There are a number of ways in which a clinical diagnosis of dementia of the Alzheimer type can be made – the application of clinical criteria is the commonest but ancillary techniques such as neuroima

Clinical Diagnosis of Alzheimer's Disease

Corticotropin-releasing factor (CRF), a 41 amino acid-containing peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.

/pdf/the-role-of-corticotropin-releasing-factor-in-depression-and-469gge7qds.pdf

The role of corticotropin-releasing factor in depression and anxiety disorders

Fatty acid amide hydrolase inhibitors of the Formula (I) are provided, wherein X is NH, CH2, O, or S; Q is O or S; Z is O or N; R is an aromatic moiety selected from the group consisting of substituted or unsubstituted aryl; substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted phenyl; substituted or unsubstituted terphenylyl; substituted or unsubstituted cycloalkyl, heteroaryl, or alkyl; and R1 and R2 are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted phenyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; with the proviso that if Z is O, one of R1 and R2 is absent, and that, if Z is N, optionally R1 and R2 may optionally be taken together to form a substituted or unsubstituted N-heterocycle or substituted or unsubstituted heteroaryl with the N atom to which they are each attached. Pharmaceutical compositions comprising the compounds of Formula (I) and methods of using them to inhibit FAAH and/or treat appetite disorders, glaucoma, pain, insomnia, and neurological and psychological disorders including anxiety disorders, epilepsy, and depression are provided.

https://escholarship.org/content/qt9vp7s85t/qt9vp7s85t.pdf?t=ovhw4w

Modulation of anxiety through blockade of anandamide hydrolysis

Objective. The clock-drawing test has achieved widespread clinical use in recent years as a cognitive screening instrument and a significant amount of literature relates to its psychometric properties and clinical utility. This review aims to synthesize the available evidence and assess the value of this screening test according to well-defined criteria.

Design. A Medline and Psycho-info literature search of all languages was done from 1983 to 1998 including manual cross-referencing of bibliographies. A brief summary of all original scoring systems is provided as well as a review of replication studies. Psychometric data including correlations with other cognitive tests were recorded. Qualitative aspects of the test are also described.

Results. Among published studies, the mean sensitivity (85%) and specificity (85%) of the clock-drawing test are impressive. Correlations with the Mini-Mental State Examination and other cognitive tests was high, generally greater than r = 0.5. High levels of inter-rater and test–re-test reliability and positive predictive value are recorded and despite significant variability in the scoring systems, all report similar psychometric properties. The clock test also shows a sensitivity to cognitive change with good predictive validity.

Conclusions. The clock-drawing test meets defined criteria for a cognitive screening instrument. It taps into a wide range of cognitive abilities including executive functions, is quick and easy to administer and score with excellent acceptability by subjects. Together with informant reports, the clock-drawing test is complementary to the widely used and validated Mini-Mental State Examination and should provide a significant advance in the early detection of dementia and in monitoring cognitive change. A simple scoring system with emphasis on the qualitative aspects of clock-drawing should maximize its utility. Copyright © 2000 John Wiley & Sons, Ltd.

Clock-drawing: is it the ideal cognitive screening test?

• We used positron emission tomography to investigate local cerebral metabolic rates for glucose (LCMRG1c) in patients with obsessive-compulsive disorder before and after treatment with either fluoxetine hydrochloride or behavior therapy. After treatment, LCMRG1c in the head of the right caudate nucleus, divided by that in the ipsilateral hemisphere (Cd/hem), was decreased significantly compared with pretreatment values in responders to both drug and behavior therapy. These decreases in responders were also significantly greater than right Cd/hem changes in nonresponders and normal controls, in both of whom values did not change from baseline. Percentage change in obsessivecompulsive disorder symptom ratings correlated significantly with the percent of right Cd/hem change with drug therapy and there was a trend to significance for this same correlation with behavior therapy. By lumping all responders to either treatment, right orbital cortex/hem was significantly correlated with ipsilateral Cd/hem and thalamus/ hem before treatment but not after, and the differences before and after treatment were significant. A similar pattern was noted in the left hemisphere. A brain circuit involving these brain regions may mediate obsessivecompulsive disorder symptoms.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=PSYCH&articleId=495860&pdfFileName=archpsyc_49_9_002.pdf

Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder.

We have tested a simple and reliable measure of visuospatial ability in Alzheimer patients--the Clock Drawing Test. To determine the usefulness of this measure, we asked 67 Alzheimer patients and 83 normal controls to draw the face of a clock reading the time of 2:45. Six independent observers blindly evaluated the results with ratings from 10 (best) to 1 (worst). The mean performance score of Alzheimer subjects was 4.9 +/- 2.7 compared to 8.7 +/- 1.1 for normal controls (P less than .001). Inter-rater reliability for the clocks drawn by Alzheimer patients was highly significant (r = 0.86; P less than .001), and there was relatively little overlap between ratings for Alzheimer patients and normal controls. Furthermore, correlations were highly significant (P less than .001) between the mean score of clock drawings and three independent global measures of dementia severity. Although the Clock Drawing Test is certainly not a definitive indicator of Alzheimer's disease, the test is easy to administer and provides a useful measure of dementia severity for both research and office settings where sophisticated neuropsychological testing is not available.

Clock drawing in Alzheimer's disease. A novel measure of dementia severity.

• Clomipramine is a potent serotonin reuptake blocker that decreases the symptoms of obsessive-compulsive disorder (OCD). To investigate whether clomipramine treatment in OCD affects brain serotonergic responsiveness, metachlorophenylpiperazine (mCPP), a selective serotonin agonist, and placebo were given under double-blind conditions to nine patients with OCD before and after treatment with clomipramine. Unlike our previous observations of a marked transient increase in obsessional symptoms and anxiety following 0.5 mg/kg of mCPP, readministration of mCPP after four months of treatment with clomipramine did not significantly increase obsessional symptoms and anxiety. Similarly, the hyperthermic effect of mCPP observed before treatment was eliminated after treatment with clomipramine. These findings are consistent with the development of adaptive subsensitivity to the serotonergic agonist mCPP during clomipramine treatment. A similar alteration in the response to endogenous serotonin may mediate clomipramine's antiobsessional effects.

Serotonergic Responsivity in Obsessive-Compulsive Disorder: Effects of Chronic Clomipramine Treatment

Rat pups, while separated from their littermates and placed in a novel environment, emit ultrasonic isolation calls. These ultrasonic calls decrease in number, power, and frequency following administration of the anxiolytic, diazepam (0.5 mg/kg). Pentylenetetrazol (20 mg/kg), which has been reported to be clinically anxiogenic, increases the number and the power of these calls. These changes following diazepam and pentylenetetrazol administration are dose dependent and do not appear to be secondary to nonspecific effects of these drugs on arousal or thermoregulation. The benzodiazepine receptor antagonist RO 15-1788, which has generally been reported to lack intrinsic activity at low doses, also decreases the number of rat pup isolation calls. These findings suggest that the benzodiazepine-GABA receptor-chloride channel complex may play a role in the physiologic mediation of the rat pup isolation call.

Rat pup ultrasonic isolation calls: Possible mediation by the benzodiazepine receptor complex

• Treatment with fluoxetine hydrochloride was compared with treatment with clomipramine hydrochloride in two groups of patients with obsessive-compulsive disorder using two different experimental designs. In the first group of 11 patients with obsessive-compulsive disorder studied using a randomized, doubleblind, crossover design, treatment with fluoxetine for 10 weeks was found to produce therapeutic effects similar to treatment with clomipramine for 10 weeks. There were significantly fewer total side effects reported during fluoxetine than clomipramine treatment. Drug tapering and placebo substitution in the 4-week crossover interval phase led to substantial relapses in obsessive-compulsive disorder symptoms and depression. Furthermore, responses to the second drug took as long to occur as responses to the first drug, although both drugs are thought to act by a common mechanism, serotonin uptake inhibition. A second group of 21 patients with obsessive-compulsive disorder that had been previously stabilized on clomipramine treatmen with at least partial benefit were crossed over to fluoxetine treat ment in a double-blind fashion. After 10 weeks of fluoxetine administration, most patients manifested behavioral rating scores of obsessive-compulsive disorder and depressive symp toms that were comparable with precrossover ratings complete during clomipramine treatment. A significant exacerbation ir obsessive-compulsive disorder and depression ratings as wel as a similar lag in therapeutic efficacy were also noted in this second cohort of patients with obsessive-compulsive disorder Platelet 5-HT concentrations were reduced 95% during both clo mipramine and fluoxetine treatment periods. These results sug gest that fluoxetine may represent a viable alternative to clomip ramine in the treatment of obsessive-compulsive disorder, al though further studies with larger sample sizes are needed.

James L. Hill

Papers

Clock drawing in Alzheimer's disease. A novel measure of dementia severity.

Serotonergic Responsivity in Obsessive-Compulsive Disorder: Effects of Chronic Clomipramine Treatment

Rat pup ultrasonic isolation calls: Possible mediation by the benzodiazepine receptor complex

Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder. Behavioral and biological results.

Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants