Serotonin: Obesity and Depression

Vernon M Neppe MD, PhD, FRCPC, FFPsych, MMed
Director, Pacific Neuropsychiatric Institute, Seattle WA
Adjunct Professor, St. Louis University Dept of Psychiatry

Educational Objectives

1. The development of a broader understanding of why antidepressants succeed and fail when they do and what to do about it.
2. To educate in the area of serotonin in the context of clinical psychiatry.
3. To evaluate the serotonin 2 receptor with regard to management options and problems.
4. To elucidate a role for norepinephrine in relation to serotonin and depression.
5. To establish alternatives for lowering antidepressant side effects and using 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.
7. To elaborate on the basic management of obesity.
8. To discuss the pharmacologic indications for anti-obesity drugs.
9. To analyze the link of serotonin with obesity.
10. To develop a framework for combination anti-depressant / anti-obesity agent use.
11. To discuss the clinical implications with regard to management options and problems.
12. The development of a broader theory of innovative psychopharmacotherapy.

The current perspectives on depression and anxiety and the entity of mixed anxiety depression are reviewed. 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.

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. This paper examines theoretical and practical options using combination serotonin antidepressant therapy and then looks at new single drug approaches as well as links with obesity.

A broader theory of management of depressed and obese patients can be developed with the understanding of concepts such as neuromodulation, partial agonism and the serotonin bathtub analogy in depression. 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 pituitary 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.

Drug action at the serotonin 1A receptor subtype is particularly important. It involves post-synaptic effects in areas of the brain of strategic relevance to psychopathology. The azapirone class generally has apparent low toxicity, lack of dependency and sedation and selectivity at the Serotonin 1 A receptor with partial agonism making their potential application in psychiatry substantial. The only marketed 5HT-1A selective drug is the azapirone, buspirone (approved for use only in anxiety and mixed anxiety depressive states). However, clinical experience in several other areas is interesting but still at various early research stages. Serotonin re-uptake inhibitors like fluoxetine induce a serotonergic akathisia which can be blocked by buspirone. When SSRI compounds stop working with re-exacerbation of depression, adjunctive use of azapirones may theoretically extend their action. High therapeutic azapirone doses may also imply some modulation of obsessionality and weak antidepressant effects. The numerous antidepressant compounds are evaluated for side-effect profile with emphasis on serotonin excess symptoms.

The classic bathtub example relates to the serotonin re-uptake inhibitor drugs with their in general unopposed effect of raising serotonin levels: this is useful in treating a biological depression with ostensible serotonin deficiency. The model is simplistic because there are numerous receptor subtypes. Serotonin 2A receptor subtype is relevant as blockade appears to be linked with anti-depressant effects. The links of sexual libidinal and other side-effects, nausea, akathisia, anxiety, agitation, insomnia and headache may potentially be modulated by the serotonin excess induced by the SSRI drugs. Potentially drugs which have more moderate effects on serotonin re-uptake could diminish these effects, particularly if they have some serotonin blockade at relevant receptors such as 2A.

The unopposed action of serotonin without norepinephric effects in depression as in the classical SSRI model is examined and alternatives such as venlafaxine which involves both receptors. The limitations of this approach may relate to the dilemma of unopposed action or modulation. In this regard the development of a new antidepressant, nefazodone, theoretically is an exciting advance as modulation not bathtub filling can occur at both these receptor levels but predominantly at the serotonergic level. This should produce theoretically efficacy with less "overfilling" side-effects. Its bathplug effects such as substantial serotonin 2 A blockade produce the potential towards anti-anxiety action in the context of depression as well as some sedation implying applicability for the agitated depressed patient.

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.

Obesity, like depression, is an extremely important and common epidemiologic condition. Overweight requires pointers as to the point when to pharmacologically intervene e.g. 20% above ideal body weight or Body Mass Index of > 27-30. Such pharmacological interventions are logical as morbidity and mortality statistics support use of the anorexigenic agents always combined with the necessary elements of calorie control, activity and change in eating habits. Such prescriptions will lower the overall risks more than the triad management of pure diet, exercise and behavioral interventions without drugs.

The link of serotonin receptors with appetite, craving and weight control is also important. Serotonin blocking agents such as cyproheptadine characteristically have been associated with weight gain and several antidepressant compounds such as the SSRI group and trazodone have at times been used in weight reduction although their effect is unpredictable. The exact receptor subtypes involved and mechanisms e.g. agonism or antagonism for weight control is unclear. Such data is confounded by approximately one third of patients with obesity having significant depressive disorder.

The development of anti-obesity agents such as dexfenfluramine have raised fascinating serotonergic links for both appetite suppression and selective carbohydrate craving and have markedly diminished the risks of the norepinephric / amphetamine like effects of previous compounds. Dexfenfluramine is the active isomer of fenfluramine meaning that half the dose previously required can be taken with the same effect and without the extra side-effects of the levo-fenfluramine. Unfortunately, these two drugs have been withdrawn from the USA and possibly other markets because of questions pertaining to heart valve lesions which may or may not be linked.

Because receptor subtype effects have not been well-studied the interaction of serotonin active drugs is complex and at times unclear. There are however good theoretical pointers suggesting reduced dosage with cautious combination use only with the shorter acting antidepressants that do not overflow the serotonergic bathtub but which may have significant norepinephric effects.