Antidepressants positive effects

In humans, the antidepressant activity of NMDA receptor antagonists has not been evaluated extensively (Skohiick 1999). In animal models of depression, NMDA receptor antagonists have been reported to exert positive effects in most studies (Trullas 1997). This concerns mainly the forced swim test (Maj 1992 Moryl et al. 1993 PrzegaUnski et al. 1997) and stress-induced anhe-donia (Papp and Moryl 1994). Amantadine but not memantine was effective against reserpine-induced hypothermia (Moryl et al. 1993). In the forced swim test, both amino-adamantanes produced specific antidepressive-like activity (Moryl et al. 1993). 

Tricyclic antidepressants (TCAs) modulate various brain neurotransmitters, especially norepinephrine and serotonin, by blocking reuptake presynaptically. The secondary amines (desipramine, nortriptyline) are more selective for noradrenergic function and have less side effects in sensitive populations. Advantages of this class of drugs include their relative long half life (approximately 12 hours), absence of abuse potential, and putative positive effects on mood and anxiety, sleep, and tics. 

Consistent with earlier studies, Muscat et al. ( 58) reported on chronic exposure to mild unpredictable stress in rats as a model to study the antidepressant-reversible decreases in the consumption of palatable sweets. Using this model, they found that certain dopamine agonists (i.e., quinpirole, bromocriptine) administered intermittently had the same positive effects as TCAs. They further postulated that the infrequent, intermittent administration of dopamine agonists (e.g., psychostimulants) may avoid problems with tolerance and abuse while providing a clinically relevant antidepressant strategy. A report by Kapur and Mann ( 59) comprehensively reviews the role of dopamine in depressive disorders. They discuss several lines of evidence, including the following ... 

The positive effects of the monoamine oxidase inhibitor isoniazid and the amine reuptake blocker imipramine were both discovered by accident. Isoniazid was being used as an antitubercular drug when patients reports of elation led Nathan Kline to test and to demonstrate its antidepressant power. Ronald Kuhn had synthesized imipramine, a tricyclic molecule, as a possible me-too analog of chlorpromazine. When Kuhn found that it had little or no antipsychotic potential, he tried it out on depressives, and voila They got better. After a while, that is. As with isoniazid, imip-ramine s antidepressant action was evident only after one to four weeks of administration. 

Pharmacological treatment of OSA is an elusive concept. A number of selective serotonin receptor inhibitors (SSRIs) and other medications were tried and found to be ineffective. SSRIs and analogous medication have been anecdotally reported to help REM-related OSA, but no study systematically confirmed this claim. Two studies showed positive effect of mirtazapine [33, 34], a tetracyclic non-SSRI antidepressant, on OSA, but further research on a bigger sample is necessary. On the other hand, one should be aware of a muscle relaxation property of some commonly used medications such as benzodiazepines (BZDs), which may result in a worsening of OSA. Assisted nasal ventilation is commonly used in patients with both hypercapnic and non-hypercapnic CSA. The administration of oxygen is observed to ameliorate the frequency of both the central and obstructive events in patients with a predomi-... 

The forced swim test and other assays that are used to identify antidepressant compounds detect compounds with different types of drug action—i.e., serotonin reuptake blockers, norepinephrine reuptake blockers, and atypical antidepressants. A major concern with these types of assays is the identification of false positive compounds. Traditionally, test compounds are evaluated in the forced swim test and in locomotor activity assays to test for stimulant activity. Stimulant compounds are considered false positives in the forced swim test since swimming is considered by some a form of locomotion. However, there are some compounds that increase dopaminergic signaling, such as nomifensine and bupropion, that had antidepressant-like effects in clinical and preclinical tests and demonstrated stimulant activity in some studies [37,38]. Interestingly, stimulant drugs are normally considered false positives in the forced swim test because they are not prescribed for depressed patients however, no controlled studies have been conducted to test this assumption. 

Experiments and data presented in this chapter demonstrate that delta opioid agonists have antidepressant-like effects in animal models used to measure antidepressant activity. The antidepressant-like effects can be separated from other behavioral effects produced by these compounds, such as locomotor stimulation, convulsions, and learning impairments. This separation lends validity to this potential target for depression by eliminating effects or sources that may produce false positives. These compounds should be tested in other models of antidepressant activity to confirm these findings in the forced swim test. 

It is hard to show improved efficacy over existing medications, especially since the positive effects of antidepressants take so long to appear. Patients who are severely depressed and unresponsive to antidepressant therapy are still treated by electroconvulsive therapy (ECT). The goal is to find targets whose targeting will provide a fast onset of antidepressant effects and in particular a rapid reduction in the suicide risk. 

The current psychopharmacologic treatments of affective and anxiety disorders are limited. A significant portion of depressed patients are resistant to treatment with existing antidepressants or combinations thereof either because of non-responsiveness or because a positive effect wears off (breakthrough depression) or is inadequate (depression... 

The combination of traditional antidepressant drugs (e.g., imipramine) and uncompetitive NMDA receptor antagonists (e.g., memantine) may produce enhanced antidepressive effects as a result of synergism. This observation may be of particular importance for the treatment of antidepressant-resistant patients. Most interesting was the observation that fluoxetine, which was inactive in the forced swimming test in rats when given alone, showed a positive effect when combined with memantine (2.5 and 5 mg/kg). 

The use of animal models for depression has two main objectives. One is to provide a behavioural model that can be used to screen potential antidepressant treatments. For this, the behaviour does not have to be an animal analogue of depression all that is needed is for it to be consistently prevented by established antidepressant agents (i.e. no false negatives) but not by drugs which have no antidepressant effect in humans (i.e. no false positives). 

In many clinical trials a positive control of a clinically established drug is often used for comparison purposes for example, a novel selective serotonin reuptake inhibitor (SSRI), may be compared with a more established tricyclic antidepressant, such as imipramine. The aim is to see whether the new SSRI is more efficacious or has fewer adverse side effects than the more established tricyclic (Chapter 12). In many such comparisons the new and older treatments are equally efficacious at relieving depression, but the newer drugs display fewer side effects this means that they are better tolerated by patients, so that they are more willing to continue taking the tablets. The high rates of compliance also mean that, in overall terms, newer drugs with fewer side effects tend to be more efficacious. 

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