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Jean-Pierre Lindenmayer, MD, Victoria E. Cosgrove, BA

Primary Psychiatry. 2002;9(11):31-39

Dr. Lindenmayer is director and Ms. Cosgrove is a research scientist at the Psychopharmacology Research Unit, Manhattan Psychiatric Center-Nathan Kline Institute for Psychiatric Research in New York City.

Acknowledgments: The authors report no financial, academic, or other support of this work. 



What are the best pharmacologic treatment strategies for schizophrenia? Adequate diagnostic assessment must precede any treatment plan. For acute schizophrenic patients presenting in a psychiatric inpatient setting, pharmacologic choices depend on the patient’s medication history and current level of agitation or aggression. The pharmacologic choices have been greatly expanded with the availability of the atypical antipsychotics risperidone, olanzapine, quetiapine, and ziprasidone. Maintenance treatment, often lifelong, requires psychoeducational interventions and side-effect management to ensure adherence to an optimal treatment regimen. Coexisting syndromes must be treated in concordance with the patient’s clinical presentation. For treatment-resistant patients, atypical compounds are generally more effective than their typical counterparts. Since response rates in resistant patients are often low, medication augmentation strategies are frequently recommended.


The pharmacologic treatment of schizophrenia has significantly evolved with the introduction of the newer atypical antipsychotics. These compounds produce fewer side effects, increase  treatment adherence for patients, and have a broader profile in effectiveness compared to traditional antipsychotics. In addition, different treatment algorithms have been developed which have contributed to a body of best practices in the treatment of this complex disorder.

This article will provide an overview of the assessment and pharmacologic strategies for the different stages of schizophrenia, including the acute phase, the postacute/maintenance phase, and treatment-resistant situations.


Assessment of patients with schizophrenia must be adequately completed before initiation of any treatment plan. The starting point is always a careful and comprehensive psychiatric interview, which should be supplemented by information from relatives or friends of the patient. This is particularly important with schizophrenia patients as their ability to communicate coherently might be impaired or their awareness of reality might be distorted. An obligatory part of the interview will be a mental status examination. It is also helpful to determine distinct domains of psychopathology which make up the clinical presentation of the patient, as they may present differential responsiveness to pharmacotherapy. Several authors have reliably identified five domains: the positive symptom domain (eg, delusions and hallucinations); the negative domain (eg, blunted affect and social withdrawal); the cognitive domain (eg, thought disorder and stereotyped thinking); the excitement domain (eg, uncooperativeness and poor impulse control); and the depression/anxiety domain (eg, depression and tension).1

In addition, clinicians need to determine the presence of comorbid psychopathology, common in patients suffering from schizophrenia. One of the more frequently comorbid conditions is substance abuse. Overall, the outcome for schizophrenic patients with comorbid psychopathology is less favorable than for those without comorbid disorders. Finally, when patients fail to respond to various treatments, a thorough diagnostic reevaluation is required, which also considers medical underlying factors contributing to nonresponse (Table 1).







Conditions, such as medication-induced delirium, seizure disorders, and other disorders of the central nervous system, may occasionally present with schizophrenia-like symptoms. In addition, medical conditions, such as cardiac disorders, ophthalmologic conditions, hepatic disorders, obesity, neurological conditions, or diabetes, may influence medication choice.

Since schizophrenia is a chronic condition with periodic psychotic decompensations, patients often have extensive medication histories. Initial assessment must include a thorough review of the adequacy and effectiveness of previous mediation trials, adherence patterns, and adequacy of dosing regimens. Patients themselves may be able to describe which medications have been intolerable in the past. Ultimately, choosing medications that patients believe will be helpful to them ensures adherence.

It is essential to assess past and present medication adherence as well as reasons for nonadherence. Patients neglect medication for many reasons—side effects, substance abuse, and cognitive impairments as manifested by unawareness of mental illness and stigma. There has been evidence to suggest that adherence is better for clozapine than other typical and atypical antipsychotics.2,3 Long-acting depot preparations, which avoid the burden of daily dosing, represent an important route of medication administration for patients with adherence problems. Other ways to ensure adherence is to tailor the medication regimen to the specific needs of the patient and through participation in illness education groups. The regimen should be as simple as possible (QD or BID). Side effects should be minimized; however, patients should be aware that some side effects might be inevitable. Through psychoeducational interventions emphasis should be placed on the long-term necessity for medication treatment in order to avoid discontinuation and psychotic relapse. In addition, a patient’s adherence increases as his level of services increases. Introduction of intensive case managers or supportive housing is helpful.

Finally, diagnostic and laboratory tests may be indicated depending on clinical circumstances (Table 2). For new patients, clinicians should assess blood chemistry and hematology including prolactin levels, urinalysis with toxicology, electrocardiogram, vital signs, and extrapyramidal symptoms.









Management of Acute Schizophrenia

Most treatment episodes for acute schizophrenia take place in a psychiatric inpatient setting. This allows time for the clinician to conduct a full diagnostic assessment, evaluate differential diagnostic considerations, and initiate an aggressive psychopharmacologic treatment plan. However, at times, this treatment plan may have to be shaped in order to satisfy the constraints of length of stay requirements. In fact, the average length of stay at this time for an acute schizophrenic inpatient episode has been reported to be ≤1 week, which will only allow for rapid stabilization.4 It will also mean that the continuation of treatment will occur in the outpatient setting.

The aim of treatment is the stabilization of acute psychotic symptoms, the control of agitation, the resolution of self destructive or aggressive behavior, and the transition to safe outpatient treatment. On occasion, the treatment of an acute episode may be accomplished in an outpatient setting, where consistent monitoring and supervision are available. The involvement of intensive case managers or of assertive community treatment may be particularly helpful in these situations.5 Outpatient treatment may be possible in situations of incipient acute psychotic decompensation or transitional environmental stress. In general, we recommend the use of a medication that had been effective in the past, had no/minimal side effects, and that is supported by patient preference.

Once acute hospitalization has been considered as the initial treatment location, the next issue to consider is whether the admission will take place under voluntary or involuntary conditions. Local regulations will determine the criteria for each of the two conditions. In general, involuntary admission can be considered in situations of presence of mental illness and imminent self-harm, danger to others, or inability to take care of oneself due to the mental illness. For voluntary admission, the patient has to be willing to sign him/herself into the hospital and the admission must be approved by the administration.6

If the present episode is a first episode or if the treatment history is not known, one would start with one of the atypical compounds, such as olanzapine 15–20 mg/day PO or risperidone 3–6 mg/day PO. The following are common dosage ranges, which have to be individualized for each patient. Alternative compounds are quetiapine 200–400 mg/day PO or ziprasidone 120–160 mg/day PO. Use of typical antipsychotics would include haloperidol 10–15 mg/day. The question of how to determine when the duration of a trial is sufficient in case of lack of response is influenced by the choice of outcome measures and the availability of support postdischarge. In the inpatient setting, switching to another compound could be considered after 1 week, if there is no hint of a response.7

Treatment of Acute Agitation and Aggression

An important associated symptom during the acute phase is agitation and aggressive behavior. Short-acting benzodiazepines (lorazepam or midazolam) are extremely helpful in the acute management of agitation and aggressive behavior. Based on a double-blind study comparing lorazepam 2 mg intramuscular (IM) and haloperidol 5 mg IM as a PRN medication for the control of assaultive or aggressive behavior, Salzman and colleagues8 found that both compounds were equally effective in controlling aggressive and psychotic symptoms, but that patients on haloperidol had significantly more extrapyramidal symptoms (EPS). Lorazepam may be particularly useful because of its short half-life and the availability of IM, intravenous (IV), and PO forms. Given that haloperidol can cause significant EPS and can worsen phencyclidine intoxications, it is generally preferable to use parenteral lorazepam in most emergency situations. Recommended dosages for haloperidol are 5 mg IM every 1–4 hours together with lorazepam 2 mg IM or chlorpromazine 25–50 mg IM every 1–4 hours. Another alternate form of administration is oral concentrate of an antipsychotic mixed in orange juice, which is at times more acceptable to patients.

Second-generation antipsychotics are clearly superior to typicals in terms of their lesser propensity to EPS and other more beneficial side-effect profiles (Table 3). Although there is currently only one available atypical in IM form, short-acting ziprasidone (dose for ziprasidone IM is 5–20 mg9), there may soon be an olanzapine IM form available.10 There are also two other atypical compound administrations that may be useful for emergency situations: a liquid risperidone form and a rapidly dissolving oral olanzapine form.







Rapid neuroleptization, which was at one time favored by physicians treating acutely psychotic patients who also were agitated, is no longer advisable. The duration of onset of action and effectiveness is not superior to traditional dosage techniques.11

In the case of agitation and violence in the context of drug withdrawal from hypnotics or sedatives, antipsychotics are contraindicated because they lower the seizure threshold. Benzodiazepines are the treatment of choice in these situations. High potency antipsychotics or benzodiazepines are preferable to low potency compounds in the treatment of agitation and violence in patients with delirium. Low potency antipsychotics, due to sedating and anticholinergic properties, may worsen the delirious states in these patients. In particular, dosages of antipsychotics need to be adjusted in situations with elderly patients or with patients who have cerebrovascular problems. Haloperidol 0.5–2.0 mg IM every 30–60 minutes can be given until the patient is calm.

Barbiturates are less frequently used, since safe and effective benzodiazepines have displaced them in the treatment of acute agitation and aggression. Barbiturates also have a high potential for abuse and dependence, and are therefore less favored. However, they can still be useful in patients who do not respond to benzodiazepines. Compounds with a shorter half-life such as sodium amytal 250 mg IM every 4 hours is preferable in order to avoid accumulation of the drug over time.

In situations of persistent agitation, it is important to rule out the presence of akathisia. This extrapyramidal motor side effect consists of objective motor hyperactivity and a subjective sense of restlessness. It often cannot be distinguished from agitated anxiety. A frequent practice is to combine a high-potency antipsychotic with a short-acting benzodiazepine (eg, lorazepam). This adjunctive treatment offers sedation, treatment for possible acute EPS (eg, acute dystonic reaction), and may also treat akathisia. Often, an anticholinergic is added later for the treatment of EPS. Another treatment intervention for akathisia is the use of β-blockers, eg, propranolol (40–60 mg/day PO).

With patients who present acutely psychotic and persistently aggressive, the clinician may want to combine the antipsychotic treatment with depakote. A recent double-blind study combining either olanzapine or risperidone with depakote in acutely psychotic patients showed that those on the combination regimen improved faster on a number of psychosis symptoms, including excitement and uncooperativeness.12

Another longer-term option to consider for persistently aggressive psychotic patients is clozapine. This atypical compound has been found in a number of open-label and one double-blind study to significantly reduce hostility, the number of violent episodes, and the need for seclusion.13

Management of Postacute Schizophrenia

It is important to remember that maintenance therapy for schizophrenia will be long-term and often life-long. However, while the preponderance of evidence supports the recommendation of long-term pharmacotherapy for schizophrenia, every patient will decide whether or not he or she will continue to take a prescribed medication. It is the job of the psychiatrist to foster a collaborative relationship in which the patient feels free to share his or her personal experience, personal opinions, and experiences with side effects regarding the prescribed medication. Psychoeducational interventions with patients and their families are helpful in setting the stage for long-term treatment. Some general guidelines for the duration of maintenance treatment are listed in Table 4.







In terms of general guidelines for dosing during the maintenance phase, recommended doses are presented in Table 5. In general, the minimum effective dose that gives the best efficacy and the lowest levels of side effects should be used. This minimum effective dose will change over time, and ongoing efforts should be made to find the minimum effective dose.







Duration of Medication Trials

In general, specific medication trials should be within recommended duration in order to ensure that the patient has had an adequate trial and that ineffective medications are discontinued in a timely fashion. Recommended trial durations are 4–12 weeks for atypical antipsychotics, 4–12 weeks for typical antipsychotics, and 3–12 months for clozapine. In the case of intolerable side effects, antipsychotics can be discontinued at any point during a trial. A special situation applies to the acute inpatient setting, where discontinuation of an antipsychotic trial could be considered after 1 week if there is no hint of a response.

Side-Effect Management

Side effects can have a number of adverse effects on treatment, including decreasing the therapeutic alliance, causing medication nonadherence, and contributing to serious morbidity and mortality. However, if side effects are managed in a collaborative manner with the patient, it can offer an opportunity to build the therapeutic alliance, support illness self-management, and minimize the risk of adverse outcomes. In general, one of the first strategies is to reduce the dose. If this fails, an additional compound can be added to reduce the side effect in question (Table 6). If this intervention fails, one should switch to a medication with a more favorable side-effect profile.



During the maintenance phase, patients are seen over several years by psychiatrists who monitor their clinical response to drugs, including vulnerability to side effects. In order to facilitate the monitoring, we have summarized some of the most important measures, which clinicians should examine and which will rapidly and efficiently yield data on side effects (Table 7).



Treatment Strategies for Coexisting Syndromes

During the maintenance phase, coexisting syndromes may emerge and may respond to the antipsychotic treatment in progress. However, some may require treatment with an augmenting strategy as outlined below in Table 8.



Treatment Strategies for Partial/Nonresponders

The traditional definition of treatment nonresponse in the past was pharmacologically driven and relatively narrow in scope; its criteria included two failed treatment trials with two different classes of neuroleptic agents and persistent illness for at least 5 years. However, the greater and wider-ranging efficacy of atypical antipsychotic agents has compelled a broader and a multidimensional definition. This new definition of treatment resistance uses (1) the concept of discrete domains of psychopathology, which can be treatment resistant; and (2) the concept response, which often is only partial. The discrete domains of psychopathology include persistent positive symptoms, persistent negative symptoms, persistent depressive-anxiety symptoms (including suicidality), persistent excitement symptoms (including aggressive behavior), and persistent cognitive symptoms. Also included are functional-disability symptoms such as social-function deficits (eg, inability to live independently in the community) and occupational deficits (eg, inability to perform adequately in a work or academic setting). Finally, continuous hospitalization or frequent rehospitalization is also included in this definition.

The atypical antipsychotic agents, clozapine, olanzapine, risperidone, and quetiapine, play an important role in the treatment of these patients. The role of ziprasidone is not yet clear, as data on its effects on partial responders is not available yet.


The first breakthrough in the treatment of refractory schizophrenia came when Kane and colleagues14 reported that clozapine, the prototypical atypical antipsychotic agent, was superior to chlorpromazine in a group of patients who met rigorous criteria for treatment resistance. In this study, 30% of clozapine-treated patients fulfilled a priori response criteria, compared with only 4% of chlorpromazine-treated patients. These results have been confirmed in a number of other comparative studies.

In a recent review by Wahlbeck and colleagues15 on clozapine’s effectiveness in schizophrenia, the drug was found to be superior in clinical improvement (Brief Psychiatric Rating Scale [BPRS] standard mean difference=0.7, 95% CI=0.5–0.9).

The one study in which results ran somewhat counter to these positive ones was a more recent trial by Rosenheck and colleagues.16 In this 1-year, randomized, double-blind trial, clozapine 100–900 mg/day was compared to haloperidol 5–30 mg/day in 205 and 218 patients, respectively, with treatment-refractory schizophrenia. Clozapine performed better than haloperidol in several aspects of the study. For example, clozapine-treated patients were significantly more likely than were haloperidol-treated patients to continue their assigned treatment for the full year (57% versus 28%; P<.001). In addition, compared to haloperidol-treated patients, clozapine-treated patients had a significantly better quality of life (P=.003), less tardive dyskinesia (P=.005), fewer EPS (P<.001), and fewer mean days of psychiatric hospitalization (144 days versus 168 days, P=.03). However, the difference between the two groups was far more modest than had been shown in previous studies, at just 5% (mean scores at endpoint: 79 with clozapine versus 84 with haloperidol; P=.02). Nevertheless, the preponderance of research evidence shows that clozapine is substantially more effective than typical neuroleptics in treatment-resistant schizophrenia.


In a study that compared risperidone to typical antipsychotics in treatment-resistant patients, Wirshing and colleagues17 reported on 67 medication-unresponsive subjects with schizophrenia who were randomly assigned to either risperidone 6 mg/day or haloperidol 15 mg/day for a fixed dose during a 4-week period and for a flexible dose for a 4-week period (mean risperidone 7.5 mg/day and mean haloperidol 19.4 mg/day). Risperidone demonstrated clinical efficacy superior (as measured with the Positive and Negative Symptom Scale for Schizophrenia [PANSS]) to that of haloperidol after the first 4 weeks of treatment, which was lost after an additional 4 weeks of treatment. Risperidone-treated patients needed significantly less concomitant anticholinergic medication, showed less akathisia, and less severe tardive dyskinesia than haloperidol-treated patients.


A subpopulation of 526 patients selected from a larger multicenter study and meeting treatment-resistant criteria (including failure to respond to a trial of at least 8 weeks’ duration of one or more conventional neuroleptics during the previous 2 years) were randomized to receive either olanzapine (mean dose, 11.1 mg/day) or haloperidol (mean dose, 10 mg/day).18 A greater proportion of patients in the olanzapine group than in the haloperidol group completed the study, and fewer olanzapine-treated patients discontinued due to of lack of efficacy. Looking at patients who completed the trial, the olanzapine-treated patients achieved significantly greater mean improvement compared with the haloperidol-treated group for all symptom measures, including BPRS total (P=.006), PANSS total (P=.005), PANSS positive symptoms (P=.017), PANSS negative symptoms (P<.001), and Montgomery-Asberg Depression Rating Scale total (P=.019).

In contrast to these positive results, Conley and colleagues19 showed that olanzapine was no better than chlorpromazine. In a controlled double-blind study, these authors compared the effect of olanzapine (25 mg/day) to chlorpromazine (1,200 mg/day) in an 8-week study of treatment-resistant schizophrenia patients. The results showed that olanzapine was therapeutically not superior to chlorpromazine, showing a response rate of only 7%.


Emsley and colleagues20 reported on an 8-week study of quetiapine 600 mg/day compared to haloperidol 20 mg/day in a group of treatment-refractory schizophrenic patients who had been included in the study after showing partial or no response after a prospective 4-week trial of 20 mg/day of fluphenazine. Significantly more patients on quetiapine (52%) than on haloperidol (38%) achieved a clinical response of at least 20% reduction of PANSS total score (P<.05). In summary, the data on clozapine, risperidone, olanzapine, and quetiapine show significant superiority over typicals in treatment-resistant patients.

Comparisons Among Atypical Agents

How do atypical agents compare to each other in terms of efficacy in treatment-resistant patients? Few controlled studies are available in this area. Bondolfi and colleagues21 compared the atypical agent risperidone to clozapine in an 8-week, randomized, double-blind trial of 86 inpatients with chronic schizophrenia who were resistant to or intolerant of at least two different classes of conventional neuroleptics. Both atypical agents significantly ameliorated symptoms of schizophrenia (P<.001 versus baseline); 67% of risperidone-treated patients and 65% of clozapine-treated patients were clinically improved at endpoint according to total PANSS criteria, and there was no statistically significant difference between the two agents. It may be notable that the dose of clozapine was rather low (291.2 mg/day clozapine versus risperidone 6.4 mg/day), which may have put clozapine at a disadvantage. Another comparative trial examined the effects of clozapine (mean daily dose 403.6 mg) and risperidone (mean daily dose 5.9 mg) in partially responding schizophrenia patients using a double-blind, 8-week design after a baseline fluphenazine treatment period.22 Clozapine proved to be superior to risperidone only in positive symptoms and parkinsonian side effects. The two compounds were comparable in their effects on negative symptoms, depressive symptoms, and BPRS total scores.

Olanzapine has also been compared to clozapine in treatment-resistant patients. In a double-blind, randomized 18-week trial, Beuzen and colleagues23 compared clozapine to olanzapine in 180 patients with schizophrenia who were deemed treatment refractory by virtue of having failed to respond to at least two previous adequate antipsychotic trials. Once again, both agents were effective, but the differences between the two did not reach statistical significance. The results numerically favored olanzapine, which decreased total PANSS scores by 25.6, compared with 22.1 for clozapine.

In a well-designed, double-blind, 14-week study comparing risperidone, olanzapine, and clozapine with haloperidol in well-defined treatment-refractory patients with schizophrenia, Volavka and colleagues24 reported significant superiority on the PANSS of clozapine and olanzapine over haloperidol.

Most recently, clozapine emerged as significantly more effective than olanzapine in the prevention of suicidal behavior in patients with a history of suicide attempts. It was also more effective than hospitalization in preventing suicide attempts within the previous 36 months, and moderate to severe suicidal ideation or command hallucinations for self-harm in the week prior to enrollment. The 2-year study included patients with schizophrenia or schizoaffective disorder (N=980) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.25

Switching or Augmentation

An important clinical concern is what type of strategy should be used in the group of patients with treatment-refractory schizophrenia who have not responded to atypicals. Is it helpful to switch patients who have failed on one atypical to another one? This question has been examined in two recent studies.26,27

Our group conducted a study in 43 inpatients who were highly treatment resistant to adequate trials of typical neuroleptics and to either clozapine or risperidone.26 All patients were switched to olanzapine 10–40 mg/day for 14 weeks after a cross taper, in an open-label, prospective trial. Results on the PANSS showed a minimal nonsignificant improvement in positive and negative symptoms, but a significant improvement in cognitive symptoms (P=.001) and depression/anxiety symptoms (P=.042). Examining improvement using the categorical approach, we found seven patients who were classified as improvers (20% decrease in BPRS), representing an improvement rate of 16.6%.

Another study examined the response of patients who had failed on olanzapine and were switched to clozapine.27 Of the 39 patients who had failed an 8-week trial with olanzapine, 21 were treated with clozapine. Of this group of patients, 52% was classified as responders with at least a 20% decrease in BPRS score. In summary, it appears that a switch from a failed trial with olanzapine to clozapine can be considered, while the reverse may not be very advantageous.

Finally, a number of augmentation strategies have been suggested for patients who have failed a trial with an atypical agent. Unfortunately, only few controlled double-blind studies are available in this very challenging area. Henderson and Goff28 reported on an open study using risperidone as an adjunct to clozapine in a 12-week trial of treatment-refractory outpatients with schizophrenia. BPRS scores decreased significantly in this group and 10 of the 12 patients improved on the BPRS.

In a retrospective study by Friedman and colleagues,29 clozapine augmentation of pimozide for partial clozapine responders was helpful in reducing mean BPRS scores from 51 to 27 in two schizoaffective and five schizophrenic patients. Another augmentation report utilized loxitane in chronic schizophrenic patients who still continued to show substantial impairment in functioning while taking clozapine.30 These patients received adjunctive loxitane lasting 18–50 weeks. All patients improved as measured by BPRS ratings ranging from 19 to 38 points, with two patients improving remarkably.

The guiding principle of augmentation strategies is to first determine the main treatment-resistant syndrome within the overall clinical presentation of the patient. Each of these persistent clinical syndromes can then become a treatment target for a specific augmentation strategy that is added to a stable atypical antipsychotic regimen (Table 5).


Schizophrenia is a severe and chronic illness that requires careful, ongoing pharmacologic management. Treatment guidelines such as those presented here help to inform clinical decisions regarding choice of medication. Second-generation atypical antipsychotics have provided clinicians with better tolerated alternatives to older typical antipsychotics. However, levels of efficacy are still widely variable among patients.


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