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Prefrontal Dysfunction and Treatment Response in Geriatric Depression

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Prefrontal Dysfunction and Treatment Response in Geriatric Depression ORIGINAL ARTICLE Prefrontal Dysfunction and Treatment Response in Geriatric Depression Balu Kalayam, MD; George S. Alexopoulos, MD Background: This study investigated the relationship tients who remained symptomatic (n = 25) had more ab- of clinical, neuropsychological, and electrophysiologi- normal initiation/perseveration scores and longer P300 cal measures of prefrontal dysfunction with treatment re- latency compared with depressed patients who achieved sponse in elderly patients with major depression. remission (n = 24) and control subjects. There were no differences between the last 2 groups. The association Methods: Forty-nine depressed elderly subjects were between psychomotor retardation, initiation/per- studied before and after 6 weeks of adequate antidepres- severation scores, P300 latency, and response to antide- sant treatment and compared with 22 psychiatrically nor- pressant treatment could not be explained by differ- mal controls. The psychomotor retardation item of the ences in demographic and clinical characteristics or Hamilton Depression Rating Scale, the initiation/ treatment intensity between remitted and nonremitted perseveration subscore of the Mattis Dementia Rating depressed patients. Scale, and the latency of the P300 auditory evoked po- tential were used as indices of prefrontal dysfunction. The Conclusions: Prefrontal dysfunction was associated with intensity of antidepressant drug treatment was classi- poor or delayed antidepressant response in depressed el- fied and monitored for a 6-week period. derly patients. This observation, if confirmed, may aid clinicians in identifying candidates for aggressive so- Results: Abnormal initiation/perseveration score, psy- matic therapies and for interventions offering structure chomotor retardation, and long P300 latency predicted of daily activities. 58% of the variance in change of depression scores from baseline to 6 weeks (F3 = 20.1, P,.001). Depressed pa- Arch Gen Psychiatry. 1999;56:713-718 RONTOSTRIATAL dysfunc- sion remains unclear. White matter ab- tion occurs in some pa- normalities were found to be associated tients with major depres- with executive dysfunction,2 and predict sion. Depression is frequent chronicity of geriatric depression,13,14 in disorders of subcortical perhaps by disruption of cortico-striato- Fstructures.1 Disturbances in planning, se- pallido-thalamo-cortical pathways quencing, organizing, and abstracting have (CSPTC). Preliminary findings in de- been reported in late-onset depression2 and pressed adults suggest that long P300 la- are similar to those occurring in Hunting- tency is associated with poor response to ton disease.3 Memory impairment resem- antidepressants at the end of 5 weeks.15 bling subcortical dementia often occurs in Based on these observations, this geriatric depression.4 study tested the hypothesis that clinical Most functional neuroimaging stud- and laboratory evidence of prefrontal dys- ies of major depression observed hypoac- function is associated with poor re- tivity in frontal regions,5-7 including the dor- sponse to antidepressant treatment. Ini- solateral, inferior and medial/anterior tiation/perseveration (IP) scores and cingulate, and the caudate nucleus,8,9 but psychomotor retardation were used as disagreement exists.10 The prefrontal ar- clinical measures of prefrontal dysfunc- eas, basal ganglia, and some limbic regions tion, because such abnormalities have been appear to be abnormally activated during de- observed in patients with frontal lobe le- pression.11 Following a word activation task, sions16 and disorders of subcortical struc- depressed elderly patients showed greater tures.17 Although deficits in IP and psy- activation of the left medial prefrontal cor- chomotor retardation are not specific to tex and less activation of the left putamen prefrontal dysfunction, functional imag- 12 From the Weill Medical College than elderly normal controls. ing studies showed that several functions of Cornell University, The relationship of prefrontal dys- tested by the IP tasks require CSPTC in- White Plains, NY. function to the course of geriatric depres- tegrity. Performance of a verbal fluency ARCH GEN PSYCHIATRY/ VOL 56, AUG 1999 713 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 SUBJECTS AND METHODS or 50 mg of sertraline. These criteria resulted in a sample of nonpsychotic depressed elderly patients with a wide range SUBJECTS of cognitive impairment and medical morbidity but not a drug- resistant current episode. The subjects were consecutively recruited elderly (age .64 years) psychiatric inpatients or outpatients. The controls MEASURES were elderly community residents recruited through ad- vertisements. Patients were included if they met Research The Schedule for Affective Disorders and Schizophrenia– Diagnostic Criteria26 for unipolar major depressive disor- Lifetime Version28 was administered within 7 days from der without psychotic features, a score greater than 16 on study enrollment. Depression ratings, cognitive assess- the 21-item Hamilton Depression Rating Scale,27 and no his- ments, and P300 assessments were performed after a 3-day tory of other major psychiatric disorders or substance abuse psychotropic drug washout; lorazepam was used as needed before the onset of depression. The control subjects had in 6 of 49 patient subjects. Depressive symptoms were as- no personal or family history of psychiatric illness or sub- sessed using the Hamilton Depression Rating Scale27 and stance abuse ascertained by the Schedule for Affective Dis- the Cornell Scale for Depression in Dementia,31 a scale vali- orders and Schizophrenia–Lifetime Version28 and the fam- dated in elderly patients with a wide range of cognitive im- ily history Research Diagnostic Criteria.29 All subjects and pairments. The Newcastle index32 was used to assess en- informants signed informed consent. dogenous features of depression. Subjects were excluded if they had (1) severe or acute Cognitive impairment was rated with the MMSE and medical illness, eg, metastatic cancer; brain tumors; decom- the Mattis Dementia Rating Scale (DRS).33 DSM-IV crite- pensated cardiac, hepatic, or renal failure; or myocardial in- ria and an MMSE score of less than 24 identified depressed- farction or stroke within the 3 months preceding the study; demented patients. The DRS yields a score for overall im- (2) neurological disorders, eg, delirium, Parkinson disease, pairment as well as a subscore of impairment in IP, or multiple sclerosis; (3) medical disorders and/or drug ex- conceptualization, construction, memory, and attention. posure that may cause depression, eg, endocrinopathies other The IP domain consists of word generation, manual se- than diabetes, lymphoma, or pancreatic cancer or exposure quencing, and graphomotor copying tasks. to steroids, b-blockers, methyldopa, clonidine, reserpine, ta- Chronic medical burden was assessed with the Cu- moxifen, or cimetidine; (4) Mini-Mental State Examination mulative Illness Rating Scale, modified for geriatrics.34 This (MMSE)30 score less than 16 at study enrollment; (5) ab- scale rates chronic medical burden from 14 organ do- sence of a reliable informant; or (6) hearing deficits of greater mains. A total score was computed by adding all domains than 55 decibels averaged over frequencies of 1, 2, and 4 kHz. except the psychiatric domain. Depressed patients were excluded if the current episode had All measures were administered by a research assistant failed to respond to an “adequate” antidepressant trial prior trained by the Clinical Research Center for Geriatric Mood to entry; ie, 6 weeks at dosages equal to or greater than 50 Disorders, White Plains, NY. The raters were blind to the hy- mg of nortriptyline, 20 mg of fluoxetine, 20 mg of paroxetine, potheses and the results of electrophysiological testing. task was shown to result in increased left dorsolateral pre- den, and greater cognitive impairment compared with frontal activity.18 Learning a new motor sequence re- controls (Table). For this reason, these 3 variables were sulted in activation of the left dorsolateral prefrontal cor- used as covariates where appropriate. tex and the anterior cingulate,19 and graphomotor copying In depressed subjects, abnormal IP scores and long was associated with activation of the premotor and the P300 latency were correlated (partial r = 0.56, P,.001, ad- inferior frontal cortex.20 The P300 evoked response was justed for education). The Hamilton Depression Rating used as an electrophysiological index of prefrontal dys- Scale psychomotor retardation item was associated with function. The P300 electrical wave is generated during both abnormal IP score (partial r = 0.47, P,.001, ad- tasks of sustained attention, in response to an unantici- justed for DRS − IP) and long P300 latency (partial r = 0.40, pated auditory stimulus, and requires integrity of the pre- P,.005, adjusted for DRS − IP). The P300 amplitude was frontal system and its limbic and temporal connec- correlated with psychomotor retardation (partial r = 0.34, tions.21,22 Functional imaging studies showed activation P,.04) but not with IP scores (partial r = 0.11, P,.94). of the prefrontal cortex, basal ganglia, and temporopa- Linear regression showed that a model consisting rietal regions during the P300 task.23 Long latency for the of IP, psychomotor retardation, and P300 latency pre- 24 2 P300 wave was associated with executive impairment. dicted a large part (R = 0.58)
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