Pharmacology antidepressants

Mocaer E, Retori MC, Kamoun A Pharmacological antidepressive effects and tianeptine-induced 5-HT uptake increase. Clin Neuropharmacol 11 [suppl 2] S32-S42, 1988... 

A large number of non-tricyclics for which (pharmacological) antidepressant activity is claimed have been described in the last 20 yr, but only those structures are selected whose pharmacology has a pronounced antidepressant profile and/or in which effectiveness in human depression may be expected now or in near future. In general, compounds of which no clinical investigation has been reported more than about 5 yr after their announcement are excluded. In cases of doubt, we made inquiries of the investigators concerned about possibly predicted clinical usefulness. For the presentation of series, the most active or the most pronounced compound of the series is described. 

Lu 3-057a (83), a monomethylindene, showed a corresponding profile [224— 226]. The dimethylamino analogue also possesses pharmacological antidepressant activity. 

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

Extension of the alkyl group on the carbon bearing the amine changes the pharmacologic profile. Reductive amination of 1-phenylbutanone-2 (60) with pyrrolidine in formic acid gives pro-litane (61), a central nervous system stimulant agent with antidepressant properties. 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

In summary, research on the use of antidepressants to treat cannabis dependence, particularly among individuals with comorbid major depressive disorder, although limited, offers a promising avenue for the development of pharmacological aids to assist in the treatment of cannabis withdrawal. There are clear parallels between this literature and the existing research on the use of antidepressants in the treatment of alcohol dependence comorbid with major depressive disorder (see Chapter 1, Medications to Treat Co-occurring Psychiatric Symptoms or Disorders in Alcoholic Patients). 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

Attempts to find the cause(s) of depression have adopted two main approaches. One is to look for the neurobiological basis of depression in human subjects and animal models of this condition. The second is to investigate the pharmacology of established antidepressant agents to see whether they consistently augment some, and ideally the same, neurobiological targets in the brain. 

Differentiate antidepressants according to pharmacologic properties, adverse-effect profiles, pharmacokinetic profiles, drug interaction profiles, and dosing features. 

Predict adverse-effect profiles of antidepressants based on pharmacology. 

The important adverse effects of the various antidepressants are often a function of their underlying pharmacologic profiles7,8 (Table 35-3). TCAs cause problematic sedative, anticholinergic, and cardiovascular adverse effects owing to their interaction with dirty receptors. While these adverse effects generally are considered to be common and bothersome, they can be quite serious in certain cases. For example, constipation in its... 

The major drug interactions of antidepressants are shown in Table 35—6.9,19,30 Antidepressants cause both pharmacodynamic (e.g., additive pharmacologic effects) and pharmacokinetic (e.g., changes in drug levels) interactions with other medications. 

Treatment of depressive episodes in bipolar disorder patients presents a particular challenge because of the risk of a pharmacologic mood switch to mania, although there is not complete agreement about such risk. Treatment guidelines suggest lithium or lamotrigine as first-line therapy.17,41 Olanzapine has also demonstrated efficacy in treatment of bipolar depression, and quetiapine is under review for approval of treatment of bipolar depression.42 When these fail, efficacy data support use of antidepressants. 

---