HANDBOOK OF PSYCHIATRIC DRUGS - PART 2 potx

antipsychotic medication has improved the acute symptoms itshould be continued at the same dose for the next six monthsbefore a lower maintenance dose is considered for continuedtreatmen

ill, there is often a tremendous temptation and external sure to increase the dose of the antipsychotic in the hope thatthe patient’s condition will improve more rapidly Despite thishope, there is little, if any, clinical evidence that a higher dose

pres-of antipsychotic is in any way advantageous; in fact, it will onlyincrease the likelihood of side effects During this difficult time

it may be necessary to add sedating medications such as acting benzodiazepines (e.g., lorazepam) to help the patientmaintain control until the antipsychotic has started to work

short-TREATMENT EVALUATION AND DRUG SWITCHING

If the first-episode patient has failed to respond to a 6-weektrial of an antipsychotic, the clinician should evaluate possiblenon-compliance with medication, the likelihood of a partialresponse or a complete nonresponse to treatment If there was noresponse, a change to a second antipsychotic from a new family isrecommended If one of the newer agents was not the clinician’sfirst choice, it should be used at this point in the decision tree

If a patient has already discontinued use of a medication,then the new treatment is selected and initiated as describedabove However, if the patient is undergoing maintenance drugtreatment and drugs are to be electively switched in the hope

of achieving a better therapeutic response or alleviating drugside effects, then the goal is to switch medications withoutdestabilizing the patient

Medication changes should be performed by a concurrentslow tapering of the initial antipsychotic while the secondantipsychotic is being slowly titrated The specific rate of cross-titration depends on the dose of the old medication and therelative stability of the patient In general, the higher the doseand the more unstable the patient, the longer and more gradualthe cross-titration schedule Although this varies, a rule ofthumb is to cross-titrate by yoked increments and decrements

of 25% every 2 to 5 days Adjunctive medications should beadjusted or tapered accordingly

If the patient is judged to be a partial responder to theantipsychotic trial, then the clinician may consider the addition

of an agent for augmentation At this point, it is again tant for the clinician to re-evaluate the presence of affectivesymptoms If there is significant depressive symtomatology in

impor-the clinical presentation, impor-then impor-the addition of an antidepressantmay be warranted If the presence of mood symptoms is consis-tent with a manic episode, the addition of a mood stabilizer such

as lithium as an augmentation strategy may be clinically useful

antipsychotic medication has improved the acute symptoms itshould be continued at the same dose for the next six monthsbefore a lower maintenance dose is considered for continuedtreatment Rapid dose reduction or discontinuation of themedications during the resolving phase may result in relativelyrapid relapse It is essential to continue to assess side effectspresent in the acute phase and modify treatment to minimizetheir negative impact, and to re-evaluate the necessity of anyadjunctive therapies used in the acute phase

If the decision has been made to switch to a long-actingdepot antipsychotic agent, this can often be achieved during thisphase This is also a good time to educate the patient and familyregarding the course and outcome of schizophrenia, as well

as factors that influence the outcome such as drug compliance

MAINTENANCE TREATMENT

The goals of treatment during the stable or maintenancephase are to maintain symptom remission, to prevent psychoticrelapse, to implement a plan for rehabilitation, and to improvethe patient’s quality of life

Current guidelines recommend that first-episode patientsshould be treated for one to two years; however, 75% ofpatients will experience relapses after their treatment is discon-tinued Patients who have had multiple episodes should receive

at least five years of maintenance therapy Patients with severe

or dangerous episodes should probably be treated indefinitely.Gradual dose reduction to identify the minimum effectivedose for the patient can be attempted in this phase, althoughrelapse rates are excessively high when doses are reduced toabout 10% of the acute dose

Antipsychotics have been proven to be effective in reducingthe risk of psychotic relapse in maintenance therapy forschizophrenia In the stable phase of illness, antipsychoticscan reduce the risk of relapse to less than 30% per year

Without maintenance treatment, 60–70% of patients relapsewithin one year and almost 90% relapse within two years.These results indicate that antipsychotic medications are effec-tive in preventing relapse in most stabilized patients There

is also strong evidence that patients who relapsed while onantipsychotic medications had episodes that were less severethan patients not on antipsychotic drugs

As atypical drugs have fewer EPS side effects, patients onthese compounds may be less likely to be non-compliant withtreatment and may thereby decrease their risk of relapse Ithas also been suggested that in addition to fewer side effects,atypical drugs may have inherently greater prophylactic effi-cacy than typical drugs and therefore be better for patientswith an increased risk of relapse

TREATING TREATMENT RESISTANCE

Treatment resistance is generally defined as a failure of twoprior drug trials of 4–6 weeks duration Although most defini-tions of treatment resistance focus on the persistence of posi-tive symptoms, there is growing awareness of the problems

of persistent negative symptoms and cognitive impairments,which may have an important impact on level of functioning,psychosocial integration, and quality of life

Approximately 10 to 15% of patients with first-episodeschizophrenia are resistant to drug treatment, and between25% and 50% of long-term patients will have severe, persistentsymptoms including psychosis

Only clozapine has consistently demonstrated efficacyfor psychotic symptoms in well-defined treatment refractorypatients; the mechanism responsible for this therapeutic advan-tage remains uncertain Serum levels of 350 g/mL or greaterhave been associated with maximal likelihood of response.Depending on the type of residual symptom, augmentationstrategies include adding another antipsychotic, anticonvulsants,benzodiazepines, and cholinergic agonists may prove useful.Since the approval of clozapine, attention has shifted to

a greater focus on the use of other second-generation chotics for managing treatment resistance in schizophrenia.Both olanzapine (15–25 mg/day) and clozapine (200–600mg/day) were shown to be similarly effective in reducing

antipsy-overall psychotic symptoms in treatment-resistant patients ically eligible for treatment with clozapine Some preliminaryreports suggest that higher doses of olanzapine may be moreeffective; however, dosage issues of olanzapine have not yetbeen adequately addressed in more controlled conditions Thereare also several recent reports of beneficial effects of quetiapine

clin-in treatment-resistant patients with schizophrenia

Given the risk of agranulocytosis, the burden of sideeffects, and the requirement of white blood cell monitoring,the second-generation agents (risperidone, olanzapine, queti-apine, ziprasidone, and aripiprazole) should be tried in almostall patients before proceeding to clozapine Many cliniciansexpress the impression that certain patients do respond pref-erentially to a single agent of this class

SCHIZOAFFECTIVE DISORDER AND VIOLENT PATIENTS

Among the specific therapeutic effects claimed for atypicaldrugs is their ability to alleviate mood symptoms associatedwith the psychotic disorder Although this has not been defini-tively proved, preliminary results indicate that mood symp-toms may selectively abate with atypical drugs This evidencesuggests that patients with schizoaffective disorder, residualmood symptoms (e.g., postpsychotic depression), a history of,

or current, suicidal behavior, and violent behavior may benefitmost from treatment with an atypical drug as compared to aconventional antipsychotic agent

ADJUNCTIVE TREATMENTS

For patients who are unresponsive to antipsychotic agents,including clozapine, and for patients who are responsive buthave substantial residual symptoms, the question is what furtheroptions exist Adjunctive medications as indicated in the algo-rithm (other than electroconvulsive therapy) have been usedextensively but without any empiric data to demonstrate theirefficacy These adjuncts include anticonvulsants, lithium, antide-pressants, benzodiazepines, and cholinesterase inhibitors

Effects of Antipsychotic Agents on Symptoms of Schizophrenia

The clinical profile of second-generation antipsychotic agents onthe symptoms of schizophrenia are summarized in Table 1-3

Positive Symptoms Antipsychotic agents have a specificeffect on positive symptoms of schizophrenia including halluci-nations, delusions, and thought disorder Approximately 30%

of patients with acutely exacerbated psychotic symptoms havelittle or no response to conventional antipsychotics, and up

to 50% of patients have only a partial response to tion Although the proportion of patients who improve andthe magnitude of therapeutic effects vary greatly, second-generation antipsychotics appear to be at least as effective forpsychotic symptoms as conventional drugs

have shown that about 70% of schizophrenics develop primarynegative symptoms such as affective blunting, emotional with-drawal, poverty of speech, anhedonia, and apathy, before theonset of positive symptoms Negative symptoms may representcore features of the illness, and may be associated with pooroutcome and prolonged hospitalization for patients

Negative symptoms can be divided into three componentsthat are usually difficult to distinguish:

• primary or deficit – enduring negative symptoms

• primary – non-enduring negative symptoms

• secondary negative symptoms that may be associated withpsychotic symptoms, EPS, depression, and environmentaldeprivation

Conventional antipsychotics are generally less effective againstnegative than positive symptoms of schizophrenia; thus, theefficacy of second-generation antipsychotics on negative symp-toms compared with that of first-generation drugs has receivedmuch attention Second-generation agents such as cloza-pine, olanzapine and risperidone demonstrate significantlygreater efficacy than conventional agents in reducing negativesymptoms

However, there is a continuing debate as to whether theseeffects are related to a reduction in EPS or to a direct effect

on primary negative symptoms Moreover, the effect sizes

of improvement on negative symptoms for second-generationagents are usually moderate to small in comparison with

placebo or conventional agents Path analyses have suggestedthat both risperidone and olanzapine exert direct effects on(primary) negative symptoms independent of differences inpsychotic, depressive, or extrapyramidal symptoms A collabo-rative working group concluded that second-generation drugsare superior in terms of the “totality” of negative symptoms,but their impact on specific components is still under investi-gation This and other clinical questions will become clear asthe new agents are tested in clinical trials.

integral characteristic of schizophrenia and may be evident in

up to 60% of patients Measurable deficits are prominent intasks involving attention, verbal fluency, memory, and exec-utive function A wide range of cognitive deficits are usuallypresent at the time of the first psychotic episode and remainrelatively stable or only slowly progressive during the course

of the illness, independent of psychotic symptoms Cognitivedeficits are particularly prominent in patients meeting criteriafor the deficit syndrome and in patients with TD They aremore strongly related to social and vocational functioning thanpsychotic symptoms and may influence the quality of life ofpatients Thus, targeting cognitive impairments appears to be

a major focus of the treatment of schizophrenia

Conventional neuroleptics produce small and inconsistenteffects on cognitive functioning In general, clozapine, risperi-done, and olanzapine have demonstrated superior efficacycompared to first-generation antipsychotics on tests of verbalfluency, digit–symbol substitution, fine motor function, andexecutive function Measures of learning and memory wereleast affected by second-generation agents Because these testsall measure performance during a timed trial, enhanced perfor-mance with second-generation drugs could result, in part,from reduced parkinsonian side effects Preliminary evidencesuggests that risperidone may be more effective for visual andworking memory than clozapine

symp-toms frequently occur in the context of psychotic sympsymp-toms

or intercurrently between psychotic episodes Antidepressant

medication used adjunctively to antipsychotic drugs is ally indicated and effective Atypical antipsychotics have beenreported to have selective benefits against mood symptoms inschizophrenia, both manic and depressive.

gener-Suicidal behavior presents a particular problem in patientswith schizophrenia Clozapine is approved for use in suicidalpatients with schizophrenia on the basis of results in theInterSePT study This study found that clozapine treatmentproduced a lower rate of suicidal behavior than the compar-ison treatment of olanzapine in patients with active or histories

is their rapid onset compared to mood stabilizers; as a result,these agents are often used preferentially or combined untilthe mood stabilizer has reached its therapeutic effectiveness.All the second-generation antipsychotics (except clozapine)are now approved for the treatment of acute manic episode

in the United States, as well as the acute treatment of mixedepisodes (except clozapine and quetiapine) Olanzapine andaripiprazole are also approved for maintenance treatment

A concern with the use of antipsychotics in this tion is the potential for TD As a result, it is recommendedthat atypical antipsychotics be used with this populationwhen clinically indicated but that attempts be made to treatthis population with mood-stabilizing agents by themselves ifpossible

popula-Drug Selection for the Treatment of Major

Depression With Psychotic Features

Clear psychotic symptoms, such as delusions or hallucinations,are observed in approximately 25% of patients with majordepressive disorder These symptoms often respond poorly toantidepressants when they are administered alone, and usuallyrequire the use of adjunctive antipsychotic agents

Treatment can be initiated simultaneously, though manyclinicians prefer to start the antipsychotic dose first and thenadd the antidepressant to the regimen Though there arelimited data on the adequate dose of antipsychotic for thisgroup, most clinicians would recommend 5 to 10 haloperidolequivalents This group of unipolar depressed patients may be

at the highest risk of TD; thus the antipsychotic dosage should

be tapered and then discontinued when the patient’s psychoticsymptoms remit

Drug Selection for the Treatment of Delusional Disorder

Delusional disorder differs from other psychotic disorders interms of family history and age distribution In addition, ithas displayed a difference in treatment response; as a generalrule, patients with delusional disorder do not respond well

to antipsychotic agents Some uncontrolled clinical data havesuggested that these patients may do better with drugs fromthe diphenylbutylpiperidine class (e.g., pimozide) However,the majority of this group of patients are untreated and do notseek psychiatric help There is only very limited experiencewith atypical drugs in this population

Drug Selection for the Treatment of Delirium

Antipsychotics are effective in treating the psychotic toms and agitation associated with deliria of various etiologies

symp-In treating a delirium, high-potency agents are preferable tolow-potency agents because low-potency agents usually havemore anticholinergic properties and cardiovascular side effects,which can adversely affect a delirious patient Antipsychoticdrugs are commonly given parenterally when used for thisindication, including by intravenous routes

Risperidone is also relatively free from anticholinergic sideeffects and has a favorable side-effect profile in relation tothe production of EPS The newer agents olanzapine andquetiapine are now being utilized for these conditions Theparenteral forms of the atypical drugs should be particularlyuseful for this indication

Drug Selection for the Treatment of Psychosis and Agitation Associated with Dementia

Antipsychotics are effective in treating the psychotic symptomsthat are often associated with dementias Additionally, theyhave been demonstrated to have anti-aggressive and calmingeffects against dysregulated behavior and affect Althoughmany patients with dementia have agitation and behavioraldisturbances that clearly require the use of antipsychotic drugs,these drugs should be used judiciously

The atypical drugs offer several potential advantages overtypical drugs in treating dementia They produce fewer EPSand less TD, side effects to which elderly patients are highlysusceptible They also may have broader efficacy against theconstellation of pathologic symptoms and behaviors (e.g.,mood symptoms, hostility) that occur in dementia To date,extensive placebo-controlled trials have been conducted withrisperidone, olanzapine and aripiprazole Other atypical drugsmust be systematically evaluated to determine their efficacy forthis disorder and to determine how well their antiadrenergicand anticholinergic properties are tolerated

Elderly patients with dementia who are treated with anantipsychotic agent are at increased risk of death Analyses ofclinical trials with a modal duration of 10 weeks suggest thatthe excess risk is 1.6–1.7 compared with placebo Most of thedeaths appear to be due to cardiovascular events (includingheart failure and sudden death) or infection Because theseevents have been associated with antipsychotics regardless oftheir chemical structure, this is probably a class effect associ-ated with their pharmacological activity and the risk appliesalso to both atypical and older antipsychotics and to drugsthat were not included in these trials The FDA has remindedprescribers that these agents are not approved for the treat-ment of dementia in older people

Drug Selection for the Treatment of Mental

Retardation and Developmental Disorders

Patients with mental retardation are another patient lation with psychotic symptoms and behavioral disturbances

popu-about whom there has been controversy As with patientswith dementia, a number of these patients have documentedpsychosis, and for these patients the use of antipsychotics isclearly indicated There are other patients, however, whoseprimary symptoms are those of behavioral dyscontrol Inthis group it is possible that the risks of antipsychotics mayoutweigh their benefits, especially in long-term treatment.Again, atypical drugs may be advantageous because of theirlower EPS and TD liabilities, to which these patients are highlysusceptible.

Drug Selection for Huntington’s Disease and Tourette’s Disorder

Antipsychotics have been shown to be effective in the ment of Huntington’s disease and Tourette’s disorder InHuntington’s, various antipsychotics have been used to helpcontrol the agitation and chorea as well as the psychoticsymptoms associated with the disorder In Tourette’s disorder,the antipsychotics used most extensively to manage patients’vocalizations and tics include haloperidol and pimozide Mostrecently, risperidone has shown promise in this patient popula-tion Beyond risperidone, there is little experience with atypicaldrugs in these disorders The exception to this is clozapine,which was found to have little therapeutic benefit in eithercondition

manage-On the basis of this evidence, the typical drugs might bethe preferred therapeutic option in these disorders; nonstriatalweak D2agents would be less likely to be effective

Substance-induced Psychoses

PSYCHOSTIMULANT- AND PHENCYCLIDINE-INDUCED PSYCOSES

Substance intoxication resulting in psychotic symptoms may

be treated effectively with antipsychotic drugs This is ularly the case with intoxication from psychostimulants such

partic-as amphetamine, methamphetamine, and cocaine and fromphencyclidine Previously the clinical approach was not to usetypical neuroleptics for fear of exacerbating the patient’s condi-tion with side effects but, rather, to employ benzodiazepines

and a calm low-stimulus environment, unless the conditionpersisted for days or well beyond the period of the toxin’selimination With the availability of the atypical drugs andtheir ability to alter the effects of NMDA receptor antagonists

as well as psychostimulants, the use of these agents should

be evaluated At present, however, only limited data on theirefficacy in these conditions are available

LEVODOPA-INDUCED AND STEROID-INDUCED PSYCHOSIS

Antipsychotics are an integral part of the treatment

of medication-induced psychotic syndromes The psychosisinduced by levodopa in the treatment of Parkinson’s diseasepresents unique clinical dilemmas Treatment of the symp-toms with first-generation antipsychotic agents will by defini-tion worsen the Parkinson’s symptoms The clinician is oftencaught between attempts to reduce the patient’s severe para-noid state and attempts to keep the patient from becomingmore immobile from worsening rigidity and akinesia Recently,case reports utilizing clozapine and risperidone in this popula-tion have shown encouraging results

Steroid-induced psychotic symptoms have proved to

be somewhat more complicated: psychotic symptoms may beprolonged, requiring the use of antipsychotics, and at thesame time, despite the emergence of psychosis, some patientsmay still require steroid treatment for their medical condition.There have been a few case reports in which patients known

to become psychotic during a steroid course were pretreatedwith antipsychotics or with a mood stabilizer, with goodresults

ADVERSE EFFECTS OF ANTIPSYCHOTICS

Antipsychotics as a group have a wide range of potential sideeffects corresponding to their pharmacologic properties Atyp-ical and typical drugs vary markedly in their side-effect profiles;clozapine has the most complicated and potentially serious sideeffects The side effects for representative high-, mid-, and low-potency typical drugs and individual atypical drugs are shown

in Table 1-4

Acute Extrapyramidal Side Effects (Dystonia, Parkinsonism, Akathisia)

Antipsychotic-induced EPS occur both acutely and afterchronic treatment All antipsychotic medications are capable

of producing EPS In general, first-generation antipsychoticsare more likely to cause EPS than second-generation antipsy-chotics when the drugs are used at usual therapeutic doses.Among second-generation drugs, clozapine and quetiapinehave been shown to carry minimal to no risk for EPS withinthe therapeutic dosage range Risperidone can produce dose-related EPS ≥ 6 mg/day With the exception of akathisia, theincidence of EPS with olanzapine, aripiprazole, and ziprasi-done is not appreciably different from that with placebo Therelative liability of the individual second-generation agents toproduce EPS will become apparent only when they have beendirectly compared with each other in prospective clinical trials.Commonly occurring acute EPS include akathisia, dystonia,and parkinsonism, with each having a characteristic time ofonset This group of acute EPS develops relatively soon afterthe initiation of antipsychotic medications and remits soonafter the drugs are discontinued These movement disordersare dose-dependent and reversible

Dystonias tend to be sudden in onset, the most dramaticform of acute EPS, and extremely distressing to patients.They present as sustained muscle contraction with contorting,twisting, or abnormal postures affecting mainly the muscula-ture of the head and neck but sometimes the trunk and lowerextremities Dystonic reactions usually occur within the firstfew days of therapy Laryngeal dystonias are the most serious,and are potentially fatal Risk factors for acute dystoniasinclude a history of prior dystonias, young age, male gender,use of high-potency neuroleptic agents such as haloperidol

or fluphenazine, high dose of medication, and parenteraladministration

Medication-induced parkinsonism is characterized by thesymptoms of idiopathic parkinsonism, including rigidity,tremor, akinesia, and bradykinesia Risk factors include olderage, higher dose, a history of parkinsonism, and underlyingdamage in the basal ganglia