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| Neuropsychopharmacology: The Fifth Generation of Progress |
Maintenance Drug Treatment for Schizophrenia
John G. Csernansky
Indefinite pharmacological treatment is required in almost all patients who suffer from schizophrenia. Schizophrenia is a life-long disorder, and prevention of recurrent psychotic episodes, as well as treatment of negative symptoms and cognitive deficits, is being increasing recognized as essential for patients’ quality of life. For this and other reasons, increasing emphasis is being placed on the importance of maintenance drug treatment in patients with schizophrenia. The major goal of this chapter is to review current knowledge about maintenance drug treatment for schizophrenia patients, in the hope that such a review will be instructive for both clinicians and researchers.
It is notable that in the case of acute drug treatments for schizophrenia, the goals of treatment have become broader in recent years. Only recently have clinicians fully appreciated the importance of treating negative symptoms, mood instability and cognitive deficits in such patients. Likewise, the goals of maintenance drug treatment for schizophrenia have broadened in recent years. Several years ago, clinical trials for maintenance emphasized only relapse prevention and minimization of side-effects. Now, improving the quality of life for patients is being recognized as an equal, if not more important, goal. Outpatients with schizophrenia who seek a good quality of life and a reintegration into work and meaningful relationships must not only be free from psychotic relapses, they must also experience relief from negative symptoms and mood instability. In addition, cognitive deficits are increasingly being recognized as a serious impediment to functioning in school and the workplace (31).
Today, clinicians and their patients have many more drugs to choose from than in previous years. The use of atypical antipsychotics, such as clozapine, risperidone and olanzapine, has recently surpassed the use of typical antipsychotics, such as haloperidol and fluphenazine. As reviewed elsewhere in this volume, atypical antipsychotic drugs have improved efficacy for some negative symptoms, and their efficacy for mood instability and cognitive deficits is being investigated aggressively. Atypical antipsychotic drugs have clear advantages in the inpatient treatment setting, and their use during maintenance treatment should also offer many advantages compared to typical antipsychotic drugs.
In this chapter, our discussion of maintenance drug treatment for schizophrenia will be organized around three key topics: 1) prevention of psychotic relapses, 2) minimization of side-effects, and 3) treatment of negative symptoms, mood instability, and cognitive deficits. Whenever possible, the relative efficacy of typical versus atypical antipsychotic drugs will be highlighted. In addition, a discussion of combining psychosocial treatments and drug treatments to enhance relapse prevention and quality of life will be offered. Little emphasis will be placed on the prevention and treatment of tardive dyskinesia in this Chapter, as this topic is covered in detail in a separate Chapter.
Prevention of Psychotic Relapses
Prevention of Psychotic Episodes Using Typical Antipsychotic Drugs
Typical antipsychotic drugs were established as effective treatments for the prevention of psychotic relapses many years ago (48). While approximately half of schizophrenia patients treated with placebo relapse within four to six months, less than one quarter of schizophrenia patients treated with typical antipsychotic drugs relapse within this time period (21). Given the common side-effects of typical antipsychotics, many relapse prevention studies using such drugs have emphasized the importance of finding the lowest effective dose (70). Studies of the two typical antipsychotic drugs available in depot form, fluphenazine and haloperidol, suggest that surprisingly low doses may be as effective as more commonly used doses in substantial numbers of schizophrenia patients. For example, fluphenazine doses as low as five and ten mg every two weeks (41, 49, 57) and haloperidol doses as low as 50 mg every four weeks (47) have been shown to be effective in preventing psychotic relapse. However, some studies of low-dose therapy using typical antipsychotics suggest that efficacy may not always be equivalent. For example, in a large, multi-center, double-blind evaluation of four doses of haloperidol decanoate (25 mg, 50 mg, 100 mg, or 200 mg every month), one year relapse rates for the four treatment groups were as follows: 63%, 25%, 23%, and 15% (47). While these results suggest that 50 mg per month and 100 mg per month have comparable efficacy and that 25 mg per month is not as effective, the results also suggest that some schizophrenia patients may need higher doses (e.g. 200 mg per month).
Another strategy for minimizing the dose of typical antipsychotic drugs used during maintenance treatment deserves mention. Intermittent use of typical antipsychotic drugs triggered by the appearance of prodromal symptoms was first suggested by Herz and Melville several years ago (37). The feasibility of this approach has been demonstrated in some research settings (15, 38). However, other studies of intermittent use of typical antipsychotic drugs reveal higher rates of relapse (13, 44, 63). Such treatment strategies do offer lower rates of side-effects; however, clear benefits for improving patients’ quality of life have not been demonstrated (13, 44, 63). An interesting treatment alternative is to combine low-dose maintenance drug therapy with intermittent augmentation of the same drug therapy when prodromal symptoms appear. In a study by Marder, et al. (57), this approach was shown to improve relapse prevention. However, the practicality of these intermittent treatment strategies can be questioned since they require intense monitoring of the patients’ symptoms and the observations of family members, which may strain clinical resources in many treatment settings. In addition, prodromal symptoms may not always be reliable predictors of impending psychotic relapse (36, 42).
While these studies suggest that lower doses of typical antipsychotic drugs can be used successfully in many patients with schizophrenia, they also illustrate an important limitation of this class of drugs - their narrow therapeutic index. Ideally, one should not have to choose among closely similar doses of an antipsychotic drug to find a dose that is both effective and tolerable. Moreover, relapse prevention using any dose of antipsychotic drug will only succeed when the drugs are taken as prescribed. While schizophrenia patients can be poorly compliant with treatment because they lack insight and judgement (78), many patients are understandably reluctant to take typical antipsychotic drugs because of the side-effects that they experience (e.g. pseudoparkinsonism, akathisia, and tardive dyskinesia) (83). Neurological side-effects and the narrow therapeutic index of typical antipsychotic drugs point out the need for fundamentally better treatment options.
Preventing Psychotic Episodes Using Atypical Antipsychotic Drugs
Atypical antipsychotic drugs are defined as such because they have a broader therapeutic index. In other words, the doses required for efficacy are substantially lower than the doses expected to cause side-effects, such as pseudoparkinsonism, dystonia, akathisia, and tardive dyskinesia (3, 56). In addition to greater tolerability, atypical antipsychotic drugs may have greater efficacy for many positive and negative schizophrenic symptoms as compared to typical antipsychotic drugs (46, 56).
Clozapine is widely considered to be the prototype for an atypical antipsychotic drug. When administered for relatively short periods of time, response rates in schizophrenia patients known to be refractory to treatment with typical antipsychotic drugs was approximately 30% (46). When used for longer periods of time, response rates may be even higher (i.e. 60%) (61). Breier, et al. (9), compared clozapine to haloperidol directly in outpatients being treated for schizophrenia, and demonstrated the superiority of clozapine for relapse prevention. These studies, taken together, suggest that clozapine may have a fundamentally different mode of action during the maintenance phase of treatment in schizophrenia patients. While typical antipsychotic drugs can aim only to prevent deterioration over time through relapse prevention, the efficacy of clozapine for psychotic symptoms may grow with the passage of time. In this way, clozapine treatment may help to point us toward the ideal form of antipsychotic drug therapy during the maintenance phase of treatment.
Risperidone, a distant chemical derivative of haloperidol, was the first atypical antipsychotic introduced in the United States following clozapine. During acute treatment, its efficacy for positive symptoms was shown to be at least equivalent to typical antipsychotic drugs and its efficacy for negative symptoms that occur together with positive symptoms in acutely ill patients has been shown to be superior to typical antipsychotic drugs (16, 18, 56). However, whether or not risperidone has efficacy for enduring negative symptoms, such as one might find in outpatients with schizophrenia, whose positive symptoms have been optimally treated, has not yet been established. Lindstrom, et al. (55), have shown, in an open study, that switching schizophrenia patients from typical antipsychotics to risperidone during the maintenance phase of treatment results in fewer relapses and rehospitalizations. Such advantages in relapse prevention may be due to lower side-effects and improved compliance.
Olanzapine, a close analogue of clozapine, was introduced after risperidone in the United States, but it has also enjoyed wide acceptance and use. Dellva, et al. (22), demonstrated in a one-year, double-blind, placebo-controlled, comparison of usual (5-15 mg/day) and very low (1 mg/day) doses of olanzapine, that usual doses of olanzapine are superior to both placebo and very low doses of olanzapine for relapse prevention. The one year rates of relapse for usual doses of olanzapine (i.e. ~ 28%) were equivalent to one year relapse rates in patients treated with typical antipsychotic drugs (47). Recently, a direct comparison of risperidone and olanzapine has been undertaken in schizophrenia patients during 28 weeks of administration (77). In this study, olanzapine was found to be superior to risperidone in the number of patients who maintained their clinical response over time (i.e. relapse prevention). While this study can be criticized for the drug doses used (i.e. the average dose of risperidone used was 7.2 mg/day, which may be higher than optimal), studies such as this one suggest that significant clinical differences between atypical antipsychotic drugs may exist.
In addition to clozapine, risperidone and olanzapine, other atypical antipsychotics are now becoming available. These drugs represent both chemical analogues of clozapine (e.g. quetiapine) and distinct chemical structures (e.g. sertindole and ziprasidone). While the acute efficacy of these drugs has been well-demonstrated (cf. 5), little data is available about their capacity to prevent relapse, particularly in comparison to other atypical antipsychotics, such as clozapine, risperidone and olanzapine.
Predictors of Psychotic Relapse During Maintenance Antipsychotic Drug Treatment
There has been substantial interest in determining non-drug predictors of relapse in schizophrenic patients undergoing maintenance treatment. If such predictors exist, they might be used to intervene during the early stages of a psychotic relapse by changing the dose of the antipsychotic drug used or adding a second drug to augment the antipsychotic effects of the first drug. This topic has been reviewed in detail by van Kammen (84) and will only be briefly summarized here. Unfortunately, most common clinical variables, such as age or age at onset of illness, have been found not to be predictors of impending psychotic relapse. Buchanan et al. (12) reported that higher antipsychotic drug doses may predict relapse when drug treatment is stopped. However, the scenario of stopping drug treatment entirely is not usually intended as a part of treatment. Lieberman, et al. (54), but not Buchanan et al.(12), found that symptoms of tardive dyskinesia might predict psychotic relapses when drug treatment is withdrawn. While this information may be useful in patients treated with typical antipsychotic drugs, it has much more limited value in patients treated with atypical drugs that are associated with a lower risk of extrapyramidal side-effects.
Because of a hypothesized relationship between brain dopamine activity and plasma concentrations of a major dopamine metabolite, homovanillic acid (HVA), this neurochemical marker have been investigated to determine its value in predicting psychotic relapse. Lower plasma HVA concentrations during maintenance treatment with typical antipsychotic drugs and increases in plasma HVA concentrations after drug discontinuation have both been shown to predict psychotic relapse (30). Unfortunately, such data is not yet available for atypical antipsychotic drugs.
Limitations of Current Work and Needs for Future Research.
Substantial work has been done to establish optimal doses of typical antipsychotic drugs for relapse prevention. However, much of this work has now been overshadowed by the advent of atypical antipsychotics and their demonstrated superiority during the maintenance phase of treatment. Research is now needed to establish relative advantages and disadvantages among these new drugs for the treatment of schizophrenia in the maintenance phase. In addition, studies to substantiate claims that a superior side-effect profile will lead to better compliance with treatment should be performed. Predictors of relapse during treatment with atypical antipsychotic drugs should be discovered if possible, but they are unlikely to be related to the side-effects (e.g. tardive dyskinesia) and neurochemical effects (e.g. changes in plasma HVA concentrations) characteristic of typical drugs.
Minimization of Drug Side-Effects During Maintenance Treatment
Side-effects can undermine the efficacy of maintenance antipsychotic drug treatment. Dose-dependent side-effects can preclude patients from taking optimal drug doses. In other cases, side-effects, such as akathisia, can be particularly distressing to schizophrenia patients and cause non-compliance. Minimization of drug side-effects is usually a greater cause for concern during maintenance treatment than acute treatment, since clinicians have few tools to influence outpatients who are ambivalent about taking their prescribed medications.
Neurological Side-effects
Pseudoparkinsonism is perhaps the most characteristic side-effect of typical antipsychotic drugs. However, akathisia, which can manifest as either a subjective or objective sense of motor restlessness, is also common (2,8). Both of these side-effects have the potential to seriously undermine maintenance antipsychotic drug therapy (83). Several studies have shown that schizophrenia patients who experience such side-effects have a poorer outcome of treatment (52, 65, 80).
The severity of pseudoparkinsonism and akathisia is dose-related (52, 65), and may be associated with the proportion of subcortical brain dopamine receptors occupied by the antipsychotic drug. The clinical efficacy of typical antipsychotic drugs has been associated with approximately 70% occupancy of subcortical dopamine receptors (D2) by drug, while the threshold for drug-induced side-effects, such as pseudoparkinsonism, has been associated with a slightly higher degree of receptor occupancy (~80%) (27). These results are discouraging in that they suggest that the doses of typical antipsychotic drugs that are needed for efficacy and the doses that produce side-effects are nearly the same. McEvoy, et al. (59), have suggested that slowly titrating the doses of typical antipsychotic drugs can achieve threshold doses that are effective but not associated with substantial side-effects. However, such strategies for dosing require special training and time and may be difficult to use in many inpatient treatment settings.
In a meta-analysis of clinical trials of typical antipsychotic drugs, Baldessarini, et al. (6), pointed out that dose-dependent side-effects, such as pseudoparkinsonism and akathisia can undermine the benefits of typical antipsychotic drugs at higher doses. While using the lowest effective doses of such drugs can minimize the side-effects of typical antipsychotic drugs, this strategy may also increase the risk of relapse and other serious complications of therapy. Attempts should be made to treat pseudoparkinsonism and akathisia with anticholinergic medications, such as benztropine mesylate, trihexyphenidyl or diphenhydramine. However, such drugs can add to cognitive impairment (see below) and some patients, particularly those that suffer from akathisia alone, may be refractory to such treatment strategies (8, 29, 81). Akathisia may also be treated with amantadine, benzodiazepines, clonidine, and drugs that block beta-adrenergic receptors (2). Finally, patients who experience serious side-effects of typical antipsychotic drugs are ideal candidates for treatment with atypical antipsychotic drugs, such as clozapine, risperidone and olanzapine.
Relationships Between Symptom Groupings and Neurological Side-Effects
There may be important relationships between various groupings of schizophrenia symptoms, and neurological side-effects (See Figure 1). Thus, the elimination and minimization of such side-effects during maintenance treatment for schizophrenia may help to improve efficacy as well. Neuroleptic-induced pseudoparkinsonism, sedation and dysphoria may confound the assessment of some schizophrenia symptoms, such as avolition and flat affect (14, 83). In addition, there may be more fundamental mechanistic overlaps among negative symptoms, pseudoparkinsonism (66) and some forms of depressive symptomatology (64, 66).
The relationship between negative symptoms, depression and pseudoparkinsonism in schizophrenia patients undergoing maintenance treatment with typical antipsychotic drugs has been evaluated (66). There is a direct relationship between the apparent severity of some negative symptoms and the severity of pseudoparkinsonism. However, the underlying nature of this relationship remains complex; the overlap may occur because the behaviors associated with negative symptoms, such as flat affect, are so similar to pseudoparkinsonism that is it difficult for clinicians to distinguish them or because there is an underlying pathophysiological link between the two phenomena. Other negative symptoms, such as avolition, may also be related to similar features of depression, such as decreased work and activities, motor retardation, and decreased libido. Until the exact nature of these neurobiological relationships can be clarified, negative symptoms that appear to overlap with other psychopathological syndromes should not be considered primary; they are more likely to be secondary and demonstrate our ongoing difficulty in distinguishing such phenomena at the clinical level.
There may also be a similar relationship between akathisia and the apparent severity of residual psychotic symptoms in schizophrenia patients undergoing maintenance treatment with typical antipsychotic drugs (65). In acute patients, Levinson, et al. (52), found that the appearance of akathisia during treatment with fluphenazine was associated with a poor antipsychotic response. However, van Putten, et al. (80) did not find a relationship between the severity of akathisia and a lack of resolution of psychotic symptoms during acute treatment with haloperidol.
Suicidal (23) and violent (50) behavior has also been related to akathisia in schizophrenia patients during maintenance treatment with typical antipsychotic drugs. In a study of both acute inpatients and outpatients undergoing maintenance therapy, an attempt was made to define the mechanisms underlying such relationships (65). In patients undergoing both acute and maintenance therapy, the severity of akathisia was directly correlated with the severity of residual positive and symptoms. Further statistical analysis suggested that these relationships were caused by an underlying dysphoria, which has been previously identified as a critical, but often overlooked, side-effect of typical antipsychotic drugs (80).
These results are also consistent with early observations that akathisia induced by treatment with typical antipsychotic drugs can be mistaken for an "agitated depression" (45), and warnings that akathisia predicts poorer clinical responses to treatment with typical antipsychotic drugs (71, 82).
Other Side-effects (e.g. Agranulocytosis, Hyperprolactinemia, Hypotension)
Neurological side-effects are not the only side-effects of concern during maintenance therapy. Other side-effects of concern occur because of adrenergic receptor blockade, disturbances of neuroendocrine and metabolic systems, and the synthesis of white blood cells. Many typical and atypical anti-psychotic drugs are antagonists at a1-noradrenergic receptors. This drug action causes orthostatic hypotension, which can be a serious side-effect in elderly or medically ill patients.
All typical antipsychotic drugs cause elevations in plasma prolactin concentrations, via blockade of dopamine D2 receptors on the pituitary lactotrophs. Among atypical antipsychotic drugs, this side-effect is variably present in relationship to the degree of ongoing dopamine D2 receptor blockade produced (27). Increases in plasma prolactin concentrations are likely to lead to loss of libido, perhaps due to suppression of the sex hormones, testosterone and estrogen. During long-term maintenance treatment, concerns have been raised about osteoporosis as a complication of chronic hyperprolactinemia, but no definitive data are yet available to evaluate this problem. Weight gain has been reported as a side-effect of many of the atypical antipsychotic drugs (3). During long-term maintenance therapy, many patients experience weight gain in excess of 10% of their usual body weight, which can raise serious medical concerns in many patients. This problem can also become a reason for treatment non-compliance in patients receiving atypical antipsychotic drugs.
Finally, treatment with clozapine is complicated by the need to monitor the white blood cell (WBC) count, since this drug can produce agranulocytosis (3). Recently, the frequency of WBC monitoring has been decreased to every two weeks in patients who have received clozapine for six months or more. Nonetheless, this requirement during long-term clozapine can be a serious disincentive for patients to continue therapy with this agent.
Limitations of Current Work and Needs for Future Research
Atypical antipsychotic drugs have a lower incidence of neurological side-effects, which enhances their value as agents for maintenance therapy. However, additional research is required to establish optimal relapse prevention doses for these drugs. Acute studies suggest that at least some of these drugs (e.g. risperidone) have an optimal dose response range (16), which should be fully exploited during maintenance treatment. The side-effects of atypical antipsychotic drugs that affect neuroendocrine mechanisms (i.e. prolactin elevation) and metabolism (i.e. weight gain) need to be more fully evaluated, especially in elderly patients. As new atypical antipsychotic drugs are developed, emphasis should be given to drugs that lack these additional problems.
Negative Symptoms, Mood Instability, and Cognitive Deficits
Research in a number of areas has demonstrated links among neurological side-effects, negative and depressive symptoms, and cognitive deficits. Moreover, these phenomena acting together can strongly influence quality of life in outpatients with schizophrenia (see Figure 2). Ultimately, the prevention of relapses is of little value ifs patients in "remission" cannot resume schooling or work. These latter measures of outcome are key in giving the person with schizophrenia a sense of their own self-worth.
Treatment of Negative Symptoms, Mood Instability and Cognitive Deficits Using Typical Antipsychotic Drugs.
The efficacy of typical antipsychotic drugs for the treatment of at least secondary negative symptoms (see below) may be highly related to the relative absence of neurological side-effects. Van Putten, et al., have shown that greater severity of such side-effects and poor efficacy for the treatment of negative symptoms occur together with the use of greater than optimal doses and plasma concentrations of typical antipsychotic drugs in acutely ill schizophrenia patients (79, 80). In these studies, van Putten and colleagues suggest that haloperidol doses of 20 mg per day or more, and plasma concentrations above 12 ng/ml, are likely to be associated with increased pseudoparkinsonism, greater dysphoria, and loss of efficacy for the treatment of negative symptoms in acute inpatients. Such relationships between the ability to assess a drug's efficacy for negative symptoms and the severity of confounding side-effects may persist into the maintenance phase of treatment.
Few studies have adequately addressed the question of the efficacy of typical antipsychotic drugs for the treatment of negative symptoms during maintenance treatment. Such studies are especially complex because enduring negative symptoms may be more predominant in outpatients with schizophrenia whose positive symptoms are optimally treated. With regard to acute treatment studies of inpatients, there remains considerable controversy regarding the effects of typical antipsychotic drugs on negative symptoms. Some early studies indicate that the negative symptoms of schizophrenia respond poorly to typical antipsychotic drugs (4, 43). However, Meltzer (62) has criticized these studies because of inadequate sample size, the use of rating instruments that may be insensitive to negative symptom assessment, and the fact that the patients had not been selected for having substantial negative symptoms. Meltzer (60) and Goldberg (32) conducted comprehensive reviews of the relevant literature and suggest that typical antipsychotic drugs are efficacious for the treatment of negative symptoms, although the magnitude of the effect is small compared to their efficacy for positive symptoms. In addition, it does not appear that improvements in primary negative symptoms contribute to these small changes (10).
As referred to above, negative symptoms may be either enduring (i.e. primary) or secondary to other psychopathological phenomena. Negative symptoms that are enduring and occur independently of positive symptoms, depression, or neurological side-effects (i.e. primary negative symptoms) have been used to identify patients with the so-called deficit syndrome (14). Increasing efforts have been made in recent years to distinguish the primary negative symptoms that occur in schizophrenia patients with the deficit syndrome from those that are secondary to positive symptoms, depression, or social isolation (14). The responsiveness of primary negative symptoms to typical antipsychotic drugs during acute or maintenance treatment has not yet been demonstrated, and studies addressing the responsiveness of non-specific negative symptoms to antipsychotic drugs in acute patients should not be used in lieu of such critical studies.
In studies of schizophrenic patients who are resistant to the anti-psychotic effects of typical antipsychotic drugs, these drugs also fail to demonstrate efficacy for even non-specific negative symptoms (46). It should be noted, however, that most of these studies are of only four-to-six weeks duration. The possibility of a delayed effect of typical antipsychotic drugs on negative symptoms in treatment-resistant patients has not been fully investigated.
Finally, typical antipsychotic drugs have not been shown to be efficacious for the treatment of depression or cognitive symptoms in schizophrenia patients undergoing maintenance therapy (28). Of course, it should be kept in mind that depression and cognitive deficits were not known to be amenable to drug therapy at the time that typical antipsychotic drugs were being tested to evaluate their benefits and risks. Recently, studies of atypical antipsychotic drugs have demonstrated that such drugs may be superior to typical antipsychotic drugs in terms of their efficacy for mood symptoms (75, 76) and at least some cognitive deficits (32).
Treatment of Negative Symptoms, Mood Instability , and Cognitive Deficits Using Atypical Antipsychotic Drugs.
There is growing evidence that atypical antipsychotic drugs have superior efficacy for the treatment of some types of negative symptoms in both the acute and maintenance treatment settings. Clozapine, the prototypical drug in this category, has been shown to be effective for the treatment of negative symptoms that occur in tandem with positive symptoms in both treatment-responsive (17) and treatment-resistant schizophrenic patients (46). However, the responsiveness of such negative symptoms may be not be predictive of the responsiveness of negative symptoms that are more clearly primary (see above). Breier, et al (9), showed that clozapine only had a modest advantage over haloperidol for the short-term treatment of negative symptoms in outpatients with schizophrenia. The outcome of this study may have had more to do with haloperidol’s poor effects on negative symptoms rather than clozapine’s unusual efficacy for such symptoms. In a later report from the same research group, Buchanan, et al (10), reported that after one year of treatment, clozapine showed efficacy for positive, but not negative symptoms, in outpatients with schizophrenia. Consistent with these results, Rosenbeck, et al (67), reported that clozapine showed no advantage compared to haloperidol for the treatment of negative symptoms in a large sample of Veteran outpatients with schizophrenia. These more definitive clinical trials suggest that clozapine does not have efficacy for primary negative symptoms. However, clozapine treatment in schizophrenia patients may still be associated with long-term benefits in patients' quality of life. In an open study of refractory schizophrenic patients followed for six months in the community, Meltzer and colleagues showed that clozapine treatment was associated with improvements in social functioning in a variety of areas, including work ability and interpersonal relationships (61).
Other atypical antipsychotic drugs have now been shown to be more effective than typical antipsychotic drugs for the treatment of at least secondary negative symptoms. In particular, risperidone has been shown to improve negative symptoms in acute inpatients with schizophrenia in a manner superior to haloperidol at intermediate doses (i.e. 6 mg/day) (16, 18). Similarly, Tollefson, et al. (74), found that olanzapine was superior to haloperidol for the treatment of negative symptoms in acute schizophrenia inpatients. Using an approach for assessing quality of life similar to that used by Meltzer in his evaluation of clozapine (see above), Hamilton, et al. (35), found that olanzapine’s efficacy for at least non-specific negative symptoms was extended over time and resulted in a significant improvement in patients’ quality of life. However, quetiapine, administered in a range of doses (75-750 mg/day) was not shown to have superior efficacy for negative symptoms compared to haloperidol (12 mg/day) (5). This is surprisingly given its relative lack of extrapyramidal side-effects. While quetiapine’s lack of efficacy for any negative symptoms is unusual among atypical antipsychotic drugs, it may reflect that the fact that this study was one where the low doses of haloperidol used as an active comparitor appeared have substantial efficacy for negative symptoms compared to placebo treatment. Thus, these finding do not rule out that quetiapine may be useful for the treatment of negative symptoms in at least acute inpatients with schizophrenia.
Finally, the question of whether atypical antipsychotic drugs are effective for the treatment of depressive symptoms in patients with schizophrenia has only begun to be examined. Tollefson, et al., have recently shown that olanzapine was superior to haloperidol for the treatment of depressive symptoms in schizophrenia patients, and that this action of olanzapine could not be attributed to the drug’s effects on positive or general negative symptoms or the relative absence of extrapyramidal side-effects (75, 76, 77) (see above for discussion of overlap between schizophrenia symptoms and extrapyramidal side-effects). The efficacy of such drugs may be related to their antagonistic effects at CNS 5-HT2 receptors, since more selective antagonists at these receptors have previously been shown to have anti-depressant effects (e.g. trazodone, ketanserin).
Evaluating the efficacy of atypical antipsychotic drugs for the cognitive deficits of schizophrenia (e.g. inattention, poor working memory and executive function) has been of great interest in recent years. Because such deficits have been linked to a poor outcome in schizophrenia (31), their treatment during the maintenance phase of antipsychotic drug therapy is of critical importance. Hagger, et al. (34), were among the first investigators to demonstrate that clozapine treatment for six months was associated with improvement in two measures of memory retrieval. However, improvement in performance on other cognitive tests, including tests of executive function (i.e. the Wisconsin Cart Sort Test), was not found. Buchanan, et al. (10), compared cognitive function after treatment with either clozapine or haloperidol treatment. While few significant differences were found during 10 weeks of controlled treatment, significant improvement was noted in verbal fluency and spatial construction ability in patients treated openly with clozapine after one year. Finally, Hoff, et al. (39), switched patients from treatment with typical antipsychotic drug therapy to clozapine treatment, and assessed a wide range of cognitive functions. Again, improvements in verbal fluency and motor speed were found after patients were switched to clozapine treatment. However, the switch to clozapine treatment was also associated with deleterious effects on Wisconsin Card Sort Test performance. Taken together, these results suggest that clozapine is effective for cognitive deficits in schizophrenia, but that such benefits may require substantial periods of time to appear, and remain limited to a subset of cognitive functions.
The effects of other atypical antipsychotic drugs on cognitive function are now under intense investigation. Acute risperidone treatment has been recently shown to improve performance on verbal memory tasks (32). Perhaps the magnitude of this benefit will improve and other benefits on cognitive performance will appear after longer periods of risperidone treatment. Promising studies of olanzapine’s effects on cognition have only begun to appear at professional meetings, and quetiapine’s effects of cognitive performance are not yet known.
Adjunctive Drugs for the Treatment of Negative Symptoms, Mood Instability and Cognitive Deficits in Schizophrenia.
Given the overlap between negative symptoms and depression, it is not surprising that anti-depressants have been tried for the treatment of negative symptoms in schizophrenic patients. In a study of schizophrenic patients with negative symptoms who also met criteria for post-psychotic depression, the addition of imipramine to ongoing fluphenazine treatment produced a modest improvement in the apparent severity of negative symptoms (72). Some (19, 86), but not all (1, 20), studies have suggested that alprazolam, a triazolobenzodiazepine with a chemical resemblance to anti-depressant drugs such as trazodone, may also be of some benefit for negative symptoms when added to typical antipsychotic drugs (19, 86). Attempts to augment the capacity of typical antipsychotics with anti-depressants that are selective serotonin uptake inhibitors has been disappointing, perhaps because such drugs interfere with the metabolism of typical antipsychotic drugs and thus increase their plasma levels and add to their dose-dependent extrapyramidal side-effects. Thus, some studies suggest that drug treatments that have shown efficacy for the treatment of depression may have limited efficacy for the treatment of at least secondary negative schizophrenic symptoms. However, this strategy for treating negative symptoms has been largely superceded by treatment with atypical antipsychotic drugs (3).
Limitations of Current Work and Needs for Future Research.
No firm conclusions can be drawn from available research studies as to the efficacy of typical antipsychotic drugs for the maintenance treatment of negative symptoms in schizophrenic patients. However, atypical antipsychotic drugs, such as clozapine, risperidone and olanzapine, have appear to show more promise than typical antipsychotic drugs for the treatment of at least non-specific negative symptoms. Unfortunately, the treatment of primary negative symptoms in patients with schizophrenia remains unresolved. Utilizing atypical antipsychotic drugs as a treatment strategy for negative symptoms in schizophrenia patients has largely replaced the use of augmentation strategies, such as the use of antidepressants in combination with typical antipsychotic drugs. However, there has been some current enthusiasm regarding the use of drugs that augment brain glutamatergic function, such as glycine and its chemical analogs, as adjuncts to antipsychotic drugs for the treatment of negative symptoms. Atypical antipsychotic drugs may also have anti-depressive effects in patients with schizophrenia, and this area of research should also be pursued, keeping in mind apparent overlaps among depression symptoms, negative symptoms, and pseudoparkinsonism.
A new and critical horizon in the maintenance treatment of schizophrenia patients is the remediation of cognitive deficits. Research with clozapine in this regard has been encouraging in that some benefits have been observed for memory and motor-related tasks, although such benefits appear to be offset by deleterious effects on executive function. Treatment of cognitive deficits with other atypical antipsychotics holds much promise, and additional research in this area should be encouraged.
Combining Pharmacological and Psychosocial Treatments
While the efficacy of psychosocial treatments for schizophrenia is not the central topic of this Chapter, optimizing the patient’s understanding of and compliance with maintenance drug treatment must involve attention to important psychosocial variables (53). Psychosocial treatments can alter environmental features related to relapse, offer opportunities and training to improve quality of life, and enhance compliance with antipsychotic drug regimens. Further, informal combinations of drug treatments and psychosocial interventions are carried out on an everyday basis in most outpatient clinics. Thus, it may be obvious that well-controlled studies are needed to guide the increasingly common practice.
The relationship between environmental stresses and a poor outcome in schizophrenia has been discussed for many years (85). High levels of interpersonal stress within the patient's family, sometimes referred to as high "expressed emotion," has been linked to higher rates of relapse in remitted patients. Psychosocial treatments aimed at educating family members about important management issues and diminishing interpersonal criticism have been found to be effective in diminishing rates of relapse in patients who are receiving maintenance treatment with typical antipsychotic drugs (25). Such benefits may have some specificity, since in one study, behavioral interventions specifically intended to decrease high levels of expressed emotion was found to be superior to a general educational program for patients and their families (73). Long-term follow-up studies of the efficacy of psychosocial interventions in patients with schizophrenia suggest that the benefits of this intervention can be relatively long-lasting (40).
Psychosocial approaches to treatment may also be useful in decreasing non-specific negative symptoms and enhancing quality of life in schizophrenic patients. In a controlled study of schizophrenia patients undergoing maintenance drug treatment, Liberman and colleagues demonstrated that the application of specific social skills training techniques improved social adjustment and decreased rates of relapse and rehospitalization (53). Further, Bellack and colleagues showed that a specific social skills training program brought about improvements in schizophrenic symptomatology and social functioning long after treatment had been completed (7).
Combining Specific Drug Treatments and Psychosocial Treatment.
There have still been relatively few studies where the interactive effects of specific psychosocial treatments and drug treatments have been studied. Hogarty, et al., examined the efficacy of a psychosocial treatment program in patients treated with either a standard or low dose of fluphenazine decanoate (41). In this study, patients who came from a high "expressed emotion" environment showed higher rates of relapse when treated with lower doses of typical antipsychotic drugs. This study suggests that when attempting to minimize the dose of maintenance antipsychotic drug, special attention should be given to elements of the patient's psychosocial environment.
Psychosocial therapies may also be used to enhance compliance with antipsychotic drug treatments. For example, Eckman, et al. (24), demonstrated that the implementation of a behaviorally-oriented program for teaching medication compliance was feasible in a large urban care-delivery system and was effective in improving some social skills.
Finally, in a large multi-center study, low dose treatment with a typical antipsychotic drug (2.5-10 mg fluphenazine decanoate every two weeks), standard dose treatment with a typical antipsychotic drug (12.5-50 mg fluphenazine decanoate every two weeks) and an intermittent dosing regimen were compared in combination with one of two possible psychosocial interventions (68, 69). The psychosocial interventions were either 1) an applied psychoeducational program to reduce family conflict and increase understanding of the illness (monthly group meetings and home sessions) or 2) a non-specific supportive family therapy (monthly group meetings alone). Following successful completion of a general psychoeducational workshop for the family members of all participants, subjects were randomly assigned to either the applied or supportive intervention for an extended period of treatment. Subjects entering the double-blind, randomized medication treatment phase of the study were first stabilized on antipsychotic medication over a period of 16 to 26 weeks.
The results of this study revealed a significant advantage for standard dose treatment over lower dose treatment, and for lower dose treatment over intermittent dosing treatment with regard to the prevention of psychotic relapses. However, the standard dose treatment group did not significantly differ from the lower dose treatment group in the amount of time prior to their first rehospitalization or in the likelihood of rehospitalization during the two year study period. Both standard dose and low dose treatment were significantly better than intermittent dosing on these measures. In contrast, however, negative symptoms were best treated by the intermittent dosing regimen and the lower dose treatment compared to standard dose treatment. Unfortunately, the two forms of psychosocial intervention employed in this study did not differ in terms of their ability to add to the efficacy of antipsychotic drug therapy to prevent relapse. Therefore, the results of this study do not support the superior efficacy of one type of psychosocial intervention over another. However, experts in the field currently accept the utility of combining antipsychotic drug treatment and psychosocial therapies during the maintenance phase of antipsychotic drug treatment in patients with schizophrenia (51).
Limitations of Current Work and Needs for Future Research.
Further research is needed to improve out understanding of the optimal ways in which antipsychotic drug treatments and psychosocial interventions can be combined in patients with schizophrenia undergoing maintenance treatment with antipsychotic drugs. Studies involving typical antipsychotic drugs are encouraging, even though such drugs have 1) significant side-effects which undermines compliance and 2) do little to improve cognitive capacities that may be needed to absorb information from psychoeducational programs. Obviously, combining psychosocial treatments with atypical antipsychotic drugs that have fewer side-effects and benefits for cognitive function is an attractive approach to minimizing relapse rates and maximizing quality of life in schizophrenia patients undergoing maintenance drug treatment. Careful studies are urgently needed in this area to guide clinical practice.
published 2000