Modern Frameworks for the Management of Depression: the New Antidepressants

Vernon M Neppe MD, PhD

Educational Objectives

1. To educate in the area of depression and anxiety and to demonstrate areas of similarity and differences.
2. To discuss the clinical implications with regard to management options and problems.
3. The development of a broader theory of innovative psychopharmacotherapy and the understanding of concepts such as neuromodulation and partial agonism.
4. To educate in the area of serotonin re-uptake inhibition and the partial agonists in the of clinical psychiatry context.
5. To discuss the clinical and theoretical frameworks for enhancing the effects of SSRIs in cases of clinical refractoriness and side-effects.
6. To develop a profile of the ideal antidepressant compound based on a pharmacologic model.

Abstract

The current perspectives on depression and anxiety and the entity of mixed anxiety depression are reviewed. Depression and anxiety manifestations are differentiated but they strongly overlap. We review special perspectives viewed along the frameworks of somatic and psychic anxiety, and cognitive and vegetative features of depression. Specialized groups such as addicts, medically ill and geriatric patients, have their own particular problems - relevant aspects are examined in the pharmacologic context. Special subdivisions lead to a more fruitful approach as to the patient’s pharmacologic needs. Legitimate approaches are examined.

The numerous antidepressant compounds are evaluated for side-effect profile with emphasis on serotonin excess symptoms. Serotonin modulates many basic functions at a large number of levels allowing explanations of why its influences are so diverse. In fact, it impacts at physiologic (circadian rhythms, hypothalamic pitutiuary function, temperature), behavioral (aggression, weight, sex, sleep) and psychological (anxiety, depression, obsessionality, stress, memory, lability) levels. The numerous serotonin receptor subtypes and specificity is critical to appreciating why drugs work and fail and why such paradoxic reactions as anxiety or anti-anxiety effects may occur with the same drug in different patients.

Three clinical scenarios relate to patients who fail treatment after receiving selective serotonin re-uptake inhibitor drugs. Acutely, they may experience the "I'm climbing out of my skin" feeling; more chronically over several weeks the "It's not working anymore" complaint; and over many months an "It worked so well before" amazement. Psychopharmacology is rapidly approaching the age of specialized receptorology and serotonin subtypes play a major role in management of both anxiety and depression. A broader theory of management of such patients can be developed with the understanding of concepts such as neuromodulation, partial agonism and the serotonin bathtub analogy. Serotonin modulates many basic functions at a large number of levels allowing explanations of such conundrums as the delayed effects of antidepressants. Finally receptor specificity is critical to appreciating why drugs work and fail. Drug action at the serotonin 1A receptor subtype is particularly important. Theoretical and practical options using combination serotonin antidepressant therapy are still at various early research stages, such as fluoxetine induced serotonergic akathisia which can be blocked by buspirone; or when SSRI compounds stop working with re-exacerbation of depression, adjunctive use of azapirones may theoretically extend their action.

The advent of the azapirones and the new antidepressants such as nefazodone and venlafaxine has been a significant advance and may exemplify the neuromodulating roles played by varying doses of drug impinging on a specific receptors and the balance of blockade and re-uptake inhibition at serotonin and norepinephrine levels. Nefazodone and venlafaxine are examined as the new post-SSRI era drugs and fruitful alternatives to the SSRIs.