Neal R. Cutler

Positron emission tomography in Alzheimer's disease

Twenty-one patients with a clinical diagnosis of dementia of the Alzheimers type (DAT) and 29 healthy, age-matched controls were studied using positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose to measure regional cerebral glucose consumption in the resting state. Reductions in ratio measures of relative metabolism in some parietal, temporal, and frontal regions were found in mild, moderate, and severe DAT groups. A significant increase in right/left metabolic asymmetry, particularly in parietal regions, also was seen in mild and moderate groups. Only in the severely demented patients was the absolute cerebral metabolic rate reduced significantly from control values. Fourteen patients had repeated PET studies, but only those patients with moderate to severe dementia showed a decline in IQ over 6 to 15 months. There were no significant changes in metabolic measures over time. PET is useful in quantifying regional cerebral dysfunction in DAT, even in the early stages of the disease.

Relations between Neuropsychological and Cerebral Metabolic Asymmetries in Early Alzheimer's Disease

Regional CMRglc (rCMRglc) values were determined with positron emission tomography (PET) in 10 patients with mild to moderate clinically diagnosed Alzheimers disease (AD) and in 26 healthy controls. rCMRglc in frontal, parietal, and temporal association cortices were significantly more laterally asymmetrical in AD patients than in controls (p < 0.05). Furthermore, lateral asymmetry of rCMRglc in AD patients but not in the control subjects correlated significantly with asymmetry of language and visuospatial functions such that lower left than right rCMRglc was associated with relatively greater impairment of language and vice versa. The results demonstrate that discrepancies between language and visuospatial deficits in patients with early AD are related to asymmetrical reductions in cerebral cortical glucose metabolism.

A Randomized Evaluation of the Effects of Six Antipsychotic Agents on Qtc, In the Absence and Presence of Metabolic Inhibition

Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.

Cholinesterase Inhibitors: A Therapeutic Strategy for Alzheimer Disease

OBJECTIVE: To provide a review of acetylcholinesterase inhibitors (AChEIs) tested as therapeutic agents for Alzheimer disease (AD). DATA SOURCES: MEDLINE searches (January 1986–July 1998) identified pertinent literature. Selected references from these articles, as well as abstracts from recent meetings and package insert literature from approved compounds, were also used as source material. DATA EXTRACTION: AChEIs were reviewed with regard to chemical structure, mechanism of inhibition, substrate specificity, pharmacokinetics/pharmacodynamics, safety/tolerability, and efficacy. DATA SYNTHESIS: Cholinergic deficits, leading to cognitive impairment, are a significant aspect of neurodegeneration in AD. AChEIs reduce the degradation of acetylcholine, thus enhancing cholinergic transmission. In addition to the two agents approved by the Food and Drug Administration, tacrine and donepezil, six other compounds of diverse chemical structure and mechanism of inhibition including physostigmine, metrifonate, rivastigmine, and galantamine are under investigation as potential therapy for AD. These compounds are structurally diverse, possess unique patterns of specificities for the various forms of cholinesterase enzymes, use distinct mechanisms of enzyme inhibition, present unique adverse event profiles, and offer relatively similar mean gains in cognitive abilities to patients with AD in controlled clinical trials. CONCLUSIONS: Relative to placebo, new AChEIs in development provide modest improvements in cognition for patients with mild to moderate AD, with improved tolerability profiles and more convenient dosing relative to tacrine. The availability of a wide array of AChEIs soon to be accessible to patients with AD will provide additional options to those who cannot tolerate or do not respond to drugs currently used for AD.

Review of the acetylcholinesterase inhibitor galanthamine

Galanthamine (or galantamine, Reminyl®) is a tertiary alkaloid acetylcholinesterase inhibitor (AChEI) which has been approved in several countries for the symptomatic treatment of senile dementia of the Alzheimer’s type. Derived from bulbs of the common snowdrop and several Amaryllidaceae plants, (-)-galanthamine (GAL) has long been used in anaesthetics to reverse neuromuscular paralysis induced by turbocurarine-like muscle relaxants and more recently, has been shown to attenuate drug- and lesion-induced cognitive deficits in animal models of learning and memory. GAL directly inhibits acetylcholinesterase activity, while demonstrating much weaker activity on butyrylcholinesterase (BuChE). GAL also stimulates pre- and postsynaptic nicotinic receptors, although the clinical significance of this finding is yet unclear. Numerous variants and analogues of GAL have also been developed, with varying potency in inhibiting AChE activity. GAL is readily absorbed after oral administration, with a tmaxof 52 min and a plasma elimination t½ of 5.7 h. The efficacy of GAL administered to Alzheimer’s disease (AD) patients has been well demonstrated by large-scale clinical trials. Typical of AChEIs, the most common adverse events associated with GAL are nausea and vomiting. In conclusion, evidence to date suggests galanthamine to be similar to other AChEIs in improving cognitive function in AD patients.

Rizatriptan (MAXALT) for the Acute Treatment of Migraine and Migraine Recurrence. A Placebo‐Controlled, Outpatient Study

Rizatriptan is a novel 5‐HT1B/1D agonist which is rapidly absorbed after oral administration. The efficacy and tolerability of oral rizatriptan (5 mg and 10 mg) were examined in this multicenter, double‐blind, outpatient study of 1473 migraineurs which featured randomized, placebo‐controlled treatment of migraine recurrences. On experiencing moderate or severe migraine headaches, patients rated headache severity prior to dosing and at 30‐minute intervals for 2 hours after dosing. Onset of effect was seen as early as 30 minutes after dosing with rizatriptan 10 mg. At 2 hours postdose, the percentage of patients with pain relief was significantly higher after rizatriptan 5 mg (62%) or 10 mg (71%) compared with placebo (35%). Complete relief was also significantly higher after rizatriptan 5 mg (33%) and 10 mg (42%) compared with placebo (10%). In patients experiencing headache recurrence after initial benefit, further relief was obtained in 71% with rizatriptan 5 mg (placebo 54%) and in 82% with rizatriptan 10 mg (placebo 44%). Complete relief of recurrent headache was obtained in 36% with rizatriptan 5 mg, 49% with rizatriptan 10 mg, and 15% with placebo (P<0.05). The most common drug‐related adverse experiences were dizziness, somnolence, asthenia/fatigue, and nausea (the incidences of which were low and dose related). There was no increase in the incidence of adverse experiences after use of up to three doses of rizatriptan within 24 hours. We conclude that both doses of rizatriptan are effective and well tolerated in the acute treatment of migraine and migraine recurrence, with the l0‐mg dose preferred as it is more effective with a faster onset of action.

Gender Differences in Depression and Antidepressant Pharmacokinetics and Adverse Events

OBJECTIVE: To review data generated by studies examining gender differences in the prevalence of depression, as well as in antidepressant pharmacokinetics, pharmacodynamics, and adverse events. DATA SOURCES: Published articles and abstracts were identified through MEDLINE (January 1966–April 1999) using the following search terms: antidepressant, response, gender, pharmacokinetic, pharmacodynamic, female, side effect, and adverse events. All articles that assessed gender differences in antidepressant response, pharmacokinetics, and adverse events, as well as articles that evaluated postulated mechanisms for these differences, were reviewed. Additional articles were identified from bibliographies of retrieved articles. STUDY SELECTION AND DATAEXTRACTION: All relevant abstracts, studies, and review articles were evaluated. DATA SYNTHESIS: Gender differences in the prevalence of depression have been reported and may result from the interaction of several factors. Women have been shown to have a higher incidence of depression, which may be due to artifact, social, or biologic reasons. Studies suggest that the pharmacokinetic disposition of popular antidepressants varies between men and women, and women taking antidepressants may exhibit a different adverse event profile. Only one study specifically evaluated gender differences in antidepressant treatment response. CONCLUSIONS: Further research elucidating gender differences in response to antidepressant treatment and on depression prevalence is needed. Some studies report that the pharmacokinetics of antidepressants may vary between men and women. Therefore, clinicians should be aware that potential differences in antidepressant pharmacokinetics may exist, and a dosage adjustment may be necessary for women to ensure a favorable drug response, compliance, and decreased incidence of adverse events.

Pharmacokinetics and Pharmacodynamics of the Triptan Antimigraine Agents A Comparative Review

The current approach to antimigraine therapy comprises potent serotonin 5-HT1B/1D receptor agonists collectively termed triptans. Sumatriptan was the first of these compounds to be developed, and offered improved efficacy and tolerability over ergot-derived compounds. The development of Sumatriptan was quickly followed by a number of ‘second generation’ triptan compounds, characterised by improved pharmacokinetic properties and/or tolerability profiles. Triptans are believed to effect migraine relief by binding to serotonin (5-hydroxy-tryptamine) receptors in the brain, where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation.Although the pharmacological mechanism of the triptans is similar, their pharmacokinetic properties are distinct. For example, bioavailability of oral formulations ranges between 14% (sumatriptan) and 74% (naratriptan), and their elimination half-life ranges from 2 hours (sumatriptan and rizatriptan) to 25 hours (frovatriptan). Clearly, such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations. This article reviews the pharmacological properties of the triptans (time to peak plasma concentration, half-life, bioavailability and receptor binding) and relates these properties to efficacy and time of onset. It also considers the effects of concomitant medication, food, age and disease on the pharmacokinetics of the compounds. In addition, the relative merits, such as headache recurrence, tolerability and route of administration, are discussed. Finally, the performance of the triptans is considered in the context of direct head-to-head comparative trials that have assessed the efficacy profile of the compounds.

Generalised Anxiety Disorder

In recent years generalised anxiety disorder (GAD) has become a much better defined disorder, with specific criteria distinguishing it from the other anxiety disorders; however, it still lacks the same public and scientific interests as some of the other anxiety disorders such as panic and social phobia. Nevertheless, refinement in the treatment of GAD is becoming more evident through the conduct of clinical trials.Up until the mid-1980’s, treatment consisted primarily of benzodiazepines. However, as a result of growing characterisation of their abuse potential, other therapeutic options were explored. Benzodiazepines became seen as an effective short-term therapy, and buspirone and some of the newer antidepressants have become the treatment of choice for patients with GAD requiring long-term treatment.Buspirone was the first available alternative to the benzodiazepines in the US; however, the initial excitement over this agent was somewhat dampened because of its mild efficacy combined with a slow onset of action. The antidepressants were seen as beneficial for the treatment of GAD because of the high comorbidity with depression, thus allowing a better outcome for these patients. The antidepressants that offer both a good adverse effect profile and efficacy are the selective serotonin reuptake inhibitors including paroxetine, and the serotonin-norepinephrine reuptake inhibitors such as venlafaxine. Clinicians should also consider the potential benefits of psychotherapy as an adjunct to medication.There are a number of potentially new pharmacotherapies being investigated, including newer serotonin 5-HT1A receptor agonists, cholecystokinin receptor antagonists, neurokinin receptor antagonists, gabapentin and its analogues, and γ-aminobutyric acid (GABA)A receptor modulators. However, these compounds are all in the early stages of investigation, and there are no new therapies expected to be released in the near future. Nonetheless, in the search for the ideal anxiolytic, a more positive outlook is allowed by imminent future research for new treatment options in patients with GAD.

Ethnicity and Antipsychotic Response

OBJECTIVE: To review the data generated by studies examining interethnic/racial differences in response to antipsychotics. DATA SOURCES: A MEDLINE search (1966-19%) identified all articles examining differences in antipsychotic response among Caucasians, Asians, Hispanics, and African-Americans, as well as articles evaluating postulated mechanisms for these differences. STUDY SELECTION: All abstracts, studies, and review articles were evaluated. DATA SYNTHESIS: Ethnic/racial differences in response to antipsychotic medications have been reported and may be due to genetics, kinetic variations, dietary or environmental factors, or variations in the prescribing practices of clinicians. Studies suggest that Asians may respond to lower doses of antipsychotics due to pharmacokinetic and pharmacodynamic differences. Research relevant to African-Americans is limited, but some studies suggest that differences in this group may be due to clinician biases and prescribing practices, rather than to pharmacokinetic or pharmacodynamic variability. CONCLUSIONS: Future research directed at validating the hypotheses that different ethnic/racial groups show variations in response to antipsychotics should focus on homogenous ethnic groups, use recent advances in pharmacogenetic testing, and control for such variables as observer bias, gender, disease chronicity, dietary and environmental factors, and exposure to enzyme-inducing and -inhibiting agents. Clinicians should be aware that potential interethnic/racial differences in pharmacodynamics and pharmacokinetics may exist that can alter response to antipsychotics.