Biomedical subjects
Publications and source records attributed to S C Dilsaver.
Depressive symptoms may be produced by many drugs and diseases. A physical examination, systems review and medical history should be included in the evaluation of any patient presenting with depressive symptoms. The same criteria for major depression should be applied to patients in psychiatric and nonpsychiatric settings. Tricyclic agents may be effective in treating depressive symptoms associated with medical illness.
Centrally active antimuscarinic agents are generally used in psychiatry to treat the extrapyramidal side effects of antipsychotic medications. However, these agents may have antidepressant and mood-elevating properties, and the literature suggests they are liable to abuse. The author reviews this literature and discusses its implication.
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Supersensitivity of a muscarinic mechanism is implicated in the pathophysiology of depression. Bright artificial light is efficacious in the treatment of Seasonal Affective Disorder (SAD). We studied the effect of constant bright light (11,500 lux) on the sensitivity of adult, male rats to oxotremorine, 1.5 mg/kg ip, using a repeated measures design. Oxotremorine challenges were proceeded by the injection of methylscopolamine, 1 mg/kg ip, by 30 minutes. Temperature was telemetrically measured every 10 minutes for 120 minutes starting 10 minutes after the injection of oxotremorine. Prior to and after 7 continuous days of exposure to bright light, the sample exhibited a hypothermic response of 2.50 +/- 0.48 degrees C (mean +/- SEM) and 0.29 +/- 0.31 degrees C (mean +/- SEM), respectively (p less than 0.0014). All 7 animals exhibited blunting to the thermic response to oxotremorine. Bright light also blocked the capacity of amitriptyline to supersensitize a central muscarinic mechanism. Exposure to light at an intensity of 300 lux for 7 days had no effect on the thermic response to oxotremorine. These data are consistent with the hypotheses that the biology of depression involves supersensitivity of central muscarinic mechanisms and that the effects of bright artificial light are not the consequence of shifting circadian rhythms.
Fluoxetine HCl, 10 mg/kg ip, twice daily produced subsensitivity to the hypothermic effects of nicotine (base), 1 mg/kg ip, after 1 (p less than 0.02) and 2 (p less than 0.002) weeks of treatment. Phenelzine sulfate, desipramine HCl and bright artificial light produced the same effect. The capacity of three chemically distinct classes of antidepressants and bright artificial light (a treatment for seasonal depression) to produce this result suggests that effects on nicotinic mechanisms may be involved in the mechanism of action of these treatments.
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The withdrawal of tricyclic antidepressants produces symptoms characteristic of cholinergic overdrive states. The authors previously proposed that these states are the consequence of the pharmacological induction of cholinergic system supersensitivity by chronic treatment with antidepressants, combined with a reduction in the plasma level of a competitive muscarinic receptor antagonist when the dose of a tricyclic is decreased. This is consistent with the facts that all tricyclic antidepressants are antimuscarinic agents and that classical antimuscarinic compounds, such as scopolamine, up-regulate and supersensitize muscarinic cholinergic systems. The authors present evidence that chronic treatment with amitriptyline supersensitizes a central cholinergic mechanism. Core body temperature is subject to influence by a central (hypothalamic) muscarinic mechanism, which is rendered supersensitive to cholinomimetic challenge by treatment with scopolamine. The authors telemetrically measured the hypothermic responses of adult male rats to various doses of the muscarinic agonist oxotremorine before and in the course of chronic treatment with amitriptyline. Treatment with amitriptyline resulted in marked enhancement of the cholinomimetic-induced hypothermia. Methylscopolamine nitrate, a peripherally active antimuscarinic agent, did not block the hypothermic response to oxotremorine, whereas scopolamine, a centrally active antimuscarinic compound, did. This study indicates that the chronic administration of amitriptyline can produce supersensitivity of a central muscarinic cholinergic mechanism. Clinical and theoretical implications of this finding are discussed.
Sixty-one adolescents hospitalized on an inpatient psychiatric unit were evaluated to determine whether they met criteria for panic and affective disorders according to Research Diagnostic Criteria. Ten (16%) and 15 (24%) met criteria for definite or possible panic disorder. Fifteen (24.5%) had major depressive disorder (MDD) endogenous subtype, 10 (16%) had MDD nonendogenous subtype, 8 (13%) had minor depressive disorder (mDD), and 27 (44%) had no diagnosable mood disorder. Four adolescents with definite panic disorders were diagnosed as having MDD endogenous subtype, three MDD, two mDD, and one had no diagnosable depressive disorder. The mean total score on the Hamilton Rating Scale for Depression (HRSD) was significantly higher among those subjects with definite panic attacks compared with those with either possible or no panic. Patients with definite panic disorder showed significant increases on the HRSD items of guilt, decreased work and interest, psychological and somatic anxiety, and weight loss compared to these samples.
1. The withdrawal of tricyclic antidepressants (TCAs) produces symptoms suggesting cholinergic rebound. 2. Amitriptyline (AMI), the most potent antimuscarinic agent among this class of drugs, produces supersensitivity to the muscarinic agonist, oxotremorine. 3. Enhancement of the sensitivity of cholinoceptive neurons to acetylcholine as a consequence of treatment with TCAs would account for many of the symptoms following the withdrawal of these drugs. 4. Desipramine (DMI) is the least potent antimuscarinic compound among the TCAs, yet its withdrawal produces withdrawal symptoms. 5. Recently, it was reported that amoxapine (AMX) weakly binds to muscarinic acetylcholine receptors (mAchR) in vitro. This may indicate that this drug lacks the effects antimuscarinic effects in vivo, and that it will not supersensitize cholinergic networks. 6. A thermoregulation paradigm was used to assess the sensitivity of a central muscarinic mechanism to oxotremorine before and after treatment with DMI and AMX. Treatment with either drug increased the hypothermic response to this agonist. 7. Mechanisms whereby drugs can produce cholinergic system supersensitivity, and the use of thermoregulation paradigms in assessing the properties of therapeutic agents is discussed.
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Transitions in the categorization of variables can contribute to changes in the concept of a psychiatric disorder. These transitions can occur with expansion of knowledge and without a concomitant change in the form of diagnostic labels. For example, the definitions of "mass" within the framework of Newtonian and Einsteinian theory are incompatible even though the same label is used to denote both concepts. Implications of the principles discussed for theory and practice in psychiatry are emphasized.
The discontinuation of tricyclic antidepressants (TCAs) can produce symptoms suggesting cholinergic overdrive. The authors previously proposed that these withdrawal states are the consequence of TCA affected cholinergic system supersensitivity. Evidence that chronic treatment with amitriptyline produces dose-dependent supersensitization of a central cholinergic mechanism is now presented. Core temperature is subject to a hypothalamic muscarinic mechanism. The thermic response of adult male rats to oxotremorine was telemetrically measured after 7 days of treatment with saline or amitriptyline 3, 10, and 20 mg/kg given intraperitoneally twice daily. Treatment with the TCA produced dose-dependent enhancement of oxotremorine-induced hypothermia. The data support the hypothesis that at least some TCA withdrawal phenomena involves supersensitization of muscarinic systems.
Substance abuse and affective disorders involve overlapping symptom complexes. The author suggests that the neurobiologies of these conditions could be related and presents a model useful in studying the pharmacologies of some of the drugs of abuse and the pathophysiology of affective disorders. This model may bridge two disciplines and render them mutually useful.
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