Tricyclic antidepressants anxiolytics

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

A number of medications used in the treatment of anxiety have effects on serotonin neurotransmission (Ch. 13). These medications include tricyclic antidepressant medications, SSRIs, and monoamine oxidase inhibitors (MAOIs). However, because these medications take weeks to exert their full anxiolytic effects, it is unlikely that blocking the reuptake (and thus increasing synaptic levels) of either serotonin or norepinephrine selectively is responsible for their anxiolytic properties — rather it is suspected that the therapeutic effects are due to changes in gene expression, protein levels, and eventually changes in synaptic connections between neurons. 

Tricyclic Antidepressants (TCAs). The TCAs were also introduced in the 1950s, and some were discovered to be effective anxiolytics in the 1960s. For example, early studies pioneered by Donald Klein and his colleagues indicated that imipra-mine (Tofranil) effectively relieved panic attacks. Like the MAOIs, the TCAs are not addictive but also require over 3 weeks to begin to achieve significant therapeutic benefit for anxiety. 

The word "tolerability" is perhaps a little clumsy but it describes accurately what is assessed, namely how well the drug is tolerated by those to whom it is administered. This last qualification is necessary because there are many instances in which a drug is better tolerated or less well tolerated by young healthy volunteers than by patients. For example, anxiolytics and tricyclic antidepressants are usually far better tolerated by patients with depression than by healthy volunteers. However, healthy volunteer studies generally provide useful information about tolerability even if it may under- or overestimate tolerability in patients. Many adverse reactions wiU be directly related to the known pharmacological activity of the drug and are therefore predictable. 

Mechanism of Action A tricyclic antidepressant, antianxiety agent, antineuralgic agent, antipruritic, and antiulcer agent that increases synaptic concentrations of norepinephrine and serotonin. TIicrapcuticEffect Produces antidepressant and anxiolytic effects. 

Equally effective as other tricyclic antidepressants for depression distinguishing characteristics include sedative, anxiolytic, antihistaminic properties... 

It became obvious, however, that psychostimulants were not effective in situations of lowered arousal resulting from mood depression. In the 1950s, antidepressants such as the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) became recognized as more effective in treating depression. The differentiation between arousal and mood thus became clearer. It is through the action of drugs that sedate and thus reduce anxiety versus those drugs that do not sedate but are anxiolytic that the basic concepts of anxiety have forcibly to be reconsidered. This inevitably led to the need for a reconceptualization of psychotropic modes of action in relation to psychiatric disorders. 

Two studies have indicated that the tricyclic antidepressant (TCA) imipramine may be as effective as BZDs in the treatment of GAD ( 58, 59). No studies longer than 8 weeks duration have been conducted, however, and imipramine s onset of anxiolytic action may be even slower than that of buspirone. Aithough adverse effects also may limit usefulness, its lack of dependence liability may make it an appropriate alternative in chronically anxious patients who also suffer from panic and depression. 

Beta-adrenoceptor antagonists, particularly propranolol, have been shown to be effective for anxiety symptoms particularly in situational anxiety and GAD. Buspirone, an azaspirodecanedione, is an agonist at 5-HTlA receptors and seems to have anxiolytic effects, though it is less potent than the BDZs and the effects take up to three weeks to become evident. There is high first pass metabolism and a considerable proportion of the effect is due to a metabolite (1-PP). The principal adverse effects of buspirone are nausea, gastrointestinal upset and headache. Antidepressant drugs, both the older tricyclic antidepressants and the newer drugs, have been demonstrated to have anxiolytic effects in mixed anxiety-depressive patients, GAD and panic disorder. 

Original drug classifications in the 1960s emphasized that there were important distinctions between the antidepressants (e.g., tricyclic antidepressants) versus the anxiolytics (e.g., benzodiazepines) available at that time. This reflected the diagnostic notions then prevalent, which tended to dichotomize major depressive disorder and... 

By the 1970s and early 1980s it was recognized that certain tricyclic antidepressants and monoamine oxidase (MAO) inhibitors were effective in treating panic disorder and one tricyclic antidepressant (clomipramine) was effective in treating obsessive-compulsive disorder. Thus, there began to be recognized that some antidepressants overlapped with anxiolytics for the treatment of anxiety disorder sub-types or for mixtures of anxiety and depression (Fig. 8—8). However, either anxiolytics... 

Psychotropic drugs Major tranquillisers, anxiolytics and hypnotics, tricyclic antidepressants, selective serotonin reuptake inhibitors ... 

Drugs and chemicals are known to cause activated interaction. The depressant action of opioid drugs is enhanced by drugs acting on the central nervous system (CNS) such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Concomitant administration of opioid analgesics and monoamine oxidase inhibitors (MAOIs) should be avoided, or extra care should be taken if such a therapy is inevitable. Fatal reactions are reported when treated along with selegiline. Interactions also are reported with cyclizine, cimetidine, mexiletine, cisapride, metoclopramide, or domperidone. 

Benzo derivatives are well known (Figure 4) and some are the basis of important therapeutic agents such as the tricyclic antidepressant clomipramine 3 and the anxiolytic agent diazepam 4. In these molecules the seven-membered rings act as extremely good scaffolds that allow a wide variety of substituent variation and exploration of conformational space during the discovery phase of drug development. 

Uremia Antihistamines Antiparkinsonian agents Antispasmodics Ophthalmic preparations OTC sleep/allergy medications Tricyclic antidepressants Other medications Analgesics/NS AIDs Anticonvulsants Corticosteroids (high dose) Digoxin H2 blockers Insulin Muscle relaxants Narcotics Psychotropics (anxiolytic, antidepressant, antipsychotic) Sedative/hypnotic Sulfonylurea... 

Clinically important, potentially hazardous interactions with antipsychotics, anxiolytics, cimetidine, ciprofloxacin, domperidone, hypnotics, MAO inhibitors, metoclopramide, ritonavir, tricyclic antidepressants... 

Interactions the sedative effects of antidepressants, anxiolytics and hypnotics are likely to be enhanced by antihistamines, as are the antimuscarinic actions and side-effects of drugs such as trihexyphenidyl, orphenadrine, tricyclic antidepressants and phenothiazines. 

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 tricyclic 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 tricyclic antidepressants marketed in the United States are Us ted in Table 2. 

Alprazoiam (Xanax) Benzodiazepine with anxiolytic activity. Mechanism of antidepressant effects unknown. Adjunct to tricyclic antidepressants for depression and panic attacks. No anticholinergic effeas. Does cause sedation and lethargy. ... 

Indalpine is a non-tricyclic antidepressant with a serotonin selective profile. It is 6-7 times more potent than fluoxetine and clomipramine in inhibiting serotonin reuptake m vitro in rat brain synaptosomes. Statistically significant clinical effects within one week of onset of treatment have been reported. An anxiolytic effect may accompany the antidepressant effect. Indalpine appears devoid of anticholinergic and cardiovascular side effects and does not promote weight gain or affect appetite. 

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