Tricyclic antipsychotics

Historically, both the tricyclic antipsychotic and antidepressant agents are derived in almost direct line from a series of tricyclic antihistaminic compounds (see 104 below). Minor changes in structure in some of the newer... 

Alkylation of the dimethylpiperazine 12 with 3-chloropropanol followed by treatment of the product 13 with thionyl chloride gives the halide 14. Alkylation of the anion from carbazole (15) with that halide leads to the tricyclic antipsychotic agent rimcazole (16) [4]. 

The tricyclic antipsychotics may be dissected into three substructures (Fig. 10.1), those being the pendent amine functionality (Site A), the diaryl heterotricyclic (Site C), and the intervening alkyl chain (Site B) (295). When considering the effect of structure on neuroleptic activity, it is informative to examine each of the three substructures of the tricyclic-in isolation to see how individual changes within each of these regions impacts the pharmacological properties of the resultant compound. 

Effect of Aromatic Substitution Within the Tricyclic System. The influence of aromatic substitution on the pharmacological profile of the tricyclic antipsychotics is fairly straightforward. For the purposes of this discussion we will examine the effect of varying substituents within the 10-(3-dimethylaminopropyl) phe-nothiazines (Table 10.3), although these influences are applicable across the various classes of tricyclic neuroleptics. 

Table 12-14 shows several dibenzazepines. Of the two dibenzoxazepines (where X = O) loxapine, marketed in 1975, is antipsychotic. The topographical similarity of this tricyclic antipsychotic to the others may be appreciated when viewed as presented in Table 12-15. Its pharmacology, including side effects, mimics those of the phenothiazines as well as...

Loxapine, a dibenzoxazepine compound, represents a new subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phe-nothiazines. Chemically, it is a 2-chloro-ll-(4-methyl-l-piperazinyl)-dibenz[b,f](l,4)-oxazepine. It is present in capsules as the succinate salt, and in the concentrate and parenteral forms primarily as the hydrochloride salt. 

Lanzac LY170053 Olansek Olanzapine Zyprexa. A serotonin and dopamine receptor antagonist with anticholinergic activity a tricyclic antipsychotic. Antipsychotic. Crystals mp = 195°. // Lilly Co. 

Antidepressant agents show almost the same degree of tolerance as to the nature of the tricyclic moiety as do the antipsychotic agents. Thus the dehydration product(s) from the condensation of ketone 9 with the Grignard reagent from 3-chloroethyl-N, J -dimethylamine affords the antidepressant diothiepin (98). ... 

The tricyclic antidepressants (as well as, incidentally the antipsychotic drugs) are characterized by a three carbon chain between the ring system and the basic nitrogen. Incorporation of one of those carbon atoms into an additional fused ring is apparently consistent with activity. Preparation of this compound involves first homologation of the side chain. Thus the carboxylic acid 147 is first converted... 

Cytochrome P450 2D6, also termed debrisoquine-sparteine hydroxylase, is a mixed-function oxidase localized in the endoplasmic reticulum which is responsible for the biotransformation of several tricyclic antidepressants, antipsychotics, beta-blockers, opioids, and many other drugs. 

Antipsychotics, bromocriptine, carbamazepine, chlorpropamide, cyclophosphamide, desmopressin, ecstasy, lamotrigine, monamine oxidase inhibitors, NSAIDs, oxcarbazepine, oxytocin, tricyclic antidepressants, selective serotonin reuptake inhibitors, vasopressin, vinblastine, and vincristine... 

Tricyclic antidepressants Monoamine oxidase inhibitors Selective serotonin reuptake inhibitors Antipsychotics Phenothiazines Risperidone Lithium... 

A number of medications have been associated with an increased risk of falling, including drugs affecting mental status such as antipsychotics, benzodiazepines, tricyclic antidepressants, sedative-hypnotics, anticholinergics, and corticosteroids. Some cardiovascular and antihypertensive drugs also can contribute to falls, especially those causing orthostatic hypotension.9... 

SGAs = second-generation antipsychotics (SGAs) FM03 = flavin-containing monooxygenase TCAs = tricyclic antidepressants Adapted from de Leon et al., 2005b... 

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). 

Tricyclic Antidepressants (TCAs). Like iproniazid, the first TCA was also developed in the 1950s for another purpose. Imipramine (Tofranil) is structurally similar to the early antipsychotics and was hoped to provide an alternative to chlor-promazine (Thorazine). It proved to be a poor antipsychotic but was surprisingly found to be an effective antidepressant. The tricyclics are so named because a three-ringed structure forms the hub of the molecule. 

Atypicai Antipsychotics. In the 1980s and early 1990s, the SSRIs began a revolution in the treatment of depression. Tried-and-true but side effect laden tricyclic antidepressants fell into disfavor as newer and safer medications became available. A similar revolution is taking place in the treatment of psychosis. A new generation of antipsychotics that have fewer of the more disturbing side effects and may well be more effective are now available. 

The key has been to avoid using treatments that worsen the disease. In this instance, this means avoiding anticholinergic (acetylcholine-blocking) medications that worsen dementia. As a result, when newer antidepressants such as the SSRIs became available, they quickly replaced the older tricyclic antidepressants because the latter are potent anticholinergics. For the same reason, the low potency anti-psychotics like chlorpromazine (Thorazine) were replaced by the higher potency antipsychotics like haloperidol (Flaldol) and more recently by the atypical antipsychotics. 

Antidepressants tricyclics, mirtazepine, fluoxetine Antipsychotics clozapine, haloperidol, olanzapine, phenothiazines... 

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