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other healthy behaviors and demonstrate an adaptive style

of coping with the disorder (5). If our findings are replicated, this notion may be equally applicable to psychiatry.
Received Feb. 14, 2002; revision received May 15, 2002; accepted
May 23, 2002. From the Division of Psychological Medicine, Institute
of Psychiatry; and the Department of Psychiatry, Royal Victoria Infirmary, Newcastle upon Tyne, U.K. Address reprint requests to Professor Scott, Psychological Treatments Research, Division of Psychological Medicine, P.O. Box 96, Institute of Psychiatry, DeCrespigny Park,
London SE5 8AF, U.K.; (e-mail).
Supported in part by the Theodore & Vada Stanley Foundation.

1. Baldessarini R, Tondo L: Does lithium treatment still work?
Arch Gen Psychiatry 2000; 47:187190
2. Schou M: The combat of non-compliance during prophylactic
lithium treatment. Acta Psychiatr Scand 1997; 95:361363
3. Guscott R, Taylor L: Lithium prophylaxis in recurrent affective
illness: efficacy, effectiveness and efficiency. Br J Psychiatry
1994; 164:741746

4. Gelenberg A, Kane J, Keller M, Lavori P, Rosenbaum J, Cole K,

Lavelle J: Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J
Med 1989; 321:14891493
5. Irvine J, Baker B, Smith J, Jandciu S, Paquette M, Cairns J, Connolly S, Roberts R, Gent M, Dorian P: Poor adherence to placebo or amiodarone therapy predicts mortality: results from
the CAMAIT study. Psychosom Med 1999; 61:566575
6. Adams J, Scott J: Predicting medication non-adherence in severe mental disorders. Acta Psychiatr Scand 2000; 101:119
7. Peet M, Harvey N: Lithium maintenance, 1: a standard education programme for patients. Br J Psychiatry 1991; 158:197
8. Stephenson BJ, Rowe BH, Haynes RB, Macharia WM, Leon G: Is
this patient taking the treatment as prescribed? JAMA 1993;
9. Colom F, Vieta E, Martinez-Aran A, Rienares M, Benabarre A,
Gasto C: Clinical factors associated with treatment non-compliance in euthymic bipolar patients. J Clin Psychiatry 2000; 61:
10. Johnson RE, McFarland BH: Lithium use and discontinuation in
a health maintenance organization. Am J Psychiatry 1996;

Brief Report

Frontal White Matter Microstructure and Treatment Response

of Late-Life Depression: A Preliminary Study
George S. Alexopoulos, M.D.
Dimitris N. Kiosses, Ph.D.
Steven J. Choi, Ph.D.
Christopher F. Murphy, Ph.D.
Kelvin O. Lim, M.D.
Objective: This study tested the hypothesis that microstructural abnormalities in white matter areas of the brain containing frontostriatal tracts are associated with a low rate of remission of geriatric depression.
Method: Thirteen older patients with major depression received open, but controlled, treatment with citalopram at a tar-

get daily dose of 40 mg for 12 weeks. Diffusion tensor imaging

was used to determine fractional anisotropy in preselected
white matter regions.
Results: Survival analysis with Coxs proportional hazards
model revealed that lower fractional anisotropy of the right and
the left frontal white matter regions 15 mm above the anterior
commissureposterior commissure plane was associated with a
low remission rate after age was considered. Remission was not
significantly associated with fractional anisotropy of lower frontal regions or a temporal region.
Conclusions: Microstructural white matter abnormalities lateral to the anterior cingulate may be associated with a low rate
of remission of geriatric depression.
(Am J Psychiatry 2002; 159:19291932)

rontostriatal dysfunction may contribute to depression (13) and influence its course. Executive impairment,
an expression of frontostriatal dysfunction, was reported
to predict a poor (4) and unstable (5) antidepressant response of geriatric major depression. White matter hyperintensities, i.e., regions of greater signal intensity shown
by magnetic resonance imaging (MRI), are associated with

Am J Psychiatry 159:11, November 2002

executive dysfunction and with chronicity of geriatric depression (6). In younger patients, remission of depression
is associated with metabolic increases in dorsal cortical
regions (1) and decreases in ventral limbic and paralimbic
structures (7). Persistence of elevated amygdala metabolism during remission of depression may be a predictor of
relapse (1). Hypometabolism of the rostral anterior cingu-


FIGURE 1. Time to Remission for 13 Depressed Elderly Subjects in Relation to Fractional Anisotropy in a White Matter Axial
Region Located 15 mm Above the Anterior CommissurePosterior Commissure Planea

Proportion Remaining Depressed

Left Hemisphere

Right Hemisphere


High fractional anisotropy (N=6)

Low fractional anisotropy (N=7)













High and low values for fractional anisotropy were divided at the median value. Eight subjects achieved remission, and five remained

late is associated with treatment-resistant depression (7).

It has been proposed (1, 7) that disruption in dorsal cortical-ventral limbic regulation perpetuates depression.
On the basis of these findings, we hypothesized that microstructural white matter abnormalities lateral to the anterior cingulate, compromising limbic-cortical balance,
are associated with a low likelihood of remission of geriatric depression.

Subjects at the Cornell Intervention Research Center who
agreed to MRI and signed written consent statements were consecutively recruited for this study. They were aged 6077 years,
met the Research Diagnostic Criteria for unipolar major depression, and had a score of 18 or higher on the 24-item Hamilton Depression Rating Scale. Exclusion criteria were other axis I disorders, dementia, metastatic cancer, brain tumors, myocardial
infarction within the 3 months before the study, delirium, stroke,
Parkinsons disease, and multiple sclerosis.
The subjects were assessed with the Schedule for Affective Disorders and Schizophrenia and the 24-item Hamilton depression
scale. Overall cognitive impairment was determined by the total
score on the Mini-Mental State Examination (MMSE), and executive dysfunction was measured with the initiation/perseveration
domain of the Mattis Dementia Rating Scale (8) and the Stroop
Color-Word Response Inhibition Test (9). Medical burden was assessed with the Cumulative Illness Rating ScaleGeriatrics (10);
the psychiatric domain was not included.
Diffusion tensor imaging was performed at Nathan Kline Institute, Orangeburg, N.Y., by using a 1.5-T Siemens Vision MR and
an echo-planar double-spin echo sequence with TR=6000 msec,
TE=100 msec, 5-mm-thick slices, skip 0, alignment with the anterior commissureposterior commissure (AC-PC) plane, 24-cm
field of vision, 128128 matrix reconstructed to a 256256 b matrix for which b=1000 sec/mm2. The tensor was computed from
seven images: the b=0 sec/mm 2 image and six images with b=
1000 sec/mm2 with gradients applied in six noncollinear directions. Six maps of the apparent diffusion coefficient were computed. Then six independent elements of the diffusion tensor
were determined, the eigenvalues and eigenvectors were computed, and a scalar measure, fractional anisotropy, was assessed


(11). Fractional anisotropy yields values between 0 (i.e., isotropic

or unrestricted diffusion, as in CSF) and 1 (i.e., anisotropic or constrained diffusion due to barriers, as in organized white matter
Circular regions of interest of fixed sizes were positioned bilaterally in the frontal white matter of five consecutive images, from
15 mm above to 5 mm below the AC-PC plane. The size of the regions of interest at 15 mm, 10 mm, and 5 mm above the AC-PC
line was 84.4 mm2, and the size on and 5 mm below the AC-PC
line was 43.5 mm2. We hypothesized that low fractional anisotropy at regions of interest 15 and 10 mm above the AC-PC plane is
associated with a low remission rate. The lower frontal regions
and a temporal white matter region of interest adjacent to the
hippocampus were used to evaluate the specificity of the hypothesized relationships.
Survival analysis with Cox proportional hazards was used to examine the relationship of fractional anisotropy to remission. Students t test and chi-square were used to examine demographic
and clinical differences at baseline, and Spearmans rank-order
correlation was used to study the relationship of fractional anisotropy to executive function. Two-tailed alpha levels of significance
were used.

Of the 13 subjects (6077 years old), eight were treated
with 40 mg/day of citalopram (target), one with 30 mg,
and four with 20 mg. Five subjects remained depressed,
and eight achieved remission, defined as no longer meeting the DSM-IV criteria for a depressive disorder and having a score less than 10 on the Hamilton depression scale
for at least 2 weeks.
Survival analysis revealed that higher fractional anisotropy of the right frontal white matter 15 mm above the ACPC plane was associated with the occurrence of remission
(2=4.02, df=1, p<0.05) (Figure 1), even when the effect of
age on remission was taken into consideration (2=4.36,
df=1, p<0.04). A similar relationship was noted for fractional anisotropy of the left frontal white matter 15 mm
above the AC-PC plane, but it fell short of statistical significance (2=3.67, df=1, p=0.06) (Figure 1). The relationship
Am J Psychiatry 159:11, November 2002


of frontal fractional anisotropy 10 mm above the AC-PC

line approached significance (right: 2=2.97, df=1, p<0.08;
left: 2=1.77, df=1, p<0.18) after the effect of age was taken
into consideration (right: 2=3.20, df=1, p<0.07; left: 2=
4.42, df=1, p<0.04). Remission was not significantly associated with fractional anisotropy of frontal regions below
the 10-mm plane (5 mm, 0 mm, 5 mm) or the temporal
There were no significant differences between the patients with remitted (N=8) and nonremitted (N=5) depression in the dose of citalopram, baseline severity of depression (Hamilton depression scale total score), overall
cognitive impairment (MMSE total score), or education.
The subjects in remission had more normal scores on executive function tests than those without remission (initiation/perseveration: t=3.04, df=11, p<0.05; Stroop: t=2.42,
df=11, p<0.05). The scores on the Stroop test were associated with fractional anisotropy 15 mm above the AC-PC
plane in frontal regions on the right side (Spearmans rank
correlation: rs=0.65, df=10, p<0.03) but not the left (rs=0.31,
df=10, p<0.36) and were also significant at 10 mm above
the AC-PC plane on both the right (rs=0.78, df=10, p<0.005)
and left (rs=0.66, df=10, p<0.03). Correlations with the
Mattis Dementia Rating Scale domain of initiation/perseveration were not significant for fractional anisotropy 15
mm above the AC-PC plane on the right (rs=0.54, df=11,
p<0.06) or left (rs=0.44, df=11, p<0.15) or at 10 mm above
the AC-PC plane on the right (rs=0.42, df=11, p<0.18) or left
(rs=0.38, df=11, p<0.22).

The principal finding of this study is that lower fractional anisotropy at the frontal white matter located 15
mm, and perhaps 10 mm, above the AC-PC line is associated with a lower rate of remission of geriatric major depression after treatment with citalopram. No such relationship was identified in lower frontal regions or in a
temporal region. To our knowledge, this is the first study to
localize microstructural white matter abnormalities associated with lower likelihood of remission of depression.
White matter 15 mm and 10 mm above the AC-PC plane
is located laterally to the anterior cingulate at the level of
the middle frontal gyrus and contains fibers of the anterior cingulate and the dorsolateral pathways (12). Compromised white matter in these regions may interfere
with the reciprocal regulation of dorsal neocortical-ventral limbic structures and lead to a disconnection syndrome with poor antidepressant response. This view is
further supported by the association of lower fractional
anisotropy in these regions with executive dysfunction,
an abnormality noted to predict poor response of depression to treatment (3, 4).
The theoretical value of these findings is that they provide a step in understanding the neural systems needed
for antidepressant response. If these observations are
Am J Psychiatry 159:11, November 2002

confirmed, subsequent diffusion tensor imaging studies

can use fiber mapping to identify with greater precision
specific frontostriatal pathways interfering with treatment response.
The clinical value of this study is that it can guide the selection of cognitive tests for studies of prediction of treatment response. Tests of specific frontostriatal functions,
validated through neuroimaging, are available. If shown to
predict treatment response, such tests can be used in
treatment planning.
The principal limitation of this study is its small study
group. Despite this limitation, the localization of microstructural abnormalities can guide studies of specific
pathways associated with treatment response and generate pharmacological investigations of novel agents targeting depressed elderly patients with abnormalities in frontostriatal systems.
Received Aug. 6, 2001; revision received April 9, 2002; accepted
May 9, 2002. From the Department of Psychiatry, Weill Medical College, Cornell University; and the Nathan Kline Institute, Orangeburg,
N.Y. Address reprint requests to Dr. Alexopoulos, Department of Psychiatry, Weill Medical College of Cornell University, 21 Bloomingdale
Rd., White Plains, NY 10605; (e-mail).
Supported by NIMH grants MH-42819, MH-51842, MH-49762, and
MH-19132 to Dr. Alexopoulos; by NIMH grant MH-53313 to Dr. Lim;
and by support to Dr. Alexopoulos from Forest Pharmaceuticals, the
Sanchez Foundation, and the Dr. I Foundation.

1. Drevets WC: Neuroimaging studies of mood disorders. Biol Psychiatry 2000; 48:813819
2. MacFall JR, Payne ME, Provenzale JE, Krishnan KRR: Medial orbital frontal lesions in late-onset depression. Biol Psychiatry
2000; 49:803806
3. Kumar A: Neuroanatomy of late-life mood disorders. Economics of Neuroscience 2001; 3:4448
4. Kalayam B, Alexopoulos G: Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry
1999; 56:713718
5. Alexopoulos GS, Meyers BS, Young RC, Kalayam B, Hull J, Kakuma T: Executive dysfunction increases the risk for relapse
and recurrence of geriatric depression. Arch Gen Psychiatry
2000; 57:285290
6. Hickie I, Scott E, Mitchell P, Wilhelm K, Austin MP, Bennett B:
Subcortical hyperintensities on magnetic resonance imaging:
clinical correlates and prognostic significance in patients with
severe depression. Biol Psychiatry 1995; 37:151160
7. Mayberg HS: Depression and frontal-subcortical circuits: focus
on prefrontal-limbic interactions, in Frontal-Subcortical Circuits in Psychiatric and Neurological Disorders. Edited by Lichter DC, Cummings JL. New York, Guilford, 2001, pp 177206
8. Mattis S: Dementia Rating Scale. Odessa, Fla, Psychological Assessment Resources, 1989
9. Ivnik RJ, Malec JF, Smith GE, Tangalos EG, Petersen RC: Neuropsychological test norms above age 55. Clin Neuropsychol
1996; 10:262278
10. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai
AH, Mulsant B, Reynolds CF III: Rating chronic medical illness
burden in geropsychiatric practice and research: application of
the Cumulative Illness Rating Scale. Psychiatry Res 1992; 41:


11. Basser PJ: Inferring microstructural features and the physiological state of tissues from diffusion-weighted images. NMR
Biomed 1995; 8:333344

12. Middleton FA, Strick PL: A revised neuroanatomy of frontal-subcortical circuits, in Frontal Subcortical Circuits in Psychiatric and
Neurological Disorders. New York, Guilford, 2001, pp 4458

Brief Report

Inpatient Antipsychotic Drug Use in 1998, 1993, and 1989

Franca Centorrino, M.D.
Marion Eakin, M.D.

tal inpatients treated with antipsychotics in 1993 (N=299) and

Boston area inpatients in 1989 (N=50).

Objective: Patterns of clinical use of antipsychotic agents have

changed greatly in the past decade. The authors goal was to examine these patterns.

Results: The most commonly prescribed antipsychotics in

1998 were atypical agents; olanzapine was prescribed more often than risperidone or quetiapine, which were prescribed
more often than other antipsychotics. Two or more antipsychotics were prescribed at some time during their hospitalization
for 150 (43%) of the patients in 1998. The total discharge dose
in chlorpromazine equivalents for the 349 patients for whom
antipsychotics were prescribed at discharge was 371 mg/day,
29% higher than the total discharge dose for patients in 1993
and 46% greater than the dose in 1989. The dose of antipsychotics was greater for patients with psychotic illnesses than for
those with affective illnesses. Higher doses were associated with
greater clinical improvement, polypharmacotherapy, and
younger patient age.

Method: They evaluated medication use in all McLean Hospital inpatients treated with antipsychotic drugs during 3 months
in 1998 (N=349) and compared the results with McLean Hospi-

Conclusions: Emerging trends toward higher total antipsychotic doses and polypharmacotherapy require critical assessments of cost-benefit relationships.

Won-Myong Bahk, M.D., Ph.D.

James P. Kelleher, M.D.
Jessica Goren, Pharm.D.
Paola Salvatore, M.D.
Samy Egli, B.A.
Ross J. Baldessarini, M.D.

(Am J Psychiatry 2002; 159:19321935)

e surveyed hospital practices in the Boston area regarding use of antipsychotic drugs in 1984, 1989, and 1993
(1, 2). In contrast to earlier American practices, mean
chlorpromazine-equivalent daily doses fell by the late
1980s, to accord with standard international practices,
and conservative dosing was sustained into the early
1990s (2, 3). More recently, growing numbers of atypical
antipsychotics have entered clinical use, along with other
innovative treatments (4). It is our clinical impression,
supported by recent research reports (58), that simultaneous use of multiple dissimilar antipsychotics is increasing. Accordingly, we completed a new survey of antipsychotic use to document current trends compared with our
earlier findings over the past decade (1, 2).

Consecutive patients admitted to McLean Hospital in March
May 1998 who were treated with antipsychotic medications were
considered. Following review and approval for confidential and
anonymous use of aggregate data by the hospitals institutional
review board, we reviewed clinical records to determine the pa-


tients sex, age, discharge DSM-IV diagnosis, and all medications

given, with their doses and times.
Doses of antipsychotics were converted to chlorpromazine
equivalents (mg/day) on the basis of potency ratios of approximate median recommended daily doses to chlorpromazine at 400
mg/day (4) (Table 1). For each patient, we compiled initial, maximum, and final (discharge) doses of primary antipsychotic agents
(those used for the majority of inpatient days), as well as the total
final dose when multiple antipsychotics were given. Comparisons
were made of McLean patients treated in 1998 (N=349) with similar McLean inpatients in 1993 (N=299) and Boston area patients
in 1989 (N=50) (2). Data on patients clinical improvement were
obtained from hospital discharge records.
Averages are means and standard deviations. Continuous data
were compared by using one-way analysis of variance, paired t
tests, or unpaired t tests for unequal groups across years. Categorical data were compared by using contingency tables (chisquare). Correlations were based on Spearman nonparametric
rank methods (rs). Factors associated with median-split final total
chlorpromazine-equivalent dose were evaluated by logistic regression multivariate methods (risk ratio and 95% confidence interval [CI]). We used Statview-5 programs (SAS Corp., Cary, N.C.)
for statistical analyses.
Am J Psychiatry 159:11, November 2002