The Importance of Early and Effective Treatment Response in Schizophrenia

Associate professor of psychiatry at Duke University Medical Center, and deputy clinical director at John Umstead Hospital in Durham, North Carolina

Introduction

Dependable, consistent control of symptoms over time is the necessary foundation upon which patients can rebuild their lives after the onset of schizophrenia. Full-blown psychotic exacerbations are all-consuming. We can hope that improved public awareness that schizophrenia is a medical brain disease requiring prompt intervention will result in expeditious treatment of first psychotic episodes. School teachers and counselors, pediatricians and family practitioners, and others who deal with young adults should be keenly aware of the risks of schizophrenia during the young adult period, and of how much they can do to preserve the function of the individuals who suffer its onset. By identifying and treating psychotic exacerbations early, we can potentially limit the initial damage they cause, and shorten the climb back to recovery. Maximizing the therapeutic benefits of treatment and maintaining these benefits over time may help make it possible for patients to pursue universal life goals (Figure 1). They may be able to re-engage with cherished family and friends, rejoin community activities, and seek the satisfaction of focused study and employment.^1,2

The Early Years of Schizophrenia

There is a frightening potential for disease progression in the early years of schizophrenia. In a comprehensive review of studies addressing first-episode psychosis, Perkins and colleagues³ demonstrated that a longer duration of untreated psychosis prior to beginning treatment with antipsychotic medications is correlated with more prominent persistent psychopathology and poorer functional outcomes at follow-up (Figure 2). Therefore, there is urgency in identifying individuals developing schizophrenia as early as possible, in schools, in the armed forces, in the offices of primary care providers, and in other settings where they may be recognized and brought to treatment.

Imaging studies reported during the past 5 years have documented that progressive loss of brain volume occurs over time in the early phases of schizophrenia, relative to matched controls. This volume loss proceeds despite treatment, especially in those patients who have a poor clinical outcome (Figure 3).⁴ For obvious ethical reasons, these studies did not include untreated control patients with schizophrenia who might have demonstrated even greater volume loss than that seen in the treated patients, so we should not underestimate the benefit sustained treatment provides.

In this tumultuous early-illness period of anatomical and physiological brain changes, there is high risk for psychotic exacerbations. In addition, young individuals do not want to view themselves as sick or needing treatment. The psychotic phenomena they experience have a subjective validity that does not lead them to label these experiences as pathological. They may not seek treatment, and may need to be convinced of its necessity. Failure to rapidly begin treatment may or may not accelerate brain volume loss; it will most likely lead to a fragmentation of patients' lives. They may be estranged from family and friends by bizarre or dangerous behaviors. School enrollments or employment may be terminated. Any progression toward recovery will be aborted, replaced by a downward spiral of increasing impairment. Function may be lost, never to be regained. Painful psychotic experiences may lead patients to attempt suicide or to engage in activities completely alien to their previous character and upbringing; these activities may result in incarceration.

Prompt Control of Psychotic Exacerbations

When psychotic exacerbations occur, we want urgent, prompt control. It appears that patients also have some appreciation of early and effective symptom control (Figure 4).^5,6 Patients who respond to treatment with early, substantial reductions in psychopathology are more likely to continue treatment over time. Conversely, poor early response predicts later nonadherence.

When treating a psychotic exacerbation, how long should we continue an initially prescribed antipsychotic that is not producing substantial symptom control before switching? As recently as 2003, Expert Consensus Guidelines recommended minimum trials of 3-5 weeks before switching.⁷ However, two recent reviews^8,9 showed that almost half of the total improvement from an effective antipsychotic tends to take place in the first 2-4 weeks of treatment (Figure 5). Therefore, if a patient is not showing clear improvement by the second week of treatment, switching to another antipsychotic should be considered. Switching makes more sense than adding antipsychotics, certainly as an early strategy. Increasing complexity of medication schedules, ie, increasing numbers of drugs and increasing numbers of dosages per day, appears to be associated with nonadherence and overall worsening outcomes.

Avoiding Relapse Into Psychotic Exacerbation

Even after we achieve a good treatment response, we must remain vigilant. In recently reported treatment studies involving patients experiencing a first psychotic episode and patients with chronic schizophrenia,¹⁰ ~3 out of every 4 patients discontinued their initial antipsychotic medication over 1-1.5 years of follow-up. In the largest percentage of patients, this may be because they viewed the medication as unhelpful, either due to a lack of insight into their illness and need for treatment or because the medication was in fact providing little benefit. Side effects tend to account for a smaller percentage of discontinuations.

We must be in regular and sympathetic contact with our patients and their family members or placement supervisors. We must bring up with patients their doubts about the necessity and value of medications, and identify any side effects they experience. Even mild side effects may become difficult to bear when experienced day after day after day without relief. Any appearance of insomnia, unexplained anxiety or distress, or worsening of psychotic symptoms may portend imminent relapse, and requires urgent attention.

There is little evidence that "compliance therapies" that review the medical nature of schizophrenia, the importance of treatment, and the wisdom of adherence offer benefit in improving adherence or in preventing relapse. Such approaches are based on explicit memory—the kind of memory that allows us to recall lecture points, the content of textbooks, or the rules by which a game is played—and patients with schizophrenia have severe impairments in explicit memory. However, patients with schizophrenia have intact implicit memory—the kind that allows us to get the hang of" a game by playing it. This may explain why individual placement and support programs, wherein patients begin a job with the support of an on-site job coach on the first day of the program, have been far more successful than traditional vocational rehabilitation programs in achieving employment for patients with schizophrenia. The pleasing aspects of a game that make us want to continue playing it include having teammates who are good to be with, the subjective experience of skill development, and the occasional delight of scoring or winning. It may be that our availability and friendliness as the patient's teammate, the patient's getting into the routine of taking a medication that simply makes him or her feel better, and the achievements that result in the patient's life are what drive adherence, rather than any cleverness of our arguments.

Summary

In summary, it appears that there are benefits to be gained by identifying psychotic exacerbations early and bringing effective treatment to bear quickly (Table).¹¹ If patients do not respond within the first 2 weeks to the initially prescribed antipsychotic, consider switching antipsychotics until you find something that works. When patients respond, our work is not finished. Optimize the response. Try to reduce psychopathology to a minimum. Attend to side effects; think of this task in terms of how you would feel if you had to take a medication every day for the rest of your life. Repeatedly inquire about patients' judgments as to their need for medication and the value of the medications they are presently taking. Treat their viewpoints with respect, express your point of view on these issues with clarity and persistence, and make it clear that their feeling better is the goal for both of you.

Our patients are consumers. We must convince them that there is value in taking their medications. Effective relief of symptoms, the avoidance of distressing side effects, and your clear concern for their well being and life goals will serve this purpose well.

Dr. McEvoy has received grants from AstraZeneca, Bristol-Myers Squibb, Lilly, Janssen, and Pfizer; and has received honoraria from Bristol-Myers Squibb, Lilly, Janssen, and Pfizer.

This feature is supported by Eli Lilly and Company.

References

1.  Anthony WA. Recovery from mental illness: The guiding vision of the mental health service system in the 1990s. Psychosoc Rehabil J. 1993;16(4):11-23.

2.  American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(suppl 2):1-56.

3.  Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry. 2005;162:1785-1804.

4.  Lieberman J, Chakos M, Wu H, et al. Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry. 2001;49:487-499.

5.  Liu-Seifert H, Adams DH, Kinon BJ. Discontinuation of treatment of schizophrenic patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs. BMC Med. 2005;3:21.

6.  Data on file, Lilly Research Laboratories, ZYP20050720A.

7.  Kane JM, Leucht S, Carpenter D, Docherty JP. Expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry. 2003;64(Suppl 12):5-19.

8.  Leucht S, Busch R, Hamann J, Kissling W, Kane JM. Early-onset hypothesis of antipsychotic drug action: a hypothesis tested, confirmed and extended. Biol Psychiatry. 2005;15;57(12):1543-1549.

9.  Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry. 2003;60(12):1228-1235.

10.  Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.

11.  Lamberti JS. Seven keys to relapse prevention in schizophrenia. J Psychiatr Pract. 2001;7(4):253-259.