Hyperresponsivity to the serotonin agonist m-chlorophenylpiperazine in Alzheimer's disease. A controlled study.

The serotonin agonist m-chlorophenylpiperazine (mCPP) was administered intravenously to 12 patients with Alzheimer's disease and ten age-matched controls. It produced distinct behavioral effects in both treatment groups; however, significantly greater responsivity to mCPP was found in patients with Alzheimer's disease than in controls in measures of psychomotor activation, restlessness, and perceptual abnormalities. Significant and similar increases in plasma prolactin and cortisol levels were found in both patients with Alzheimer's disease and controls following the administration of mCPP vs placebo. Furthermore, blood pressure and pulse changes following mCPP were not significantly different between the groups. Elderly controls, however, did show a significantly greater temperature response following mCPP than did patients with Alzheimer's disease. The overall cognitive effects of mCPP were minimal; however, mCPP produced significantly greater worsening in recent memory and knowledge memory in patients with Alzheimer's disease than in controls. These findings could not be explained by pharmacokinetic differences across populations, because plasma concentrations of mCPP were similar in patients with Alzheimer's disease and controls. The increased behavioral responsivity but unchanged neuroendocrine or other physiologic responsivity to mCPP may be related to damaged brain serotonin neurons or other neuronal systems that interact with serotonin neurons that have been found in postmortem and biopsy studies of patients with Alzheimer's disease.

The effects of acute scopolamine in geriatric depression.

In an intensive multidrug, multidose study, nine elderly depressed patients were administered 0.1, 0.25, and 0.5 mg of scopolamine hydrobromide, 1 mg of oral lorazepam, and placebo in a double-blind investigation aimed at assessing the status of the central cholinergic nervous system in geriatric depression. Significant cognitive and behavioral effects of scopolamine were observed only at the high dose (0.5 mg), while lower doses and lorazepam showed no significant differences from placebo. Cognitive deficits caused by scopolamine were in the areas of new learning, access to semantic memory, vigilance, and continuous performance. Behavioral effects consisted of activation, restlessness, and anxiety, but there was no significant effect on depressed mood. These results suggest that elderly depressed patients with mild to moderate cognitive impairment seem to be more similar to previously studied elderly controls rather than to patients with Alzheimer's disease in their reaction to short-term cholinergic blockade, and suggest that the cognitive and mood changes often seen in geriatric depression may involve factors other than disturbed muscarinic cholinergic mechanisms.

L-deprenyl in Alzheimer's disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition.

Since monoamine neurotransmitter disturbances exist in some cases of dementia of the Alzheimer's type (DAT), monoamine-enhancing drugs may ameliorate some symptoms of DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor that is generally free of undesired effects. At low doses (10 mg/d) it selectively inhibits MAO-B, an enzyme whose level is elevated in the brains of patients with DAT who are studied post mortem. At higher doses it has more complex effects, including inhibition of MAO-A plus MAO-B. We administered 10 mg/d and 40 mg/d of L-deprenyl to 17 patients with DAT in a double-blind, placebo-controlled, serial treatment. Total Brief Psychiatric Rating Scale scores decreased significantly during 10-mg/d treatment, with decreases in measures of anxiety/depression, tension, and excitement. Approximately one half of the patients' conditions were judged to be improved clinically, with evidence of increased activity and social interaction along with reduced tension and retardation. Similar but smaller changes were observed during 40-mg/d treatment. The behavioral changes were associated with improvement in performance on a complex cognitive task requiring sustained effort. There were minimal physiologic and side effects. The greater effect of low-dose L-deprenyl therapy suggests that it is the inhibition of MAO-B, and not MAO-A, that may be important in the behavioral effects of L-deprenyl administration to patients with DAT.

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.

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.

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 preliminary study of the effects of nighttime administration of the serotonin agonist, m-CPP, on sleep architecture and behavior in healthy volunteers.

The effects of m-chlorophenylpiperazine (m-CPP) (0.5 mg/kg) on sleep architecture and behavior were examined in six healthy volunteers following a single oral dose of the drug in a randomized, double-blind, placebo-controlled study. m-CPP reduced total sleep time (TST) and sleep efficiency in all subjects. Slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep were decreased and stage 1 sleep was prolonged in a majority of subjects. Prominent behavioral and psychological effects were reported in five out of six subjects following m-CPP (but not following placebo) that interfered with sleep. The sleep disruption and behavioral activation following nighttime administration of m-CPP contrasts with the sedative properties of its parent compound, trazodone, suggesting that the hypnotic effect of trazodone is not related to the agonist profile of its metabolite, m-CPP.

Effects of daily oral m-chlorophenylpiperazine in elderly depressed patients. Initial experience with a serotonin agonist.

Six patients (mean age 62.5 +/- 7.6 years) with major depression were treated for 2 weeks with the serotonin agonist m-chlorophenylpiperazine (m-CPP), 80 mg/day in a double-blind, placebo-controlled, crossover-design pilot study. Two patients showed clinically significant improvement in depressive symptoms during active drug treatment, whereas two others showed modest effects. All patients tolerated the drug, with no major side effects and no changes in vital signs or in liver, renal, thyroid, or hematological function. Further studies are needed to determine the characteristics of the possible antidepressant effects of m-CPP; such work may yield greater understanding of the role of serotonin in affective and other psychiatric disorders.

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.

A preliminary study of the effects of intravenous m-chlorophenylpiperazine, a serotonin agonist, in elderly subjects.

m-Chlorophenylpiperazine (m-CPP), a serotonin receptor agonist, is currently being investigated as a probe of serotonergic responsivity in various neuropsychiatric disorders. The safety of m-CPP in elderly populations and its potential usefulness in exploring possible serotonergic dysfunction in Alzheimer's disease and normal aging were assessed by examining the behavioral, neuroendocrine, and physiological effects of this agent in 15 elderly subjects (mean age 69 +/- 2 years): 9 Alzheimer patients and 6 healthy normal volunteers. Intravenous m-CPP (0.08 mg/kg) was well tolerated in all subjects and produced no serious adverse effects. The behavioral effects were modest; in particular, minimal anxiety was observed, a finding that contrasted to results from an earlier study reporting that intravenous m-CPP at a slightly higher dose induced marked anxiety and panic attacks in younger subjects. m-CPP produced significant increases in plasma cortisol and prolactin, and significant changes in blood pressure and temperature in these elderly subjects. The results of this preliminary study suggest that intravenous m-CPP is safe and well-tolerated in elderly subjects. Future studies at higher doses can now proceed to study more definitively the question of possible age- and disorder-related reductions in central nervous system (CNS) serotonergic responsivity.

A new scale for the assessment of depressed mood in demented patients.

Twenty-one subjects with clinically diagnosed dementia of the Alzheimer type were rated on the Dementia Mood Assessment Scale, a new instrument intended to measure the severity of depressed mood in cognitively impaired patients. Ratings were based on direct observation and a semistructured interview of the patient. Interrater reliability was established. There were highly significant correlations between patients' scores on the instrument's 17-item depression subscale and their scores on global measures of depression and sadness. The potential usefulness of this new scale in assessing the severity of depression in demented patients longitudinally or under drug treatment conditions is discussed.

CSF somatostatin in patients with Alzheimer's disease, older depressed patients, and age-matched control subjects.

Somatostatin-like immunoreactivity was measured in the CSF of 12 patients with Alzheimer's disease, 15 age-matched control subjects, and 20 older depressed subjects. Patients with dementia or depression were found to have lower CSF somatostatin concentrations than control subjects despite markedly different clinical presentations. Severity of depression was clearly different in all three groups but showed no significant correlation with CSF concentration of somatostatin. There was a significant positive correlation between CSF somatostatin-like immunoreactivity and cognitive functioning in all 47 subjects, but this association was not statistically significant within individual diagnostic groups. These data raise interesting questions about possible biological links between Alzheimer's disease and depression in older patients.

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.

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.

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.

On the conductance pathway traversed by strontium in mediating the asynchronous release of acetylcholine by motor nerve impulses.

A study was made to determine whether the Sr2+ dependent asynchronous release of acetylcholine by nerve impulses is mediated by the conventional Ca2+ conductance channel or, as has been suggested recently, through an alternative ion pathway. Experiments were performed on the frog neuromuscular junction by the use of standard electrophysiological techniques. Repetitive nerve stimulation in Sr2+-Ringer solutions caused a marked increase in miniature end-plate potential (m.e.p.p.) frequency which was dependent on Sr2+ concentration and inhibited in a competitive fashion by the known Ca2+ antagonists, Co2+ and Mg2+. The equilibrium dissociation constants (KdS) determined for both Co2+ (0.09 +/- 0.01 mM, mean +/- s.e. mean, n = 5) and Mg2+ (3.7 +/- 0.3 mM, mean +/- s.e. mean, n = 4) were essentially the same as the reported values for these antagonists in blocking Ca2+ -mediated transmitter release by nerve impulses. These results suggest that Sr2+ mediates asynchronous evoked transmitter release through the conventional calcium conductance channel.

Dissociation of specific binding of 25-OH-D3 and resorption in fetal rat bones.

Specific binding of 25-OH-D 3 was measured in cytosol prepared from isolated fetal rat bone cells. Binding was significant after 2 h incubation at 0 degrees C and appeared to be approaching a plateau at 4 h. Binding was half-maximal at 1.7 X 10(-10) M 25-OH-D3. 24(R),25-(OH)2D3, which was approximately equipotent with 25-OH-D3 in bone culture, had approximately the same binding activity. 1,25-(OH)2D3, which was 2--3 orders of magnitude more active on resorption, was a much weaker competitor for binding. Vitamin D3, which was inactive in culture, was at least as effective a competitor as 1,25-(OH)2D3. The results suggest that the cytosol site which specifically bind 25-OH-D3 is not the mediator of the bone-resorbing activity.

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.

Neuroendocrine, physiologic, and behavioral responses following intravenous nicotine in nonsmoking healthy volunteers and in patients with Alzheimer's disease.

In separate studies, nonsmoking nicotine-naive subjects (11 young and middle-aged normal volunteers and 11 nonsmoking patients with Alzheimer's disease) received up to three doses of intravenous nicotine bitartrate (0.125, 0.25, and 0.5 micrograms/kg/min) and placebo for 60 min. Measurement of plasma ACTH, cortisol, and prolactin showed that nicotine produced in both groups a dose-dependent increase in cortisol, with ACTH in both groups and prolactin in the Alzheimer's group significantly elevated only by the 0.5 micrograms dose. Physiologic measures showed dose-dependent increases that were consistent with previous reports of nicotinic cholinergic stimulation. Behavioral effects included increases in anxiety and decreases in mood, especially following the 0.5 micrograms dose. Physical side effects were modest. The results indicate that nicotinic cholinergic stimulation can activate pituitary hormonal secretion in the human and suggest that nicotinic cholinergic stimulation may constitute an important part of cholinesterase inhibitor-induced endocrine stimulation and behavioral activation.

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.