Antidepressant drugs antidepressants described

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

The biochemical theory of depression is in a state of crisis. The data just do not fit the theory. The neurotransmitter depletion studies that I described earlier in this chapter show that lowering serotonin or norepinephrine levels does not make most people depressed. When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree. And the effect of anti-depressants, which was the basis for proposing the chemical-imbalance theory in the first place, turns out to be largely a placebo effect. 

Healy, David. Let Them Eat Prozac The Unhealthy Relationship between the Pharmaceutical Industry and Depression. New York New York University Press, 2004. The psychiatrist author prescribed Prozac when it first came out but found that many patients who took it became agitated and a few attempted suicide. His book reviews the history of Prozac and similar antidepressants, describes the controversies over the drugs, and ultimately criticizes the pharmaceutical industry for overstating the benefits and minimizing—or hiding—the risks. 

In this chapter, we have discussed the mechanisms of action of the major antidepressant drugs. The acute pharmacological actions of these agents on receptors and enzymes have been described, as well as the major hypothesis that attempts to explain how all current antidepressants ultimately work. That hypothesis is known as the neurotransmitter receptor hypothesis of antidepressant action. We have also introduced pharmacokinetic concepts relating to the metabolism of antidepressants and mood stabilizers by the cytochrome P450 enzyme system. 

The type of research described under this heading aims at correlating therapeutic outcome and pre-therapy sleep as well as therapy-induced sleep alterations. This section is voluntarily limited to the two therapies whose relationships to sleep are the most documented, i.e., antidepressant drugs and sleep deprivation therapy. The effects of these two therapies are examined in the light of the three theories. According to these theories, effective therapies have either to decrease the arousal level, to increase process S, or to restore the aminergic/cholinergic balance. 

Early formulations of the monoamine theory of depression cited two strands of evidence. One was the effects of antidepressant drugs and the other was the effects of reserpine. Skildkraut believed that studies have shown a fairly consistent relationship between drug effects on catechloamines, especially norepinephrine, and affective or behavioural states (Schildkraut 1965, p. 509). He went on to describe how drugs that cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioural stimulation or excitement and generally exert an antidepressant effect in man (p. 509). 

The fact that a disease-centred view of the nature and action of antidepressants has dominated psychiatric research since the 1960s means there has been little research into what drug-induced effects these drugs produce. Patient or user literature on their effects is also more often dominated by a disease-centred view than similar literature on neuroleptic drugs, perhaps because no alternative view of their action has ever been established. The first point to appreciate from a drug-centred perspective is that the drugs currently referred to as antidepressants come from many different chemical classes. We would expect them therefore to have quite different profiles of action. I will describe available evidence on two of the main classes of antidepressant drugs. 

It is possible that antidepressant drugs have other targets in addition to their actions at cell surface monoamine transporters. AI-Damluji and Kopin (107) have described a novel amine uptake process in peptide-containing hypothalamic neurons, which they, named "transport-P." Like the vesicular transporters this process is driven by a proton gradient, but it is distinct from the vesicular transporters in being insensitive to reserpine, but sensitive to a variety of tricyclic antidepressants at micromolar concentrations (108). It is not clear, however, what role if any transport-P plays in the inactivation of the monoamine neurotransmitters. 

Fig. 2. CYP2D6 genotype dependent quantitative changes in pharmacokinetics of antidepressant drugs expressed as percent dose adaptations. CYP2D6 PM (whit, IM (gray), EM (dark gray), UM (black). Dose adaptations were calculated as described in [1]. Dose adaptations are based on an average dose of 100% and are aimed for the Caucasian population. Data from studies in Asiatic or African or other populations were not incorporated because PM data are lacking. (From Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004 9f.5) 442 7.3 with permission.)...

Side Effects of Antidepressant Drugs - Recent publications pertaining to the clinical side effects of antidepressant agents are by Hollister, Kahr et al. 5, Tschen et al. 6, Blair and Simpson and Simpson et al. 8. The toxicology of amitriptyline has been described by Myers et al. 9. 

A number of additional examples of litigations involving crystal forms (e.g. terazosin hydrochloride, cefadroxyl, aspartame etc.) are described in Ref. [3b]. A more recent high profile case involved the Glaxo SmithKline antidepressant drug Paxil , paroxetine hydrochloride, which involved an anhydrate and a hemihydrate form of the API [44, 45]. 

With respect to the role of the brain monoamines in mental depression, it may be stated that all of the antidepressant drugs described in this section are capable of increasing brain levels of norepinephrine, Serotonin, and dopamine. Recent work by Spector (103) would seem to indicate that norepinephrine may be the critical neurohormone which mediates the effects of the MAO inhibitors, inasmuch as pargyline was incapable of counteracting the depressant effects of reserpine (even in the presence of significant amounts of Serotonin and dopamine) until there was a small but definite rise in norepinephrine levels. This work was done in rabbits which had previously been depleted of brain monoamines by the administration of reserpine. 

Describe the general duration of action of antidepressant drugs. 

Examples of this technique are described for artificial receptors for the alkaloid yohimbine binding peptides obtained from a phage display library [57], for the steroid libraries related to lla-hydroxyprogesterone [58], corticosterone [58] (reported in Fig. 12), and cortisol [59]. A molecularly imprinted polymer working as a synthetic receptor for a series of chiral benzodiazepines [47], artificial receptors for the tricyclic antidepressant drug nortriptyline—obtained by covalent and noncovalent molecular imprinting and studied by capillary liquid chromatography with a simulated combinatorial library [60,61]—were also examined. 

High-throu put, multi-dimensional substrate-catalyst screening was described by Adolfsson et al. for the ATH of heteroaryl alkyl ketones. The evaluated mthenium and rhodium precatalysts were derived from a library of modular amino acid-based ligands. The results of screening were used as a key step in the formal synthesis of the antidepressant drugs, (/f)-Huoxetine and (5)-Duloxetine. The ATH... 

This paper describes the formation of reactive intermediates from acetylhydrazine and isopropylhydrazine, hepatotoxic metabolites of the tuberculostatic drug, isoniazid, and the antidepressant drug. 

Chlorpromazine had been shown to produce a tranquil state in animals and since it had a similar effect in humans it became known as a major tranquiliser but the term is rarely used today. Sometimes the drugs used to treat schizophrenia are called anti-psychotics but more commonly neuroleptics. Leptic means to activate (take hold of) and in animals these compounds produce a state of maintained motor tone known as catalepsy. This is an extrapyramidal effect and in schizophrenics the neuroleptics can cause a number of extrapyramidal side-effects (EPSs) including Parkinsonism. The new term neuroleptic is unsatisfactory as a description of clinically useful drugs. It really describes a condition (catalepsy) seen in animals and is more indicative of a compound s ability to produce EPSs than to treat schizophrenia. Antipsychotic is more descriptive but could imply a more general efficacy in psychoses than is the case. It would seem more appropriate to call a drug that is used to treat schizophrenia an antischizophrenic just as we use the terms antidepressant or antiepileptic irrespective of how the drug works. Despite such personal reservations, the term neuroleptic will be used in this text. 

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

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