Involvement of the central serotonergic system in affective illness.
01 Jul 1981-Journal of Clinical Psychopharmacology (J Clin Psychopharmacol)-Vol. 1, Iss: 4, pp 232-237
TL;DR: The authors conclude that the function of the brain serotonergic system in patients with affective disorders is relatively unexplored and would be a fruitful area of study for both the clinician and researcher.
Abstract: This paper reviews the neuroanatomy and neuropharmacology of the central serotonergic system. Clinical evidence implicating altered serotonergic function in patients with affective disorders is summarized, as are the attempts to uncover central serotonergic dysfunction in these patients using pharmacological challenges. The authors conclude that the function of the brain serotonergic system in patients with affective disorders is relatively unexplored and would be a fruitful area of study for both the clinician and researcher.
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TL;DR: The results suggest that the central serotonergic system is less responsive in depressed patients than controls, and fenfluramine, a serotonin releasing agent, was administered to 18 depressed patients and 10 controls.
243 citations
TL;DR: An alternative hypothesis (the "ven disorder" hypothesis) is presented, suggesting the possibility that tricyclic and other antidepressant-responding patients have a core disorder with common psychobiologic abnormalities but multiple clinical and diagnostic presentations.
Abstract: Murphy, Dennis L., Larry J. Siever and Thomas R. Insel: Therapeutic responses to tricyclic antidepressants and related drugs in non-affective disorder patient populations. Prog. Neuropsychopharmacol. and Biol. Psychiat. 1985, 9 (1): 3–13. 1. 1. Although therapeutic responsiveness to tricyclic antidepressants has been primarily associated with the affective disorders, clinical investigations in the last decade have suggested that non-affective disorders such as panic disorder, obsessive-compulsive disorder, anxiety disorder, bulimia, eneuresis, migraine, and the chronic pain syndrome may also respond to tricyclics and other antidepressants. 2. 2. This therapeutic responsiveness may sometimes be related to improvement in secondary depressive symptoms, but may also clearly occur in the absence of secondary depression; in particular, improvement in the core symptoms of at least some of these disorders may occur without a change in mood. 3. 3. Furthermore, many patients with these disorders display psychobiologic abnormalities that show many similarities, but also some differences, compared to those observed in patients with affective disorders, despite the frequent absence of affective symptoms. 4. 4. While an improvement in subclinical or “masked” depression remains one hypothesis linking tricyclic responsiveness and shared biological abnormalities in this diverse group of diagnostic entities, an alternative hypothesis (the “ven disorder” hypothesis) is presented, suggesting the possibility that tricyclic and other antidepressant-responding patients have a core disorder with common psychobiologic abnormalities but multiple clinical and diagnostic presentations. 5. 5. An alternative hypothesis (the “shotgun” hypothesis) suggests that the multiple actions of tricyclics (e.g. on adrenergic receptors vs. muscarinic receptors vs. serotonin system changes) may each be differentially important in the therapeutic outcome in patients with specific or predominant problems in one or another of these areas.
30 citations
TL;DR: It is suggested that when used acutely Fen can mimic long-term antidepressant effects, whereas the acute effects of Dex are similar to its stimulating effects in normals.
12 citations
Cites background from "Involvement of the central serotone..."
...Evidence against this hypothesis comes from Murphy et al. (1978) who reported that a single dose of 60 mg Fen had no antidepressant effects in depressed patients....
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01 Jan 1984
TL;DR: Sabelli and associates have proposed to extend Dale’s principle as follows: Each neuron releases at all its endings the same transmitter and metabolically related co-transmitters, and contains the same receptors throughout its surface membrane.
Abstract: There is an extensive body of indirect evidence from animal studies which indicates that the “biogenic amines” act as central nervous system (CNS) neurotransmitters, particularly in critical integrative brain pathways. The catecholamines (CA) norepinephrine (NE) and dopamine (DA), the indoleamine (IA) serotonin (5-HT), and the quaternary alkyl-amine acetylcholine (ACh) are the brain amines on which most interest has been focused. In addition, the brain has also been found to contain and form other adrenergic amines, such as phenylethylamine (PEA) and octopamine, and indoleamines such as tryptamine, etc. One or more of these amines may act as co-transmitters, modulators, or regulators of synaptic transmission mediated by chemically related transmitters. Thus, tryptamine may be a modulator of serotonergic synapses [1] and PEA may be a modulator of CA synapses [1,2], as evidenced by studies on the ocular sympathetic system [3]. Octopamine appears to be co-transmitter in sympathetic nerves [4]. Based on the metabolic and functional unity of the neuron [5], Dale [6] proposed that a neuron releases the same transmitter at all its endings. Although Dale’s law has been interpreted to mean that there is only one transmitter, this latter assumption does not appear to hold true. Sabelli and associates [7] have thus proposed to extend Dale’s principle as follows: Each neuron releases at all its endings the same transmitter and metabolically related co-transmitters, and contains the same receptors throughout its surface membrane. In addition, there may be cells which contain the metabolic machinery for producing more than one family of transmitters; for instance, sympathetic neurons contain not only CA and metabolically related amines (octopamine, PEA) but also ACh [7–12] and possibly histamine [7,12,13]. Thus, we may have to allow for complex interactions at the synapse. One biogenic amine may affect the metabolism or levels of another, and there may be complex interactions between monoaminergic systems and other neurotransmitters or neuromodulator systems.
3 citations
TL;DR: Monoamine oxidase inhibitors (MAOIs) investigations indicate greater anti-depressant efficacy for (+)-tranylcypromine, the more potent MAOI, than for the (-) isomer, a more effective uptake inhibitor.
Abstract: Publisher Summary This chapter discusses the objectives to develop new anti-depressant drugs with fewer side effects and a rapid onset of action. Tricyclic compounds with antidepressant activity (TCAs), their therapeutic utility, biology, metabolism, and side effects also combined TCA-antipsychotic therapy was investigated. The influence of the seven-membered ring conformation of “6-7-6” TCAs and imine analogs of TCAs were studied of which the cyclopropa(c)cycloheptene derivatives were the most potent. Alprazolam, a benzodiazepine derivative with combined anti-anxiety–anti-depressant actions, was the most effective. Presynaptic α-blockade was noted only in molecules with an overall bent shape. “Second generation” antidepressants were discussed in the chapter. 2-C 6 H 5 CH 2 C 6 H 4 O(CH 2 ) 4 NHCH 3 (MCI-2016) was one of the most potent members (0.78x amihptyline) of aminoalkoxyaryl compounds in a test for the prevention of reserpine-induced hypothermia in mice. Antidepressant actions were also produced by many bicyclic compounds. Foremost among these were 1,4-benzodiazepines and related structures that combine anti-anxiety and anti-depressant actions. A number of quinolines and related structures have antidepressant properties. The piperazinylquinoline DU 24565, a quipazine analog and 5-HT uptake inhibitor, is being studied as a potential antidepressant. Several ben-zodioxanylimidazoline apparently owe their antidepressant activity to blockade of central α 2 -adrenergic receptors. Anti-depressant effects have been associated with thyrotropin releasing hormone (TRH), pyroGlu-His-ProNH 2 , a peptide that potentiates the effects of imipramine on brain 5-HT systems. Monoamine oxidase inhibitors (MAOIs) investigations indicate greater anti-depressant efficacy for (+)-tranylcypromine, the more potent MAOI, than for the (-) isomer, a more effective uptake inhibitor. Central nervous system (CNS) stimulant effects of caffeine was recently correlated with their ability to bind to central adenosine (A 1 and A 2 ) receptors, thus preventing the depressant action of endogenous adenosine on nerve firing. ECS therapy, for which memory impairment is a major side effect, may find increased application in the future because new technologies are enhancing its precision, efficacy, and safety.
1 citations