Principles of the pharmacotherapy of of the...  25 Principles of the pharmacotherapy of schizophrenia

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  • 25 Principles of the pharmacotherapy

    of schizophreniaCAROL A. TAMMINGA


    Schizophrenia is an illness that has been recognized formillennia; despite this, the discovery of medications forits treatment has occurred only in the past half century(Carpenter and Buchanan, 1994). Neither the etiologyof schizophrenia nor its pathophysiology has been clar-ified; nonetheless, empirical treatments that provideconsiderable symptomatic benefit are available (Davis,1969; Tamminga, 1997). Theoretical strategies for newdrug development have been proposed and are cur-rently being used to identify new compounds (Creese,1976; Robertson et aI., 1994; Meltzer, 1995; Grace etaI., 1997). Based on these strategies, effective antipsy-chotic drugs have appeared and have vastly improvedsymptom manifestations and outcome in schizophre-nia; moreover, this process shows further promise forthe development of new therapies (Tamminga, 2002).This chapter will focus first on a review of the symp-tomatic dysfunctions that are the target for antipsy-chotic treatment, then on representative traditional andnew drugs available for use, and finally on practicalpoints for effective treatment.


    Schizophrenic symptoms manifested by individuals af-fected by the illness include positive psychotic symp-toms that are prominent during acute periods, but alsocognitive dysfunction and negative symptoms. TheWorld Health Organization (WHO), in its 1971 pilotstudy, looked at symptom type and frequency in sev-eral countries (Sartorius et aI., 1974). The WHO list ofthe most frequent acute psychotic symptoms (Table25.1) identifies characteristics of the illness that requiretreatment. Acute psychotic symptoms do not vary bysex, by presentation, or by geographical region. Thesymptom identified as "lack of insight" is nearly ubiq-uitous among schizophrenic persons and is highly crip-pling. This descriptor means that schizophrenic personsexperience their psychotic perceptions as real sensoryinformation. Not only are schizophrenics troubled byinvoluntary thoughts and sensory experiences, but they

    identify the psychotic experiences as true events in theirlives. Treatments that could merely convert these "real-life experiences" into symptoms, and dissociate theirmeaning from relevance to the schizophrenic person,could vastly improve the patient's outcome. Traditionalanti psychotics can do this to some extent; clozapinemay be superior in this regard.

    Several large factor analytic studies of symptoms inrepresentative treated and stable schizophrenic popu-lations have consistently reported three clusters ofsymptoms in the illness: (1) positive psychotic symp-toms (e.g., hallucinations, delusions, and paranoia), (2)reality distortion (e.g., thought disorder and bizarre be-havior), and (3) negative symptoms (e.g., anhedonia,asociality, and alogia) (Carpenter and Buchanan,1994). In addition, evidence of cognitive dysfunctionin schizophrenia is ubiquitous (e.g., attention and short-term memory impairments). Anyone of these symptomclusters can express itself predominantly in an individ-ual, even though all symptoms may be present at somelevel. Whether these clusters represent distinct but re-lated illnesses (e.g., like symptoms of chronic heart fail-ure) or a single illness with multiple manifestations(e.g., like symptoms of diabetes), is frequently debated.Although these domains have been phenomenologicallyderived, subsequent testing has identified several psy-chological, physiological, and functional group differ-ences that are consistent with a distinct biology (Car-penter et aI., 1993).

    With respect to treatment, different symptom tractsin schizophrenia respond differently to pharmacother-apy. Hallucinations, delusions, paranoia, and thoughtdisorder show an overall good response to traditionaland new antipsychotics. Both cognitive dysfunction andnegative symptoms are poorly responsive, if at all, totreatment. Cognitive dysfunction, particularly poorverbal memory and/or reduced vigilance, predicts broadoverall failure in long-term psychosocial rehabilitation.Negative symptoms predict poor social problem solv-ing, but not necessarily poor community functioning orlow skill acquisition (Green, 1996). Since enduring neg-ative symptoms and cognitive dysfunction impact crit-



    TABLE 25.1 Frequency of Psychotic Symptoms inSchizophrenia (WHO International Pilot Study)Lack of insight 97%

    Auditory hallucinations 74%Verbal hallucinations 70%

    Ideas of reference 70%

    Suspiciousness 65%

    Flatness of affect 65%

    Voices speaking 65%~m=~~~ M%Thought alienation 52 %

    Thoughts spoken aloud 50%Source: Sartorius, er at (1974).

    ically on overall recovery and rehabilitation, thesesymptom domains have become targets for treatmentdevelopment. Depressive symptoms in schizophreniaare variably responsive to antipsychotic treatments. De-pression occurring with acute psychotic relapse resolveswith the acute episode; depression occurring outside ofan acute psychosis can be enduring and critically affectrelapse in schizophrenia (Geddes et aI., 1994). Newneuroleptics may impart benefit in these areas.

    Treatment of schizophrenia with antipsychotic drugsrarely, if ever, produces a cure or entirely wipes outsymptoms of the illness. Only 5%-10% of schizo-phrenic persons go on to achieve a full recovery withor without these medications. Some 30% show a goodbut partial response, and another 30% showing an in-adequate but partial response. The remaining 20%-25% of schizophrenic persons are resistant to treatmentwith any antipsychotic drugs. These treatment-resistantschizophrenics suffer considerably and use a dispro-portionate amount of health care services. Thus theirtreatment is a priority.

    Antipsychotic drugs, as their name implies, treat psy-chosis in multiple diagnostic categories. Positive psy-chotic symptoms in bipolar mania, psychotic depres-sion, and dementia with psychosis all respond positivelyto the antipsychotic treatments described here and arethe indicated drugs in these disorders. Schizophreniacharacteristically requires continuous treatment fordecades, whereas these other psychotic illnesses usuallyrequire only targeted treatment during active psychoticphases. Moreover, certain patient groups are more sus-ceptible to the motor side effects of antipsychotic drugs,such as the elderly and those with mood disorder di-agnoses (Kane and Smith, 1982). Dosing considerationsare comparable, with accommodation for age and size,especially in the elderly and in children.


    The antipsychotic action of the first neuroleptic, chlor-promazine, was discovered serendipitously when the

    drug was first tested in France by Delay and Deniker(1952) as a sedative agent for schizophrenia. Its selec-tive antipsychotic properties were quickly noted. In thedecade following this discovery, not only was the prob-able mechanism of antipsychotic drug action articu-lated as dopamine receptor blockade (Carlsson andLindquist, 1963), but many additional antipsychoticcompounds were generated. These drugs have formedthe traditional antipsychotic drug armamentarium forpsychiatrists throughout the past half century. Each ofthe traditional anti psychotics is associated with a dif-ferent side effect profile but with the same primary an-tipsychotic actions (Davis, 1969).

    Apart from historical interest, there are several rea-sons to remain interested in traditional antipsychoticstoday, including their demonstrated effectiveness intreating the psychosis of schizophrenia and their eco-nomic advantage. Moreover, considerably more clini-cal prescribing experience exists for the traditional an-tipsychotics than for the new drugs.

    Chlorpromazine (Thorazine)

    Chlorpromazine was developed by Rhone-Poulenc andfirst tested in the United States in the early 1950s inseveral large multicenter trials (Davis, 1969). These tri-als inevitably included drug-naive individuals becausethis was the first effective drug treatment for psychosis.The response was brisk and extensive; full improve-ment gradually occurred over several weeks. Reduc-tions of 80% or more in symptom profiles occurredcommonly, including hallucinations, delusions, andthought disorder. The residual symptoms in the nega-tive and cognitive domains were not immediately notedbecause of the extensive response of positive symptoms.It is no wonder that this drug was widely, applied andthe development of additional compounds encouragedby these data, because of its overall efficacy in treatingflorid psychosis.

    Side effects of chlorpromazine included not onlyparkinsonism and akathisia, but also hypotension, se-dation, constipation, weight gain, and amenorrhea.Hepatotoxicity, electrocardiographic changes, andseizures were less frequent but more serious side effects.Changes in skin color with sun exposure and retinalchanges were described. Tardive dyskinesia occurred aswell. Today the use of chlorpromazine has graduallydiminished, based mostly on its sedation, cardiovascu-lar side effects, and still significant parkinsonism, butit has not disappeared entirely.

    Haloperidol (Haldol)

    Haloperidol was developed by Janssen PharmaceuticalCompany in the 1950s. Until very recently, it was themost widely used antipsychotic for the treatment ofschizophrenia. Its potent antipsychotic action with lit-

  • tle sedation, despite considerable motor side effects, hassustained its widespread use. Today, these same char-acteristics, coupled with its relative economic advan-tage, keep it a viable antipsychotic treatment. It remainsto be seen if the new neuroleptics will offer such sideeffect advantages over haloperidol to increase compli-ance and reduce relapse sufficiently to balance their in-creased cost.


    The pharmacology of