (F 5 0.029, df 5 1,19, p 5 .867).

Decreased DBH in Delusional Depression

Because our subjects had variable exposure to pharmacotherapy prior to admission and the inherent unreliability of this information, preadmission treatment data were not considered in baseline analyses. Reports that recent neuroleptic exposure can decrease DBH activity (Markainos et al 1976; Goodnick et al 1983) would be consistent with differences in preadmission treatment received by psychotic compared to nonpsychotic depressives contributing to baseline differences; however, the majority of both delusional and nondelusional subjects received ECT, and controlling for type of hospital treatment did not affect the finding of significantly lower predischarge DBH activity in delusional depressives. Demonstration of an association between treatment and an increase in DBH activity in subjects with repeated assays adds to an emerging literature on this issue. Diminished DBH activity has been reported previously in drug-naive outpatients with psychotic major depression (Sapru et al 1989). The tendency for DBH to increase in ECT- but not medication-treated subjects, with no interaction by diagnostic group, should be considered cautiously in light of the small sample size. We cannot explain the mechanism of a potential ECT effect and cannot assess whether the trend would persist if the interval between ECT and reassessment was longer. All of our pharmacotherapy-treated subjects received antidepressants, and the delusional subgroup received neuroleptics as well. Neuroleptic treatment in the delusional subject 2 treated with pharmacotherapy only and in none of the medication-treated nondelusional subjects could have somewhat decreased the magnitude of significant between-group differences identified. Previous studies have reported conflicting findings on the effects of antidepressants on DBH activity (DamaseMichel et al 1991; Mathew et al 1981). The reported association between lithium discontinuation and decreases in DBH in remitted bipolar patients (Sofuoglu et al 1995) is consistent with the possibility that specific therapies increase DBH in patient subgroups. We are unable to assess the contribution of antidepressants to changes in DBH because of the diversity of antidepressants used in our nondelusional subjects. Our findings are consistent with the previous conceptualization of unipolar psychotic depression as a biologically distinct form of depression (Schatzberg and Rothschild 1992). It is of interest to speculate that psychotic depressives have genetically determined low DBH activity, which contributes to both increased central dopamine and diminished noradrenergic functioning, in determining the phenomenology of psychotic major depression. Despite the small number of subjects studied and the absence of a mechanism for validating the classification of

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patients as delusional, the careful assessment of a systematically diagnosed sample of elderly subjects with unipolar depression presumably contributed to our ability to identify diminished DBH activity in patients with delusional depression. Additional studies are needed to replicate these findings and to determine their clinical relevance, including whether low DBH activity is associated with specific biological and clinical sensitivities to affective distress.

This work was supported by NIMH grants MH43856 and MH51954.

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