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 potential 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, PϽ.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- structures.F1 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

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©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 Ͼ64 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, ␤-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, PϽ.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, PϽ.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- PϽ.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 PϽ.04) but not with IP scores (partial r = 0.11, PϽ.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) of the variance (F3 = 20.1, Moreover, long P300 latency is found in subcortical dis- PϽ.001) in Cornell Scale percent change over 6 weeks. orders.25 The model was significant even when only nortriptyline- 2 treated subjects were included (R = 0.57, F3 = 16.2, RESULTS PϽ.001). Percent change in Cornell Scale score from baseline was correlated with abnormal IP scores (partial Seventy-one subjects were studied. Forty-nine were pa- r = 0.40, PϽ.001, adjusted for DRS − IP), psychomotor tients with major depression (33 inpatients and 16 out- retardation (partial r = 0.38, PϽ.01, adjusted for DRS − patients) and 22 were normal controls (Table). There IP), and long P300 latency (partial r = 0.74, PϽ.001, ad- was no significant difference in age or sex between de- justed for DRS − IP), but not P300 amplitude (partial pressed patients and controls (Table). Depressed pa- r = 0.11, PϽ.50). The relationships of IP and P300 la- tients had fewer years of education, greater medical bur- tency to Cornell Scale percent change were significant

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 The P300 evoked response was recorded using a Nico- tricyclic antidepressants or history of tricyclic resistance. (2) let CA-2000 system (Nicolet Instruments Corp, Madison, Nontricyclic agents (bupropion, 150-400 mg; fluoxetine, Wis) after breakfast. The signals were 1-kHz standard and 20-30 mg; paroxetine, 20-30 mg; phenelzine, 30-45 mg; ser- 2-kHz target tones (ratio, 4:1) delivered binaurally every traline, 50-100 mg; tranylcypromine, 30 mg; trazodone, 200- 1.1 seconds at 70 decibels sound pressure level above hear- 325 mg; or venlafaxine, 150 mg) were used in patients who ing level. The subjects were instructed to press a switch held did not qualify for nortriptyline treatment. During each week, in the right hand when a target tone was detected. All sub- the intensity of treatment was scored according to the Lon- jects identified at least 85% of the target tones. Electrodes gitudinal Interval Follow-up Evaluation treatment inten- on the outer canthi of both eyes and above and below the sity scale modified for geriatric patients.36 right eye were used to control for eye-movement artifacts. At the end of 6 weeks of treatment, the Cornell Scale31 The electroencephalogram was recorded from frontal (Fz), was readministered. Remission was defined as a reduction central (Cz), and parietal (Pz) scalp electrode sites, refer- of Cornell Scale score to below 7, because this score best dis- enced to linked-mastoids, and bandpass-filtered at 0.5 to tinguishes depressed from nondepressed elderly patients.31 30 Hz. Between 50 and 60 artifact-free trials for the target tone were obtained. An average response was constructed STATISTICAL ANALYSIS for the standard and the target tones and the P300 wave was identified in the target response as a positive-(P2)- Partial correlation was employed to examine the relation- negative-(N2)-positive-(P3) complex at the range of 280 ship of IP, psychomotor retardation, P300 latency, and Cor- to 650 milliseconds, and maximal at the parietal site.35 La- nell Scale score percent change from baseline in de- tency was measured at Pz at the intersection of extrapo- pressed patients, after adjusting for total DRS score minus lating lines from the ascending and descending portions IP score (DRS − IP) and education. Linear regression analy- of the P300 wave. If 2 P300 peaks were seen within the main sis examined the variance in Cornell Scale score percent peak, the whole peak was scored as a single peak. If the change from baseline and its association to a model con- peaks were distinct, the second peak was used to deter- sisting of IP, psychomotor retardation, and P300 latency mine latency.35 Peak amplitude was measured as the high- in depressed patients. The Tukey post hoc test was used est point of the P300 peak at the Pz electrode site and re- to investigate differences in distribution of IP scores, psy- ferred to the prestimulus baseline. The P300 recordings were chomotor retardation, and P300 latency among unremit- performed by a trained technician blind to the hypotheses ted patients, remitted patients, and controls. The sensitiv- and the results of psychometric testing. ity and specificity of IP, psychomotor retardation, and P300 latency in identifying remission was studied using linear TREATMENT COURSE discriminant function analysis with jackknife classifica- tion. Logistic regression examined the ability of the 3 mea- Depressed subjects were treated according to the follow- sures in predicting remission in patients following treat- ing guidelines. (1) Nortriptyline (plasma levels Ͼ50 ng/ ment. Significance was 2 tailed. The ␣ level of significance mL) was used in patients without a contraindication to in all instances was below .05.

(IP partial r = 0.37, PϽ.02; P300 latency partial r = −0.71, Unremitted depressed patients had more abnormal PϽ.001) even after controlling for psychomotor retar- IP scores and longer P300 latency than remitted depressed dation. patients and controls, while remitted patients and controls Of the 49 patients, 42 were nondemented (score Ͼ23 had comparable values (Table, Figure 1, Figure 2, and on the MMSE). In nondemented patients, IP, psycho- Figure 3). Unremitted patients had comparable P300 am- motor retardation, and P300 latency were significantly plitude to remitted patients and controls and greater psy- associated with percent change in Cornell Scale scores chomotor retardation than remitted patients (Table). The 2 (R = 0.50; F3 = 12.2, PϽ.001). This approached signifi- differences in IP, psychomotor retardation, and P300 la- cance in the 7 depressed-demented patients (R2 = 0.75; tency between remitted and unremitted patients could not F3 = 3.1, PϽ.19). be attributed to demographic and clinical differences, be- At 6 weeks, 24 patients achieved remission; 17 of cause variables that may have influenced remission were 30 patients treated with nortriptyline and 7 of 19 pa- similarly distributed in the 2 groups (Table). Moreover, tients treated with other antidepressants (F1 =2.0,PϽ.16). treatment intensity assessed with the modified treatment Nortriptyline plasma levels were similar in remitted intensity scale,36 was similar in remitted and unremitted (mean, 111.1 ng/mL; SD, 50.4 ng/mL) and unremitted patients during each of the 6 weeks of treatment (week patients (mean, 99.6 ng/mL; SD, 36.2 ng/mL; t28 = 0.66, 1: t47 = 1.4, PϽ.17; week 2: t47 = 0.49, PϽ.63; week 3: PϽ.51). In patients treated with other antidepressants, t47 = 0.87, PϽ.38; week 4: t47 = 0.90, PϽ.38; week 5: t47 = 0.59, remitted patients had treatment equivalent to unremit- PϽ.55; week 6: t47 = 0.10, PϽ.92). ted patients. Remitted patients received trazodone (200 Discriminant function analysis showed that 23 of the mg, n = 1), venlafaxine (150 mg, n = 1), fluoxetine (20 24 remitted depressed patients were correctly identified mg, n = 2), bupropion (150 mg, n = 1; 300 mg, n = 1), and based on pretreatment scores on IP, P300 latency, and sertraline (50 mg, n = 1). Unremitted patients received psychomotor retardation (cross-validation method: sen- trazodone (325 mg, n = 1), venlafaxine (150 mg, n = 2), sitivity, 95.8%; specificity, 65.9%). Logistic regression phenelzine (45 mg, n = 1), tranylcypromine (30 mg, n = 1), showed that P300 latency was associated with remis- 2 paroxetine (20 mg, n = 1), bupropion (200 mg to 400 mg, sion (␤ = −0.07, SE = 0.02, Wald ␹ 1 = 8.9, PϽ.003). In- n = 4), and sertraline (75 mg, n = 1; 100 mg, n = 1). crements in P300 latency value of 9.7 milliseconds pre-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Demographic and Clinical Characteristics of Elderly Patients With Major Depression and Control Subjects*

Patients With Major Depression (n = 49)

All Depressed Remitted Unremitted Control Patients Patients Patients Subjects (n = 49) (n = 24) (n = 25) (n = 22) Comparisons†

Age, y 74.8 (5.6) 74.0 (5.7) 75.3 (5.6) 71.8 (4.7) (1) t69 = 1.9, PϽ.06; (2) t47 = 0.91, PϽ.36 2 2 Sex, M/F 1/2.7 1/3.3 1/2.4 1/1.5 (1) ␹ 1 = 0.06, PϽ.82; (2) ␹ 1 = 1.5, PϽ.21 Race, No. of subjects White 46 23 23 20 . . . African American 1 1 0 1 . . . Hispanic 2 0 2 0 . . . Other 0 0 0 1 . . .

Education, y 12.6 (2.4) 12.9 (2.2) 12.3 (2.5) 14.1 (2.5) (1) t69 = 2.4, PϽ.02; (2) t47 = 0.97, PϽ.33

Age at depression onset, y 55.7 (21.2) 51.6 (24.1) 60.3 (19.3) . . . (2) t47 = 1.8, PϽ.09

Duration of depressive episode, wk 43.3 (33.8) 37.9 (34.5) 48.6 (33.7) . . . (2) t47 = 1.1, PϽ.29

No. of prior episodes 3.8 (3.5) 3.7 (3.5) 3.8 (3.6) . . . (2) t47 = 0.1, PϽ.93

Hamilton Depression Rating 22.5 (5.4) 22.1 (4.7) 22.8 (5.9) 1.4 (1.9) (2) t47 = 0.45, PϽ.65 Scale27 score at enrollment

Psychomotor retardation 0.7 (1.0) 0.3 (0.6) 1.0 (1.1) 0.0 (0.2) (2) F46 = 7.1, PϽ.02 (Mattis Dementia Rating Scale33 score minus initiation/perseveration score as covariate) 31 Cornell Scale for Depression in Dementia 18.6 (5.4) 18.1 (5.4) 18.7 (5.5) 0.9 (1.5) (2) t47 = 0.62, PϽ.54 score at enrollment Cornell Scale score at 6 wk 11.1 (7.4) 4.7 (1.5) 16.9 (5.5) 1.0 (1.5) . . . 33 Mattis Dementia Rating Scale score 131.1 (12.2) 135.5 (9.9) 125.1 (14.2) 140.9 (2.5) (1) F1,66 = 9.3, PϽ.02 (education as covariate) Attention 35.5 (1.6) 35.9 (1.6) 35.3 (1.6) 36.4 (0.6) . . . Initiation/perseveration 33.3 (4.8) 35.4 (3.4) 30.7 (5.6) 36.6 (0.7) ...‡ Construction 5.7 (0.8) 5.9 (0.6) 5.4 (1.1) 6.0 (0.0) . . . Conceptualization 35.4 (4.0) 36.8 (2.2) 33.7 (4.8) 37.3 (2.4) . . . Memory 21.3 (4.3) 21.9 (4.8) 20.3 (4.1) 24.4 (0.9) . . . 32 Newcastle index 5.8 (1.8) 5.4 (1.8) 6.1 (1.8) . . . (2) t47 = 1.6, PϽ.12 34 Cumulative Illness Rating Scale score 4.9 (3.1) 4.6 (2.4) 5.4 (3.8) 3.3 (2.9) (1) t69 = 2.4, PϽ.02; (2) t47 = 0.97, PϽ.33 P300 latency, ms 383.1 (44.9) 351.7 (25.3) 410.4 (40.5) 341.6 (28.1) ...§ P300 amplitude, µV 4.0 (2.4) 4.1 (2.3) 3.9 (2.5) 4.6 (1.7) . . . ࿣

*Data are presented as mean (SD) unless otherwise indicated. Ellipses indicate not applicable; M, male; and F, female. †1, Depressives vs controls; 2, remitted vs unremitted patients. ‡Unremitted patients vs remitted patients and control subjects; df = 66, PϽ.01, Tukey posthoc test. §Unremitted patients vs remitted patients and control subjects; df = 66, PϽ.001, Tukey posthoc test. ࿣Unremitted patients vs remitted patients and control subjects; df = 66, PϽ.93, Tukey posthoc test.

dicted a 2-fold increase in the likelihood of nonremission (adjusted odds ratio = 0.93; 95% CI, 0.88-0.97). 40

COMMENT 35 The principal finding of this study is that abnormal IP scores, psychomotor retardation, and long P300 latency are associated with poor or delayed response to antide-

IP Score 30

pressant treatment. Each of these measures has been –

associated with prefrontal dysfunction.18-23 DRS To our knowledge, this is the first study to demon-

strate a relationship between clinical and electrophysi- 25 ological indices of prefrontal dysfunction and response of geriatric depression to antidepressant treatment. Our findings are consistent with studies in younger adults suggesting that poor response to antidepressants in 20 depressed patients is associated with hypometabolism Unremitted Patients Remitted Patients Controls 37 of the rostral anterior cingulate pathway, long P300 Figure 1. Total Mattis Dementia Rating Scale score minus latency,15 and white matter hyperintensities.13,14 Simi- initiation/perseveration subscale scores in patients and controls.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 larfindings have been reported in geriatric patients; sub- 600.0 cortical white matter hyperintensities and decreased psychomotor speed were associated with poor treatment response.14 The volume of white matter hyperintensities is correlated with executive dysfunction.2 512.5 These findings suggest that prefrontal dysfunction is an essential part of the pathophysiology of depression and its response to treatment. Others have reported that 425.0 low P300 amplitude predicts poor antidepressant response.38 Our failure to replicate this finding may be P300 Latency, ms P300 Latency, explained by differences in the sample and the P300 task characteristics. 337.5 Prefrontal dysfunction may result from various causes, including cerebrovascular39 and degenerative disorders.40 Stroke of the caudate head and the left frontal 250.0 pole are the most likely ischemic lesions to cause de- Unremitted Patients Remitted Patients Controls pression.41,42 Approximately 75% of patients with major depression and silent cerebral infarction have lesions Figure 2. P300 latency in patients and controls. within the perforating arteries,43 which supply the basal ganglia. Patients with late-onset depression and vascu- Unremitted Patients Remitted Patients Controls lar risk factors have neuropsychological abnormalities sug- 44 gesting a prefrontal dysfunction. Finally, in patients with 7 Alzheimer disease or frontotemporal dementias, depres- 6 P2 sion is most likely to occur in those with subcortical at- 5 45 P300 rophy. These observations suggest that damage of fron- 4 tostriatal circuits contributes to the development of 3 depression.

V 2 In this study, the associations among psychomotor µ 1 retardation, abnormal IP scores, and P300 latency were 0 significant but rather weak. An explanation may be that these measures are not highly specific to prefrontal dys- Amplitude, –1 function. However, psychomotor retardation, abnormal –2 IP scores, and long P300 latency jointly predicted 58% –3 N2 of the variance in treatment response. Therefore, de- –4 –5 spite the lack of a high level of specificity, these 3 mea- N1 –6 sures may have identified distinct aspects of prefrontal 0 200 400 600 dysfunction that collectively are associated with poor treat- P300 Latency, ms ment response. Neuropsychological, electrophysiological, and functional imaging techniques focusing on Figure 3. Average waveforms for target stimuli showing long latency for P300 wave in unremitted patients compared with remitted patients and specific prefrontal circuits may further clarify the patho- controls. physiology of antidepressant response. Abnormal IP scores and P300 latency do not seem to be influenced by the depressive state. In 137 elderly tients. Although the intensity of treatment was compa- patients with major depression studied by our institu- rable in remitted and unremitted patients, differences in tion, IP scores during depression were similar to IP scores the type of treatment may have confounded our find- obtained after recovery (paired t136 = 0.23, PϽ.82). Simi- ings. For this reason, a controlled treatment study is larly, baseline P300 latency correlated strongly with P300 needed. latency at recovery (r = 0.99, df = 37, PϽ.001). The sta- On a heuristic level, this study provides the back- bility of IP and P300 latency suggests that examining these ground for pharmacological interventions aimed at neu- measures when the subjects were depressed may not have rotransmitter systems that mediate prefrontal circuitry, compromised the value of our findings. Abnormal IP including dopamine, acetylcholine, and opiates. Such scores and P300 latency in depressed patients seem to drugs may be studied alone or as augmenting agents in be signs of permanent brain change associated with a treat- depressed elderly patients with evidence of prefrontal dys- ment-resistant depression. function. This study cannot ascertain whether patients with On a clinical level, if confirmed, our findings would prefrontal dysfunction had poor as opposed to slow an- aid clinicians in identifying elderly depressed patients who tidepressant response. The duration of study was shorter may be resistant or slow responders to antidepressants than the time required by some elderly patients to achieve and, thus, would be useful in treatment planning. De- remission.36,46 Longer follow-up will be required for this pressed patients with prefrontal dysfunction may re- purpose. quire aggressive pharmacotherapy or electroconvulsive The naturalistic treatment design of this study per- therapy. Studies may also examine if there is a clinical mitted recruitment of a wide range of depressed pa- advantage to stimulating the prefrontal over other brain

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 regions in these patients during treatment with electro- 17. Cummings JL, Benson DF. Subcortical dementia, review of an emerging con- cept. Arch Neurol. 1984;41:874-879. convulsive therapy or with transcranial magnetic stimu- 18. Firth CD, Friston KJ, Liddle PF, Frackowiak RSJ. A PET study of word finding. lation. Moreover, interventions specifically targeting ex- Neuropsychologia. 1991;29:1137-1148. ecutive deficits, including daily structure and support, 19. Jueptner M, Stephan KM, Frith CD, Brooks DJ, Frackowiak RSJ, Passingham RE. Anatomy of motor learning, I: frontal cortex and attention to action. J Neuro- may be used to remediate disability resulting from pre- physiol. 1997;77:1313-1324. frontal dysfunction. Such interventions may interrupt the 20. Van Mier H, Tempel LW, Perlmutter JS, Raichle ME, Petersen SE. 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