Response of Patients With Major Depression and Silent Cerebral Infarction to Antidepressant Drug Therapy, With Emphasis on Central Nervous System Adverse Reactions
Background and Purpose We previously found that silent cerebral infarction (SCI) is present in most patients older than 50 years with major depression. The present study was designed to clarify the response to antidepressant pharmacotherapy in patients with major depression associated with SCI.
Methods Using clinical charts, we retrospectively studied patients older than 50 years who were admitted for antidepressant drug therapy. Patients with bipolar affective disorder and those with focal neurological symptoms were excluded. All patients underwent magnetic resonance imaging and were classified as SCI-negative or SCI-positive. The SCI-positive group was subclassified into those with moderate SCI (either perforating area or cortical area) (n=15) and those with severe SCI (both perforating and cortical areas) (n=7). Duration of treatment in hospital and the incidence of central nervous system adverse reactions to the antidepressant drugs were compared between the two groups.
Results The duration of hospital treatment in patients with severe SCI was significantly longer than in those with moderate SCI (P<.01). The percentage of patients with adverse central nervous system reactions to antidepressant drugs was significantly higher in the SCI-positive group than in the SCI-negative group (P<.05). Patients with severe SCI had significantly more adverse reactions than those with moderate SCI (P<.05).
Conclusions Depressed patients with severe SCI required longer hospital treatment and had more drug-related adverse reactions of the central nervous system. These findings suggest that the depression associated with severe SCI may be resistant to treatment.
A cerebral infarction that is detected by MRI or other imaging modalities in the absence of associated stroke or focal neurological symptoms is referred to as an asymptomatic or silent cerebral infarction. Such infarcts are placed in classification III of cerebrovascular disorders, as defined by the National Institute of Neurological Disorders and Stroke.1 Except for vascular dementia, classification III excludes cases associated with psychiatric symptoms. Psychiatric symptoms, such as those observed in patients with affective or delusional disorders, may, however, be a consequence of SCI.2
We previously found that SCI is observed in half of the patients with major depression of presenile onset (ages 50 to 65 years) and in most patients with major depression of senile onset (patients aged >65 years).3 Depressed patients with SCI infrequently have a family history of affective disorders but more often exhibit risk factors for cerebral infarction (hypertension, for example). Patients with SCI exhibit more severe depressive symptoms than do depressed patients without SCI.4 Our data suggest that mania of late onset (at ages >50 years) is associated with larger areas of brain damage than is major depression of late onset (at ages >50 years).5 Post6 and Murphy7 reported that 40% to 65% of patients with senile depression exhibited an incomplete or poor recovery throughout the follow-up period. Those authors concluded that this poor prognosis was related to organic brain disease.
The present study used MRI to establish the diagnosis of SCI in patients older than 50 years of age who were admitted for antidepressant pharmacotherapy. Data on prognosis, duration of hospital treatment, and CNS adverse reactions to antidepressant drugs were evaluated.
Subjects and Methods
We retrospectively evaluated patients older than 50 years of age who were admitted for pharmacotherapy of unipolar depression at the Department of Psychiatry and Neurosciences at Hiroshima University School of Medicine between January 1993 and August 1995 by reviewing their clinical charts. All patients underwent MRI as a routine procedure within 3 months after admission and met the criteria for major depression described in the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R)2 as determined by a clinical interview. Patients with a history of stroke or of focal neurological symptoms were excluded from study, as were those with alcoholism, cerebral degenerative disease or dementia, brain injury, or systemic disease that could induce a depressive state. Patients with evidence of bipolar affective disorder, patients who had received ECT for the treatment of depression, and patients with severe somatic complications that required hospital treatment were also excluded. All patients and their family members underwent detailed questioning regarding any previous episodes of affective disorders and the patient's age at onset of depression. All patients received adequate and appropriate pharmacotherapy for depression. This study was designed in accordance with institutional guidelines and was approved by an institutional review committee.
Patients were classified as SCI-positive or SCI-negative. The SCI-positive patients were subclassified as those with moderate SCI and those with severe SCI. Groups were compared in four respects: (1) the number of patients with manic episodes in the hospital, (2) the number of patients in remission at discharge, (3) the duration of treatment in the hospital, and (4) the number of patients with adverse CNS reactions to antidepressant pharmacotherapy. Manic episodes in the hospital were diagnosed according to DSM-III-R criteria.2 Remission at discharge was diagnosed by a score <10 on the Hamilton Rating Scale for depression8 at discharge. Other patients were classified as having had an incomplete or a poor recovery. Antidepressant drugs used for treatment of depression included tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, dosulepin, imipramine, lofepramine, nortriptyline, and trimipramine), tetracyclic antidepressants (maprotiline, mianserin, setiptiline), selective serotonin reuptake inhibitors (trazodone), and sulpiride. Monoamine oxidase inhibitors are not used in Japan. The use of concomitant minor tranquilizers and hypnotics was surveyed in groups studied.
MRI was performed by use of a 1.5-T apparatus (General Electric Co) at the Hiroshima University School of Medicine. T2-weighted images (repetition time [TR], 2000 ms; echo time [TE], 100 ms) were obtained in the transverse plane that was parallel to the orbitomeatal line, and T1-weighted images (inversion-recovery; TR, 2000 ms; TE, 100 ms) were obtained as coronal slices at 10-mm intervals. Twelve slices of each type of image were obtained. Lesions that demonstrated a low signal intensity on the T1-weighted images and a high signal intensity on the T2-weighted images included both état criblé (Virchow-Robin spaces) and cerebral infarctions. Braffman et al9 have reported that état criblé lesions are <5 mm in diameter, whereas a cerebral infarction exceeds 5 mm in diameter. Infarcts were therefore defined as high-intensity lesions that were >5 mm in diameter on T2-weighted images and that coincided with low-intensity lesions on T1-weighted images. To avoid the overdiagnosis of SCI, lesions that measured 5 to 20 mm were classified as small infarcts, whereas lesions >20 mm were classified as large infarcts. Although detectable lesions <5 mm in diameter may also have represented small infarcts, they were excluded from analysis because they are difficult to distinguish from état criblé.
Regarding the number of small infarcts that can be interpreted as representative of an SCI, Shimada et al10 reported that the mean number of small infarcts in hypertensive asymptomatic elderly subjects was 2.8±4.6, whereas the mean number in normotensive elderly subjects was 1.1±1.5. Matsubayashi et al11 reported that four or more small infarcts were associated with the development of cognitive impairment in elderly patients. SCI was therefore defined as the presence of one or more large infarcts or four or more small infarcts in the same cerebral hemisphere. Patients with fewer than four small infarcts and no large infarcts were classified as not having SCI. Periventricular hyperintensity was not assessed.
Cerebral infarctions were classified as follows: SCI in perforating area refers to lesions in the basal ganglia, the internal capsules, and the thalami that belong to the perforating branch system; SCI in cortical area refers to lesions in the cerebral cortex and subcortical white matter that belong to the cortical branch system. Details regarding the location and hemisphere of SCIs were not assessed because almost all patients had multiple lesions.
Parametric data are reported as mean±SD. Student's t test was used to compare mean differences in parametric data between groups. The χ2 test was used to compare nonparametric numerical data. A probability value of <.05 was considered statistically significant.
A total of 46 patients were admitted once between January 1993 and August 1995. Six patients had been admitted twice during that period; the first admissions of these 6 patients were studied. Eleven patients were excluded according to our exclusion criteria. A total of 41 patients were therefore eligible for study. On the basis of MRI findings, 22 patients were SCI-positive and 19 patients were SCI-negative. The SCI-positive group was subclassified into moderate SCI (either perforating area or cortical area) (n=15) or severe SCI (both perforating area and cortical area) (n=7). All patients in both groups were using minor tranquilizers and hypnotics at the time of admission.
Demographic data are shown in Table 1⇓. The mean age of the 19 patients in the SCI-negative group was significantly lower than that of the 22 patients in the SCI-positive group (P<.05).
There were no statistically significant differences between groups in the number of manic episodes in the hospital (Table 2⇓). The percent of patients in remission at discharge was lower in the SCI-positive group than in the SCI-negative group, but this difference was not statistically significant. In addition, fewer patients with severe SCI were in remission at discharge than were patients with moderate SCI (P=NS). All patients who were not in remission had an incomplete recovery or a poor recovery at discharge.
The mean duration of treatment in the hospital did not differ significantly between the SCI-negative and the SCI-positive groups (Table 2⇑). However, the duration of treatment in the hospital of patients with severe SCI was significantly longer than that of patients with moderate SCI (P<.01).
Seven patients (32%) in the SCI-positive group versus none in the SCI-negative group (P<.05) had adverse CNS reactions. Of the seven patients with severe SCI, five (71%) had adverse CNS reactions compared with two (13%) of the patients with moderate SCI (P<.05).
Adverse CNS reactions to antidepressant drugs include delirium, parkinsonism, dyskinesia, and akathisia. Delirium was experienced by four patients taking tricyclic antidepressants (two patients taking clomipramine 150 mg/d, and two patients taking imipramine 150 mg/d). Of the patients taking sulpiride, four experienced parkinsonism, two had akathisia, and one had dyskinesia (dosage in all cases, 150 mg/d). No patient taking tetracyclic antidepressants or the selective serotonin reuptake inhibitors had adverse CNS reactions.
Senile depression is associated with a poor prognosis, such as a poor recovery and recurrence, as well as complications associated with somatic disease and dementia. Post6 followed 92 elderly, depressed inpatients for 3 years. Only 24 patients (26%) achieved a sustained recovery; 23 (25%) had chronic, mild depression, 34 (37%) relapsed, and 11 (12%) remained continuously ill throughout follow-up. Murphy7 followed up 124 elderly (>65 years old) patients with depression, of whom a total of 43 (35%) had a good outcome, 24 (19%) relapsed, 36 (29%) were continuously ill, 4 (3%) had dementia, and 17 (14%) died. Both Post and Murphy concluded that the poor prognosis of senile depression is related to the presence of organic brain disease as well as physical disease.
Hickie et al12 recently showed that the presence of hyperintense white matter lesions, as seen with MRI, is correlated with a poorer response to treatment of depressed inpatients. White matter changes are correlated with a poorer response both in patients who receive ECT and in those who receive pharmacotherapy alone.
The depressed patients with severe SCI in the present study tended to have a poor response to antidepressant drug therapy. In particular, the duration of hospital treatment of patients with severe SCI was significantly longer than that of other patients. Our findings suggest that the depression associated with severe SCI is resistant to treatment.
Figiel et al13 14 15 reported that depressive patients with basal ganglia lesions on MRI experience a higher incidence of adverse effects, notably delirium, when treated with antidepressant or ECT. The presence of severe SCI in the present study was associated with an increased incidence of adverse CNS reactions to antidepressant drugs. Our findings suggest that organic brain disease is associated with a decreased tolerance to antidepressant drugs.
Selected Abbreviations and Acronyms
|CNS||=||central nervous system|
|MRI||=||magnetic resonance imaging|
|SCI||=||silent cerebral infarction|
- Received February 20, 1996.
- Revision received June 24, 1996.
- Accepted July 26, 1996.
- Copyright © 1996 by American Heart Association
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