Antipsychotics tolerance

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). ... 

Principally because of its efficacy/tolerability ratio, prescriptions for quetiapine are growing faster than for any other atypical antipsychotic drug at present (personal communication, Astra Zeneca). 

It is not surprising that a DA antagonist (especially those acting primarily on Di receptors) should produce the symptoms of Parkinsonism, a disorder caused by inadequate DA function (see Chapter 15), nor that its intensity or rate of onset over some weeks or months should increase with Dj antagonistic potency. Tolerance to this adverse effect can develop without affecting antipsychotic activity but the speed with which Parkinsonism resolves after stopping therapy may be from 3 to 12 months and can persist indefinitely in some cases. 

Several diverse, potent, and selective GlyT-1 inhibitors have appeared in the literature and many are reported to be efficacious in animal psychosis models. Several of these have advanced into Phase I and Phase II clinical studies. Recent Phase II results from a double-blind, 320-patient study with the investigational GlyT-1 inhibitor RG1678 (33) [17] demonstrated that the compound improved negative symptoms and social functioning of stable patients currently on atypical antipsychotic therapy and was well tolerated at all doses tested [18]. 

The answer is d. (Hardman, p 420. Katzung, p 4852) Tourette s syndrome is effectively treated with haloperidol, a high-potency antipsychotic. If patients are unresponsive or do not tolerate haloperidol, they might be switched to pimozide. 

First, optimize current mood stabilizer or initiate mood-stabilizing medication lithium,0 valproate,0 or carba-mazepine0 Consider adding a benzodiazepine (lorazepam or clonazepam) for short-term adjunctive treatment of agitation or insomnia if needed Alternative medication treatment options carbam-azepine0 if patient does not respond or tolerate, consider atypical antipsychotic (e.g., olanzapine, quetiapine, risperidone) or oxcarbazepine. 

Both typical and atypical antipsychotics are effective in approximately 70% of patients with acute mania associated with agitation, aggression, and psychosis, and atypical antipsychotics are better tolerated. 

In partial responders who are tolerating the antipsychotic well, it may be reasonable to titrate above the usual dose range. 

Tolerance to this effect usually occurs within 2 to 3 months. Reducing the dose or changing to an antipsychotic with less a-adrenergic blockade may also help. 

Quetiapine (Seroquel). Another atypical antipsychotic, quetiapine has also been approved by the FDA for the treatment of acute mania. It is usually administered twice daily at doses of 150-750mg/day. Like its counterparts, quetiapine is a well-tolerated medication. Its common side effects are drowsiness, dizziness, and headache. It causes less weight gain than olanzapine or clozapine but more than ziprasidone or aripiprazole. Quetiapine also does not cause agranulocytosis nor does it increase the risk of seizures. It can occasionally cause mild changes in liver function tests, but these usually return to normal even if the patient continues taking quetiapine. 

Carbamazepine is also most beneficial for patients with mixed episodes and rapid cycling. However, many patients find the side effects of carbamazepine more troublesome than those of valproate, and becanse carbamazepine has a penchant for nntoward drug-drug interactions, we reserve the use of carbamazepine for those patients who are unable to tolerate valproate, lithium, and the atypical antipsychotic... 

When an antipsychotic is needed, we prefer using one of the newer atypical agents olanzapine, ziprasidone, risperidone, quetiapine, or aripiprazole. Each of these medications reliably reduces agitation and is well tolerated. In particular, they decrease the potential for acute dystonic reactions and tardive dyskinesia caused by the typical antipsychotics. Both ziprasidone and olanzapine are now available in an injectable form that is very rapidly acting and effective in this setting. 

Lithium is somewhat effective for the treatment of agitation however, elderly patients do not tolerate it well. In particular, demented patients are at risk for lithium toxicity, and this toxicity may not be easily detected in these patients. Despite its effectiveness, lithium has been abandoned in the treatment of agitation due to the availability of several effective and better-tolerated treatments, including the atypical antipsychotics described earlier. 

The medication of choice was for many years haloperidol (Haldol), a high potency antipsychotic, that can be given orally or by injection. When used, haloperidol should be administered in low doses (0.5-1.0mg) and only on an as-needed basis. Due to concerns regarding the tolerability of haloperidol in patients with dementia, its role in the management of agitation associated with delirium has largely been supplanted by atypical antipsychotics. A number of atypical antipsy-chotics are available by either an oral or intramuscular (injection) route of administiation. 

Formal study of the newer, atypical antipsychotics in the treatment of STPD is limited to a pilot study of risperidone (Risperdal). This study suggested that risperidone, given in low doses (0.5-1.0mg/day), is well tolerated by patients with STPD and helps reduce the paranoia and social isolation of the disorder. Despite this limited formal study, atypical antipsychotics are increasingly used on an empirical... 

Antidepressants. In our experience, clinicians who are trying to manage the behavior of impulsive or aggressive patients too often overlook antidepressants. Antidepressants are often just as effective as anticonvulsants, antipsychotics, or benzodiazepines, especially when managing mild-to-moderate behavioral disturbances. Furthermore, antidepressants are generally easier to use and easier to tolerate than these alternatives. Once again, the SSRIs are best studied and so represent the favored first-line treatment for managing mild-to-moderate behavioral lability... 

Intended for use in chronic psychotic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication, and should have been treated with, and well tolerated on short-acting haloperidol in order to exclude the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation... 

The antischizophrenic actions of these drugs may not consist simply of postsynaptic blockade of hyperactive dopamine systems. Such a blockade occurs within hours, while most symptoms improve over weeks. This discrepancy in the latency to therapeutic effect has been hypothesized to be linked to drug-induced changes in dopaminergic activity after initiation of therapy, dopamine turnover increases, but after continued antipsychotic treatment, tolerance develops and dopamine metabolism returns to normal. This downward adjustment of dopaminergic activity is consistent with the decreased plasma concentrations of the dopamine metabolite homovanillic acid, an observation that correlates temporally with the clinical response to drug treatment. 

Sedation is common after use of all antipsychotic drugs and is especially notable with the low-potency phenoth-iazines this is a result of their activity at aj-adrenergic and Hi-histaminergic receptors. However, sedation decreases during long-term treatment, and many patients become tolerant to this effect. Single daily doses given at bedtime minimize this problem. 

The risk of agranulocytosis and seizures limits use to patients who have failed to respond or were unable to tolerate treatment with appropriate courses of standard antipsychotics. 

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