TV 3326 for Alzheimer's dementia: a novel multimodal ChE and MAO inhibitors to mitigate Alzheimer's-like neuropathology.

OBJECTIVES: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and a well-recognized cause of dementia with ageing. In this review, we have represented the ChE and MAO inhibitory potential of TV 3326 against AD based on current scientific evidence. KEY FINDINGS: The aetiology of AD is quite complex and not completely understood. However, it has been observed that AD involves the deposition of abnormal amyloid beta (Aß), along with hyperphosphorylation of tau, oxidative stress, low acetylcholine (ACh) level and biometal dyshomeostasis. Due to the complex nature of AD aetiology, active research is required in the areas of development of multitarget drugs with 2 or more complementary biological functions, as they might represent significant progress in the AD treatment. Interestingly, it has been found that TV 3326 (i.e. ladostigil) is regarded as a novel therapeutic agent since it has the potential to cause inhibition of monoamine oxidase (MAO) A and B, and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain. Furthermore, it has the capacity to reverse memory impairments, which further suggests the ability of this drug to elevate cholinergic activity in the brain. SUMMARY: TV 3326 can avert oxidative-nitrative stress and gliosis. It has also been confirmed that TV 3326 contains neuroprotective and anti-apoptotic properties. Therefore, this distinctive combined inhibition of ChE and MAO along with its neuroprotective property makes TV 3326 a useful drug in the treatment of AD.

Patients on psychotropic medications and herbal supplement combinations: clinical considerations.

Populations using herbs and herbal preparations are widespread and growing. As many herbal ingredients exert actions on psychotropic drug targets, psychiatrists should be well informed and aware of potential drug-drug interactions in clinical practice. Reliable and clinically useful information in this area, however, is fragmented, if not deficient. This paper reviewed the clinical aspects of herb-drug interactions, focusing in particular on the monoamine oxidase enzyme and P450 cytochrome enzyme-inhibitory properties of herbs and their potential interference with psychotropic drug actions and clinical judgement.

[Atypical depression: Clinical perspectives]. / La dépression atypique : perspectives cliniques.

OBJECTIVE: This paper examines whether atypical depression is still a valid entity as a diagnosis subtype in the light of publications with most recent antidepressants. METHOD: First, we present the origins of the diagnosis sub-specification of atypical depression, which is based on a different drug response to tricyclic antidepressants and mono amino oxydase inhibitors. Secondly, we discuss the different definitions that can be found for the terms of atypical depression. We present more specifically the definition of atypical depression as it is described in the DSM-IV, with its most important criterion: mood reactivity. Then we present a review of scientific publications questioning atypical depression validity as a clinical syndrome (based on medline researches). We will see whether this diagnosis is still relevant with the latest drugs used to treat mood disorders. A special focus is made on the link between atypical depression and bipolar disorder, based on Benazzi's work. RESULTS: Most of publications confirm that atypical depression is a valid syndrome regarding first antidepressants clinical trials. Nevertheless, more studies with the latest antidepressants and atypical antipsychotics are needed to confirm this hypothesis. The link between atypical depression and bipolar disorders seems to be quite strong although it requires further investigations. DISCUSSION: There are very few double-blind drug trials focusing on atypical depressions and results need to be confirmed by trials with new drugs. Moreover, we regret that there are no studies including cerebral imagery. More studies are also needed on neurobiology and psychotherapy specificity. CONCLUSION: Atypical depression is still a useful concept, because of its specific clinical presentation, evolution and treatments, even if more studies should be done. Atypical depression could also be useful to diagnose more easily some bipolar disorders and should help clinicians to focus more on suicidal risks and addiction evaluation for these patients, considering the mood reactivity and the link with bipolar disorder. To conclude, we propose that atypical depression should still figure in the future DSM-V for these different reasons.

CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model.

UNLABELLED: CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate. PERSPECTIVE: This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.

Serotonin syndrome: a reported case.

We describe a patient treated with SSRI and Ldopa, who developed agitation, rigidity, hyperreflexia, restlessness, autonomic instability, fever and finally death. CSF examination, MRI of the brain, laboratory investigations, except for serum CK, glycemia and WBC, were normal. His condition was thought to result from an central serotonin activity. The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan alone or in combination with monoamine oxidase inhibitors).

A systematic review of newer pharmacotherapies for depression in adults: evidence report summary.

BACKGROUND: Depressive disorders are persistent, recurring illnesses that cause great suffering for patients and their families. PURPOSE: To evaluate the benefits and adverse effects of newer pharmacotherapies and herbal treatments for depressive disorders in adults and adolescents. DATA SOURCES: English-language and non-English-language literature from 1980 to January 1998 was identified from a specialized registry of controlled trials, meta-analyses, and experts. STUDY SELECTION: Randomized trials evaluating newer antidepressants (such as serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and St. John's wort) that reported clinical outcomes were selected. DATA EXTRACTION: Two persons independently abstracted data that were then synthesized descriptively; some data were pooled by using a random-effects model. DATA SYNTHESIS: Of 315 eligible trials, most evaluated antidepressants in adults with major depression, were conducted among outpatients, and examined acute-phase treatment. Newer antidepressants were more effective than placebo for major depression (relative benefit, 1.6 [95% CI, 1.5 to 1.7]) and dysthymia (relative benefit, 1.7 [CI, 1.3 to 2.3]). They were effective among older adults and primary care patients. Efficacy did not differ among newer agents or between newer and older agents. Hypericum (St. John's wort) was more effective than placebo for mild to moderate depression (risk ratio, 1.9 [CI, 1.2 to 2.8]), but publication bias may have inflated the estimate of benefit. Newer and older antidepressants did not differ for overall discontinuation rates, but side effect profiles varied significantly. Data were insufficient for determining the efficacy of newer antidepressants for subsyndromal depression, depression with coexisting medical or psychiatric illness, or depression in adolescents. CONCLUSIONS: Newer antidepressants are clearly effective in treating depressive disorders in diverse settings. Because of similar efficacy, both newer and older antidepressants should be considered when making treatment decisions. Better information is urgently needed on the efficacy of newer antidepressants in patients with nonmajor depression and in special populations, including adolescents.

St. John's wort: a new alternative for depression?

OBJECTIVE: The primary purpose of this article is to review the existing literature concerning the therapeutic uses, adverse effects, and possible drug interactions of St. John's wort (Hypericum perforatum) as compared to other antidepressant medications. METHODS: Reference material was obtained through database searches with time restrictions of 1985 to the present. Studies selected were those written in the English language which compared the role of St. John's wort, tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin-selective reuptake inhibitors in the treatment of depression. Other studies were selected based on their evaluation of the safety and efficacy of St. John's wort as an antidepressant for a minimum of four weeks. RESULTS: A review of existing literature recognized nine clinical trials that reported the efficacy of St. John's wort as compared to placebo and to other antidepressant medications. Of these nine, four controlled studies were chosen based upon their large patient populations and their consistency in brand and dosage of St. John's wort used. These four studies demonstrated that St. John's wort was as effective as other antidepressant medications and more effective than placebo, as the clinical symptoms of depression greatly decreased upon administration of H. perforatum. The side-effect profile of H. perforatum at this time appears to be superior to any current U.S.-approved antidepressant medication. CONCLUSIONS: From the existing literature, St. John's wort appears to be a safe and effective alternative in the treatment of depression. Tricylic antidepressants and monoamine oxidase inhibitors can produce serious cardiac side-effects, such as tachycardia and postural hypotension, and many unwanted anticholinergic side-effects, including dry mouth and constipation. St. John's wort has proven to be free of any cardiac, as well as anticholinergic, side-effects normally seen with antidepressant medications. Based upon limited studies, St. John's wort appears to be an acceptable alternative to traditional antidepressant therapy, although trials on a larger scale are warranted in this area. Hypericum is available to the lay public as an over-the-counter preparation and may be misused if not fully understood.

A risk-benefit assessment of pharmacological treatments for panic disorder.

Panic disorder, a psychiatric disorder characterised by frequent panic attacks, is the most common anxiety disorder, affecting 2 to 6% of the general population. No one line of treatment has been found to be superior, making a risk-benefit assessment of the treatments available useful for treating patients. Choice of treatment depends on a number of issues, including the adverse effect profile, efficacy and the presence of concomitant syndromes. Tricyclic antidepressants (TCAs) are beneficial in the treatment of panic disorder. They have a proven efficacy, are affordable and are conveniently administered. Adverse effects, including jitteriness syndrome, bodyweight gain, anticholinergic effects and orthostatic hypotension are commonly associated with TCAs, but can be managed successfully. Selective serotonin (5-hydroxytryptamine; 5HT) reuptake inhibitors are also potential first line agents and are well tolerated and effective, with a favourable adverse effects profile. There is little risk in overdose or of anticholinergic effects. Adverse effects include sedation, dyspepsia and headache early in treatment, and sexual dysfunction and increased anxiety, but these can be effectively managed with proper dosage escalation and management. Benzodiazepines are an effective treatment, providing short-term relief of panic-related symptoms. Patients respond to treatment quickly, providing rapid relief of symptoms. Adverse effects include ataxia and drowsiness, and cognitive and psycho-motor impairment. There are reservations over their first-line use because of concerns regarding abuse and dependence. Monoamine oxidase inhibitors, because of their adverse effects profile, potential drug interactions, dietary restrictions, gradual onset of effect and overdose risk, are not considered to be first-line agents. They are effective however, and should be considered for patients with refractory disease. Valproic acid (valproate sodium), while not intensively studied, shows potential for use in panic disorder. More studies are needed in this area before the available data can be confirmed. As a supplement to drug therapy, cognitive behavioural therapy is effective. It is well tolerated, and may be beneficial in certain clinical situations. Its main drawback is the time commitment and effort needed to be made by the patient.

Are metabolites of l-deprenyl (selegiline) useful or harmful? Indications from preclinical research.

A frequent topic of controversy has been whether metabolism of l-deprenyl (selegiline) to active metabolites is a detriment to clinical use. This paper reviews possible roles of the metabolites of l-deprenyl in producing unwanted adverse side effects or in augmenting or mediating its clinically useful actions. Levels of l-amphetamine and l-methamphetamine likely to be reached, even with excessive intake of l-deprenyl, would be unlikely to produce neurotoxicity and there is no preclinical or clinical evidence of abuse liability of l-deprenyl. In contrast, there is evidence that l-amphetamine and l-methamphetamine have some qualitatively different actions than their d-isomer counterparts on EEG and cognitive functioning which might result in beneficial clinical effects and complement beneficial clinical actions of l-deprenyl itself.

Salvia divinorum and salvinorin A: new pharmacologic findings.

The diterpene salvinorin A from Salvia divinorum (Epling and Jativa-M), in doses of 200-500 micrograms produces effects which are subjectively identical to those experienced when the whole herb is ingested. Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity. Traditionally the herb is consumed either by chewing the fresh leaves or by drinking the juices of freshly crushed leaves. The effects of the herb when consumed this way depend on absorption of salvinorin A through the oral mucosa before the herb is swallowed.

Treatment of winter depression in Norway. II. A comparison of the selective monoamine oxidase A inhibitor moclobemide and placebo.

Thirty-four patients with seasonal affective disorder, winter depression type (WD) were randomly distributed to receive the selective monoamine oxidase-A inhibitor moclobemide (400 mg daily) or placebo in a double-blind, parallel group study lasting for up to 14 weeks. Severity measures were the Montgomery-Asberg Depression Rating Scale (MADRS) extended with characteristic symptoms of WD; summed score of the "atypical" symptoms hypersomnia, hyperphagia and carbohydrate craving; and Clinical Global Impressions (CGI). After 3 weeks, patients with unsatisfactory response were switched to open moclobemide. Three patients on placebo dropped out before 3 weeks. Extended MADRS and CGI showed no significant difference between the groups at 3 weeks, whereas the atypical score was reduced significantly more on moclobemide than on placebo already after one week. Nonresponders after 3 weeks (9 of 16 on moclobemide and 7 of 15 on placebo) improved rapidly after being given open moclobemide. Predictor analysis showed a remarkably high negative correlation between improvement at 3 weeks (extended MADRS) and age in the placebo group and a strong, nonsignificant trend in the same direction in the moclobemide group. Dichotomizing the patients according to the median age (45 years) resulted in a somewhat better effect of moclobemide than placebo in the older age group. There were no significant differences in side effects between moclobemide and placebo.

Contraindications to vasoconstrictors in dentistry: Part III. Pharmacologic interactions.

This article discusses the relative contraindications to the use of vasoconstrictor in patients currently medicated with tricyclic antidepressants, monoamine oxidase inhibitors, phenothiazines and beta-blockers. It reviews drug interactions and emphasizes potential detrimental systemic effects that epinephrine contained in local anesthetics can have when administered concomitantly with these drugs. Finally, special considerations are expressed concerning patients who abuse illicit drugs such as cocaine.