Race, psychiatric diagnosis, and mental health care utilization in older patients.

To evaluate the impact of race on mental health care utilization among older patients within given clinical psychiatric diagnoses, the authors examined a retrospective sample of 23,718 elderly veterans treated in Department of Veterans Affairs inpatient facilities in 1994. Significant racial differences in mental health care utilization found over a subsequent 2-year period were related to outpatient (but not inpatient) care; for instance: 1) African American patients with psychotic disorders had significantly fewer outpatient psychiatric visits; and 2) African American patients with substance abuse disorders had significantly more psychiatric visits than Caucasian patients in their respective groups. Although inpatient utilization appeared to be similar among races, findings related to outpatient utilization may be associated with such factors as compliance, treatment efficacy, access to health care, or possible clinician bias.

Treatment of agitation in AD: a randomized, placebo-controlled clinical trial.

BACKGROUND: Treatment of agitation is a crucial problem in the care of patients with AD. Although antipsychotic and antidepressant medications and behavior management techniques (BMT) have each been used to treat agitation, clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment designs. OBJECTIVE: To compare haloperidol, trazodone, and BMT with placebo in the treatment of agitation in AD outpatients. METHODS: A total of 149 patients with AD and their caregivers participated in a randomized, placebo-controlled, multicenter trial. Blind assessment was conducted at baseline and after 16 weeks of treatment. The three active treatments were haloperidol, trazodone, and BMT. The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure. Secondary outcomes included patient agitation, cognition, and function, and caregiver burden. RESULTS: Thirty-four percent of subjects improved relative to baseline. No significant differences on outcome were obtained between haloperidol (mean dose, 1.8 mg/d), trazodone (mean dose, 200 mg/d), BMT, or placebo. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm. No other significant difference in adverse events was seen. Symptoms did not respond differentially to the different treatments. CONCLUSIONS: Comparable modest reductions in agitation occurred in patients receiving haloperidol, trazodone, BMT, and placebo. More effective pharmacologic, nonpharmacologic, and combination treatments are needed.

Serotonin dysregulation in adolescents with major depression: hormone response to meta-chlorophenylpiperazine (mCPP) infusion.

This study examined central serotonin disturbance, as reflected by neuroendocrine hormones, among adolescents with major depression. Prolactin, cortisol, and growth hormone were measured following the infusion of a serotonin agonist, meta-chlorophenylpiperazine (mCPP). Twelve (M=6, F=6) medication-free adolescents with major depression (MDD) were compared with 12 (M=6, F=6) matched normal control subjects, ranging in age from 13 to 17 years. Baseline evaluations and a battery of laboratory tests were completed. mCPP, 0.1 mg/kg i. v., was administered in a placebo-controlled design. Analyses of the neuroendocrine hormones revealed that the depressed group had a higher baseline prolactin level and an augmented prolactin response to mCPP challenge than did the control group. The depressed group experienced a sharper baseline-cortisol decline between 08.00 and 11.00 h, and compared to control subjects they displayed an augmented response to the challenge. The depressed group reported more side effects than the control group during saline infusion, but not during mCPP infusion. Findings suggest that depressed adolescents have an elevated baseline prolactin level, and also experience enhanced prolactin and cortisol responses to the serotonergic challenge. These preliminary findings will be confirmed during our ongoing study.

Race and inpatient psychiatric diagnoses among elderly veterans.

OBJECTIVE: Limited data exist on differential rates of psychiatric diagnoses between ethnocultural groups in the elderly population. The purpose of this study was to examine more closely the issue of race and rates of psychiatric diagnoses among elderly inpatients. METHODS: The national sample included 23,758 veterans age 60 or over admitted in 1994 to acute inpatient units in Department of Veterans Affairs (VA) hospitals. Psychiatric diagnosis determined inclusion in one of six diagnostic groups: cognitive, mood, psychotic, substance use, anxiety, and other disorders. The study also assessed rates of psychiatric diagnoses among patients admitted to psychiatric units only and by age group and treatment setting, such as the size of the hospital and whether it had an academic affiliation. RESULTS: Compared with elderly Hispanic and Caucasian patients, a significantly higher proportion of elderly African-American patients were diagnosed as having cognitive disorders and substance use disorders, and a significantly lower proportion were diagnosed as having mood and anxiety disorders. Hispanic and African-American patients had significantly higher rates of psychotic diagnoses than Caucasian patients. For all diagnoses except cognitive disorders, these differential rates were also found among patients admitted to psychiatric units only. Age and treatment setting appeared to moderate some of the differences in diagnostic rates, except for mood disorders. In every analysis performed, the rate of mood disorder diagnoses among elderly African-American patients was less than half the rate among elderly Caucasian patients. CONCLUSIONS: The findings suggest that elderly African-American veterans admitted to VA inpatient units have strikingly lower rates of mood disorder diagnoses. Future studies should examine the contribution of both patient and provider factors to these differences.

The efficacy, safety, and tolerability of antipsychotics in the elderly.

Antipsychotic medications are among the most widely prescribed class of medications for elderly patients. Despite their high use, few studies document the efficacy, safety, and tolerability of these agents in this patient population. This is unfortunate because, as a group, the elderly are exceptionally sensitive to the adverse effects associated with antipsychotics, in particular, the extrapyramidal side effects (EPS). The atypical antipsychotics with their lower propensity to cause EPS and lower need for augmenting anticholinergic medication have introduced new options for elderly patients who need antipsychotic therapy for a number of psychiatric and neurologic disorders with psychotic manifestations. This review covers the pharmacologic, clinical, and regulatory issues involving antipsychotic use in elderly patients that warrant consideration by the practicing psychiatrist.

Health care utilization by older patients with coexisting dementia and depression.

OBJECTIVE: Few studies have examined the course of coexisting dementia and depression. The purpose of this study was to compare elderly patients who had coexisting dementia and depression with elderly patients who had either disorder alone in terms of their utilization of inpatient and outpatient services. METHOD: The study group included 7,115 veterans aged 60 years or older who had been discharged from Department of Veterans Affairs inpatient units in 1992 with diagnoses of major depression, dementia, or both. Outcome measures were analyzed for a 2-year period following the index hospitalization for each diagnostic study group. RESULTS: Patients with coexisting dementia and depression had significantly more psychiatric inpatient days than the other two study groups and more medical inpatient days and nursing home readmissions than patients with depression alone. Patients with coexisting dementia and depression had significantly more total inpatient days than the other two groups. Notably, patients with coexisting dementia and depression did not utilize more outpatient resources than the other study groups; in fact, they had significantly fewer medical, psychiatric, and total visits than patients with depression alone. CONCLUSIONS: The findings suggest that patients with coexisting dementia and depression are high utilizers of inpatient services, with a course of illness that may resemble dementia in terms of nursing home and inpatient medical care utilization and depression in terms of inpatient psychiatric care utilization; however, these patients utilized significantly fewer outpatient resources than the group with depression alone. Aggressive outpatient treatment approaches might reduce utilization of inpatient care for patients with coexisting depression and dementia.

Differential trace amine alterations in individuals receiving acetylenic inhibitors of MAO-A (clorgyline) or MAO-B (selegiline and pargyline).

Marked, dose-dependent elevations in the urinary excretion of phenylethylamine, para-tyramine, and meta-tyramine were observed in depressed patients treated for three or more weeks with 10, 30, or 60 mg/day of the partially-selective inhibitor of MAO-B, selegiline (l-deprenyl). In comparative studies with other, structurally similar acetylenic inhibitors of MAO, pargyline, an MAO-B > MAO-A inhibitor used in doses of 90 mg/day for three or more weeks, produced elevations in these trace amines which were similar to those found with the highest dose of selegiline studied. Clorgyline, a selective inhibitor of MAO-A used in doses of 30 mg/day for three or more weeks (a dose/time regimen previously reported to reduce urinary, plasma, and cerebrospinal fluid 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) > 80%, indicating a marked inhibitory effect on MAO-A in humans in vivo) produced negligible changes in trace amine excretion. In comparison to recent studies of individuals lacking the genes for MAO-A, MAO-B, or both MAO-A and MAO-B, the lack of change in trace amine excretion in individuals with a mutation affecting only MAO-A is in agreement with the observed lack of effect of clorgyline in the present study. Selegiline produced larger changes in trace amines--at least at the higher doses studied--than found in individuals lacking the gene for MAO-B, in agreement with other data suggesting a lesser selectivity for MAO-B inhibition when selegiline was given in doses higher than 10 mg/day. Overall, trace amine elevations in individuals receiving the highest dose of deprenyl or receiving pargyline were approximately three to five-fold lower than the elevations observed in individuals lacking the genes for both MAO-A and MAO-B, suggesting that these drug doses yield incomplete inhibition of MAO-A and MAO-B.

Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease.

BACKGROUND: Excitotoxicity may contribute to neuronal degeneration in Huntington's disease (HD). N-methyl-D-aspartate (NMDA) receptor antagonists can prevent neuronal degeneration caused by excitotoxicity, but their effects in HD patients are not known. METHODS: We investigated the acute cognitive, behavioral, and motor effects of the NMDA-receptor antagonist ketamine in HD patients. Double-blind infusions of 0.10, 0.40, and 0.60 mg/kg/hr ketamine were given to 10 HD patients on one test day and compared with placebo infusions on a second, identical testing day. Linear mixed-effects models and randomization tests were used to identify whether, and at which dose, a significant change from baseline occurred in outcome variables. RESULTS: We demonstrated that ketamine is well tolerated at low and intermediate subanesthetic doses. Intermediate ketamine doses produced specific decline in memory and verbal fluency. Higher subanesthetic doses caused a significant increase in psychiatric symptoms and impairment of eye movements. CONCLUSIONS: These results describe the spectrum of clinical effects produced by increasing NMDA receptor blockade in HD patients. The clinical effects appearing with higher levels of NMDA receptor blockade can identify the range of doses used in clinical trials of NMDA receptor antagonists.

Management of treatment resistance in the depressed geriatric patient.

The treatment of depression in geriatric patients is challenging on all levels. Recognition, compliance, medical comorbidity, tolerance of drug regimens, and accessibility of the patient to therapy all represent major clinical problems. Treating depression in elderly, disabled patients requires patience, keen observation skills, and much flexibility. It is critical that these patients trust their physicians and have ready access if problematic side effects develop. In general, when treating patients with a history of failure to respond, the clinician should choose a medication with a tolerable side-effect profile, and persist with it as long as steady, slow gains are being made. Dosages should be maximized to clinical tolerance prior to considering switching agents or augmentation strategies. It is probably wiser to augment than switch if a partial response has been obtained. Particularly among the medically ill elderly, any "lost ground" may be very difficult to replace. All available psychosocial resources should be assessed and brought to bear productively in the treatment context. We are quite far from a full clinical understanding of "treatment resistance" in elderly depressive patients, but the eminent treatability of depression in elderly patients encourages creative exploration of treatment regimens. Rigorous, placebo-controlled studies of representative samples of elderly patients are needed to clarify the diverse interactions among the many pharmacologic agents available to treat resistant/refractory depression in the elderly.

High-dose selegiline in treatment-resistant older depressive patients.

BACKGROUND: We examined the effect of high-dose selegiline in 16 treatment-resistant older depressive patients. We hypothesized that selegiline, at a dosage of 60 mg/d, would be at least partially effective but that the higher doses would not maintain the monoamine oxidase B selectivity observed with the lower doses of selegiline. METHODS: Sixteen treatment-resistant subjects (mean [+/- SD] age, 65.6 +/- 9.3 years) entered a double-blind, randomized, crossover study of placebo vs 3 weeks of selegiline at a dosage of 60 mg/d. Objective measures of mood and behavior were obtained in all subjects, and 10 of the subjects underwent repeated lumbar punctures for analysis of monoamine metabolites in the cerebrospinal fluid. RESULTS: Objective measures of mood and behavior revealed significant improvement in the Hamilton Depression Rating Scale score (37.4% decrease), the Global Depression score (22.7% decrease), and the Brief Psychiatric Rating Scale score (19.3% decrease); subjective behavioral measures, however, did not show significant improvement during the 3-week medication trial. Cerebrospinal fluid values revealed a statistically significant drop in 3-methoxy-4-hydroxyphenylglycol (51%) and 5-hydroxyindoleacetic acid (17%) levels, and there was a significant lowering of systolic blood pressure on standing (15%), but these changes were not accompanied by clinical side effects. CONCLUSIONS: Our results suggest that high-dose selegiline can be an effective antidepressant in treatment-resistant older depressive patients. While the selegiline dose required has nonselective monoamine oxidase effects and thus would not be free of possible tyramine interactions, other advantages suggest that further investigations with selegiline are warranted in this population.

Sodium valproate in the treatment of behavioral disturbance in dementia.

Management of the behavioral complications of dementia, including agitation and aggression, presents a tremendous challenge to families and caregivers of afflicted patients. Most previous pharmacotherapies have shown minimal efficacy and significant side effects. We report our initial, open-label experience using the anticonvulsant sodium valproate in four dementia patients with severe behavioral disturbance. The drug was well tolerated by all patients, with no side effects or laboratory abnormalities, during 1- to 3-month trials. Two patients showed significant improvement in behavior, and a third had a transient response. Valproate may be a useful agent in the treatment of behavioral disturbance in dementia; controlled trials are needed to document its efficacy.

CSF somatostatin in Alzheimer's disease and major depression: relationship to hypothalamic-pituitary-adrenal axis and clinical measures.

Patients with Alzheimer's disease (AD) and major depression have been shown to have overlapping clinical symptoms and biological markers, including decreased concentrations of cerebrospinal fluid (CSF) somatostatin-like immunoreactivity (SLI), which may be related to alterations in the hypothalamic-pituitary-adrenal axis activity. As in prior studies, we found that CSF SLI was significantly decreased in a group of AD patients (N = 49) and a group of elderly patients with major depression (N = 18), as compared with 13 age-matched controls (F[2, 77] = 12.9, p < .001). In the present study, CSF SLI and CSF corticotropin-releasing factor correlated significantly within the group of AD patients (r = 0.49, p < .0004) and almost attained significance in the depressed patients (r = 0.47, p < .07). CSF SLI correlated significantly with urinary free cortisol within each patient group (r = -0.51, p < .03). Clinical measures of dementia severity and depression did not consistently correlate with CSF SLI in either patient group.

Antidepressant treatment of pathologic laughing or crying in elderly stroke patients.

Pathologic laughing or crying (PLC), a complication of many neurologic disorders, involves behavior that is either inappropriate to the context or to the patient's subjective feeling state. It is due to a dysregulation of the motoric components of emotional experience. PLC is distinct from, but often associated with, major depression. The relatively few reports on treatment of PLC are primarily with tricyclic antidepressants. We report the effective treatment of PLC due to stroke in three patients with nortriptyline or fluoxetine. The cases also illustrate the broad spectrum of depressive symptoms (from none to a major depression) seen in patients with PLC. We discuss treatment implications and directions for future research.

The effects of thyrotropin-releasing hormone and scopolamine in Alzheimer's disease and normal volunteers.

Thyrotropin-releasing hormone (TRH), a neuromodulator and possibly a neurotransmitter in the central nervous system, was shown in a prior study of young normal volunteers to attenuate the memory impairment induced by the anticholinergic drug scopolamine. In the present study, the cognitive, behavioral and physiologic effects of high dose TRH (0.5 mg/kg), both alone and following administration of scopolamine, were examined in 10 Alzheimer's disease (AD) patients (mean age±SD=63.5 years) and 12 older normal volunteers (mean age=64.9±8.8 years). On the day AD subjects received TRH alone, modest but statistically significant improvement from baseline performance was documented on some tests of learning and memory, especially in those with mild dementia severity. In comparing cognitive test performance between the scopolamine alone and scopolamine+TRH conditions, only two test scores were significantly higher in the latter condition. In the group of older volunteers, TRH did not attenuate scopolamine-induced cognitive impairment, contrary to prior findings in a group of younger controls. In fact, older subjects performed worse after receiving scopolamine followed by TRH than after receiving scopolamine alone. In addition, no change from baseline cognitive performance was detected after subjects received TRH alone. These findings raise several questions and speculations on possible age-related changes in the cholinergic system, as well as on the mechanism of the interaction of TRH with the cholinergic system.

The TRH stimulation test in Alzheimer's disease and major depression: relationship to clinical and CSF measures.

A blunted thyroid-stimulating hormone (TSH) response to exogenous thyrotropin-releasing hormone (TRH) has been reported to occur consistently in patients with major depression and less consistently in patients with Alzheimer's disease (AD). In this study we compared the TSH response to TRH in a large group (n = 40) of AD patients, elderly patients with major depression (n = 17), and age-matched controls (n = 14) to further characterize how it may relate to clinical variables, baseline thyroid function tests, and cerebrospinal fluid measures. Comparisons of TRH stimulation test response across all three groups revealed that patients with major depression had lower stimulated TSH levels (delta maxTSH) (p less than 0.02) and higher (though still within normal limits) mean thyroxine (T4) levels (p less than 0.05) than the AD patients or controls. AD patients with a blunted TSH response had a significantly higher mean free T4 (FT4) level (p less than 0.03) and tended to be more severely demented (p less than 0.01) than those with a nonblunted response.

A pilot placebo-controlled study of chronic m-CPP administration in Alzheimer's disease.

Meta-Chlorophenylpiperazine (m-CPP), a serotonin agonist and metabolite of the anti-depressant trazodone, was administered chronically to eight moderate to severely affected Alzheimer patients to determine whether it would produce improvement in behavioral symptoms complicating this illness. In doses up to 80 mg/day for 16 days, m-CPP was well tolerated and resulted in small but significant increases in anergy and depression-related symptoms compared with placebo. The effects of chronic m-CPP in this study contrast with the reported beneficial effects of the parent compound trazodone and selective 5-HT reuptake inhibitors in treating behavioral symptoms in Alzheimer patients.

CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression.

Decreased cerebrospinal fluid (CSF), somatostatinlike immunoreactivity (SLI) and alterations in the CSF monamine metabolites 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) have been reported in patients with probable Alzheimer's disease (AD) and in patients with major depression. In this study, we found CSF SLI to be significantly lower in a large group of AD patients (n = 60) and in a group of age-matched patients with major depression (n = 18) as compared with normal controls (n = 12). Mean CSF, MHPG, 5-HIAA, and HVA levels were not significantly different among diagnostic groups. Within a group of "depressed" AD patients, CSF levels of 5-HIAA showed a significant positive correlation (p = 0.03) with CSF SLI; a similar relationship was found within the group of patients with major depression. Further exploration of the relationship between the somatostatin and serotonin systems may provide clues as to how neuropeptides interact with monoamine neurotransmitters and what role they have in depression.