Antipsychotic Mechanism of Action

Seeman P (2002) Atypical antipsychotics mechanism of action. Can J Psychiatry 47(l) 27-38... 

Seeman, P. (2002). Atypical antipsychotics Mechanism of action. Canadian Journal of Psychiatry, 47, 27-38. 

While candidate gene studies have provided an insight into the role of established pharmacokinetic and pharmacodynamic targets in antipsychotic treatment response (Table 3), these studies are restricted to our current limited understanding of antipsychotic mechanisms of action. An alternative approach is the use of genome-wide association studies (GWAS), which investigate the... 

Seeman P. Atypical antipsychotics mechanism of action. Can J Psychiatry 2002 47(l) 27-38 Staddon S, Arranz MJ, Mancama D et al. Clinical applications of pharmacogenetics in psychiatry. Psychopharmacology 2002 162(l) 18-23. 

More interesting is the mechanism of action of atypical antipsychotics, particularly clo2apine (60). It is also probably the least selective antipsychotic used in the clinic, having high affinity for numerous receptors including 5-HT2, 5-HT, and dopamine D, D3) and receptors ... 

The answer is c. (Hardman, pp 574—575.) Phencyclidine is a hallucinogenic compound with no opioid activity Its mechanism of action is amphetamine-like. A withdrawal syndrome has not been described for this drug in human subjects. In overdose, the treatment of choice for the psychotic activity is the antipsychotic drug haloperidol. 

In other cases, it makes sense to switch medications. If the previons medication was a typical antipsychotic, then we recommend switching to an atypical antipsychotic to take advantage of a different mechanism of action and a different side effect profile. If the previons medication was an atypical, then switching to another atypical is reasonable. 

Miyamoto S, Dnncan GE, Marx CE, et al. Treatments of schizophrenia a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005 10 79-104. 

The mechanism of action of neuroleptics is not sufficiently clear. However, it is believed that they are antagonists of dopamine and dopaminomimetics, and that their effect is connected in some way with the blockage of dopamine D receptors, which results in changes of behavioral reactions. Moreover, it is possible that they also block action on the serotonin receptors and M-choline receptors. It also is possible that antipsychotic agents disrupt the process of the release and return neuronal uptake of a number of biogenic amines. 

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

Tricyclic antidepressants are chemically, pharmacologically, and toxicologically very similar to antipsychotics of the phenothiazine series. The mechanism of action of tricyclic depressants is not conclusively known, and not one of the proposed hypotheses is currently capable of fully explaining their antidepressant effect. 

The exact mechanism of action of the antipsychotic agents is unknown however, it is thought to be due to their antagonistic actions on the receptors of several neurotransmitters. 

Mechanism of Action An antipsychotic agent that provides partial agonist activity at dopamine and serotonin (S-HTj ) receptors and antagonist activity at serotonin (5-HTja) receptors. Therapeutic Effect Diminishes schizophrenic behavior. Pharmacokinetics Well absorbed through the GI tract. Protein binding 99% (primarily albumin). Reaches steady levels in 2 wk. Metabolized in the liver. Eliminated primarily in feces and, to a lesser extent, in urine. Not removed by hemodialysis. Half-life 75 hr. 

Mechanism of Action An antipsychotic, antiemetic, and antidyskinetic agent that competitiveiy biocks postsynaptic dopamine receptors, interrupts nerve impulse movement, and increases turnover of dopamine in the brain. Has strong extrapyrami-dai and antiemetic effects weak antichoiinergic and sedative effects. Therapeutic Effect Produces tranquiiizing effect. 

Mechanism of Action A phenothiazine that acts as an antihistamine, antiemetic, and CNS-antipsychotiC typical hypnotic. As an antihistamine, inhibits histamine at histamine receptor sites. As an antiemetic, diminishes vestibular stimulation, depresses labyrinthine function, and acts on the chemoreceptor trigger zone. As a sedative-hypnotic, produces CNS depression by decreasing stimulation to the brainstem reticular formation. Therapeutic Effect Prevents allergic responses mediated by histamine, such as rhinitis, urticaria, and pruritus. Prevents and relieves nausea and vomiting. Pharmacokinetics ... 

Mechanism of Action An antipsychotic that blocks postsynaptic dopamine receptor sites in brain. Has alpha-adrenergic blocking effects, and depresses the release of hypothalamic and hypophyseal hormones. Therapeutic Effect Suppresses psychotic behavior. 

TCAs in more serious forms of depression such as melancholic or psychotic depression. Some studies have suggested that the SSRls do not work as well as the TCAs in melancholic depression (Roose et al. 1994]. Likewise, one study has suggested that venlafaxine, a drug with a mechanism of action similar to that of the TCAs, was superior to fluoxetine in the treatment of inpatients with melancholic depression (Clerc et al. 1994]. Still, other metaanalyses have failed to find a difference in the efficacy of SSRls versus TCAs in serious forms of depression [Nierenberg 1994]. Nonetheless, given that most studies have employed TCAs, and some debate exists about the utility of SSRls in severe subtypes, it may be prudent to start with a TCA in most patients until the debate is further resolved. For patients who present a significant suicide risk or who have not been able to tolerate TCAs, the SSRls in combination with a standard antipsychotic appears an effective option. 

Aripiprazole is the most recently approved atypical antipsychotic. This medication has a high affinity for D2 and D3 receptors, as well as 5-HTand 5-HT2a receptors. Although the mechanism of action is not known, aripiprazole may mediate its effects via a combination of partial agonist activity at the D2 and 5-HTj receptors and antagonist activity at the 5-HT2 receptor. 

Despite its relatively fast and thorough rebuttal, the serotonin hypothesis of schizophrenia was fruitful in two respects it gave rise to the development of sensitive serotonin assay methods and proof that serotonin does occur in the brain (Carlsson, 1987) and it served as the prototype for other simple and thus readily testable biochemical hypotheses of mental illnesses. Interest in serotonin has been reawakened in recent years in relation to the mechanism of action of some antipsychotics (see below) however, this development had little to do with the serotonin hypothesis of schizophrenia in its original version. 

D2 receptor, albeit with different specificity. Older examples of dopamine antagonists are chlorpromazine, haloperidol and many derivatives of these prototype compounds. Newer antipsychotic drugs such as risperidone, olanzapine and quetiapine have retained this mechanism of action, although no longer exclusively. 

Reserpine, used as a folk medicine in India, was found to have antipsychotic properties at about the same time as CPZ. Both agents affected the dopaminergic system, albeit in different ways, but the functional results were similar (i.e., lowering dopamine activity). This phenomenon has continued to be an important factor in hypotheses about the mechanism of action of these drugs and for biological theories about the pathophysiology of psychotic disorders. 

One common denominator of all antipsychotics is the biockade of centrai dopamine (DA) receptors. As a result, extrapyramidal reactions, particularly parkinsonian symptoms, are a major adverse effect of many of these drugs, as well as an important clue to their mechanism of action. True Parkinson s disease is caused by a DA deficiency in the nigrostriatal system. Further, crystallographic data have demonstrated that CPZ s molecular configuration is similar to that of DA, which could explain its ability to block this neurotransmitter s receptors. Drugs with similar structures that do not block DA receptors (e.g., promethazine, imipramine) do not have antipsychotic activity. Another example is the isomer of flupenthixol, which blocks DA receptors is an effective antipsychotic, but the isomer that does not is ineffective (7). The other family of dopamine receptors, D and Dg, have not yet been implicated in psychosis. 

Because clozapine may block specific DA receptors, its antipsychotic activity could be consistent with an antidopaminergic mechanism of action. Conversely, clozapine does not typically induce extrapyramidal symptoms, which are presumably subserved by the A-9 system. Thus, while clozapine is known to block striatal DA receptors, in positron emission tomography (PET) studies, resolution is not sufficient to clarify effects on other tracts. Furthermore, low doses of metoclopramide, which significantly decrease the number of DA neurons spontaneously active in A-9, do not have antipsychotic effects (except at high doses) but can induce tardive dyskinesia (TD), as well as acute extrapyramidal side effects (EPS). 

The earliest effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations rather than from scientific knowledge of the neurobiological basis of psychosis or the mechanism of action of effective antipsychotic agents. Thus, the fist antipsychotic drugs were discovered by accident in the 1950s when a putative antihistamine (chlorpromazine) was serendipitously observed to have antipsychotic effects when tested in schizophrenic patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action. 

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