Prevention and Early Interventions

It was not too long ago that the management of schizophrenia was generally viewed as pessimistic, and focused primarily on symptom relief. Over the past two decades, there has been a paradigm shift in our approach to the overall management of schizophrenia, toward preventive and early interventions. These approaches are being increasingly guided by recent pathophysiological models. In particular, it has become clear that neurobiological alterations are seen before onset of the illness (the premorbid phase) (Johnstone et al., 2002) and may progress during the early stages of the illness (the prodromal phase).

Further deterioration in brain structure and function may appear in some cases after characteristic symptoms of the illness begin (the psychotic phase), especially during the initial years. These observations suggest a critical window of opportunity, early in the illness, to effect lasting modifications in overall illness course (Keshavan et al., 2005a).

The three key questions for the field are:

• Can schizophrenia be prevented in those at risk for the disorder (primary prevention)?
• Can the first episode of psychosis be prevented in patients experiencing the prodromal phase of the illness (secondary prevention)?
• Can we prevent relapses and further functional decline in patients who have already experienced the first episode of psychosis (tertiary prevention)?

Recent work, outlined below, suggests that considerable progress has been achieved in these areas over the years.

Prodromal Intervention

Primary prevention is best realized by removing a cause before the illness develops (e.g., preventing dental cavities by adding fluoride to the water). In schizophrenia, this remains speculative at best for now. The widely reported risk factors for schizophrenia include genetic factors, season and place of birth, pregnancy and birth complications, and antenatal exposure to viruses. Possible interventions for the families of genetically at-risk individuals include genetic counseling, prevention of viral infections during pregnancy and adequate prenatal care for women with schizophrenia.

In the future, it hopefully will be possible to design interventions that are specific to those individuals genetically at risk who display neurobehavioral and neurobiological precursors found by ongoing prospective studies to be accurate predictors of later illness (Keshavan et al., 2005b). For example, a program for an adolescent at genetic risk for schizophrenia who also displays cognitive and social deficits might include improvement of the home environment, prevention of abuse and neglect, a structured school environment combined with cognitive remediation, and possibly social skills training.

Pharmacotherapy

Secondary prevention strategies seek to prevent conversion to the full-blown psychotic illness in people experiencing the prodromal phase of the illness. The view that the attenuated psychotic-like symptoms characterizing the prodrome might be mediated by phasic dopaminergic excess has encouraged early treatment with low doses of dopamine-blocking drugs.

In a single-blind design, McGorry et al. (2002) compared low-dose risperidone (Risperdal) plus cognitive-behavioral therapy (CBT) with a needs-based intervention (i.e., counseling and case management) for six months. This was followed by a six-month observation period of all patients on needs-based therapy only. The combined specific intervention led to a significant preventive treatment effect in a modest sized population of 59 participants. Using a double-blind, randomized approach, Woods et al. (2003) compared the efficacy of olanzapine (Zyprexa) versus placebo. At eight weeks, a modest improvement was seen in symptoms associated with olanzapine treatment, though significant weight gain was also seen.

The German Research Network on Schizophrenia (Bechdolf et al., 2005; Ruhrmann et al., 2005 ) reported promising but very preliminary results in a randomized, open-label design, comparing amisulspride to psychological management for prodromal symptoms. Using a naturalistic treatment strategy Cornblatt et al. (2002) observed that for individuals in the earlier prodromal stages with moderate positive symptoms, antidepressants may be an effective alternative to antipsychotics.

Other, more experimental approaches are being investigated as well. Researchers in Melbourne, Australia, have been conducting a one-year trial with low-dose lithium (Eskalith, Lithobid), the definitive results of which are expected soon. Using predictions derived from the membrane model of schizophrenia, Woods et al. (2002) conducted a three-month study with ethyl-eicosapentaenoic acid, an omega-3 fatty acid. The results are awaited.

Some studies suggest that psychological treatments such as CBT may have advantages over standard treatments for psychosis in terms of reducing the transition from pre-psychotic states to full-blown psychosis (Haddock and Lewis, 2005). Morrison et al. (2002) randomized prodromal patients into those receiving CBT versus monitoring only. At one-year followup, 6% of the CBT arm versus 22% of the control arm had developed psychosis (Haddock and Lewis, 2005).

Preventing Relapse

Tertiary prevention seeks to prevent disability and relapse in patients who have already developed psychosis. First-episode patients show higher response rates to treatment (46% to 96%) compared to multi-episode patients but also show high rates of relapse due to noncompliance (Robinson et al., 2005). There is increasing evidence that relapse rates are reduced by early introduction of family intervention to reduce levels of expressed emotion, CBT to address cognitive distortions and individual psychotherapy aimed at restoring a sense of self and achieving mastery over the illness (for a review, see Haddock and Lewis, 2005).

Comprehensive early psychosis treatment packages involving pharmacologic and psychosocial treatments as outlined above are more cost-effective than treatment as usual in improving long term recovery, as shown by recent controlled trials. Petersen et al. (2005) randomized 547 patients to either integrated treatment over two years, consisting of assertive community treatment with family involvement and social skills training or standard treatment offering contact with a community mental health center. Patients in the integrated treatment limb had significantly better recovery of positive and negative symptoms, less comorbid substance misuse, better adherence to treatment, and more satisfaction with treatment. Investing in early and comprehensive intervention can therefore improve our patients' lives in the longer term as well as reduce overall costs of treatment.

First-episode patients with schizophrenia also have high rates of comorbid substance abuse, depression, noncompliance, and impairments in cognition and social skills. Dual diagnosis patients with psychosis and substance abuse are more likely to relapse. A recent controlled trial has shown that, compared to standard care, such patients are likely to benefit from combined psychosocial treatment packages including motivational enhancement (Barrowclough et al., 2001).

Patients with the first episode of psychosis are also likely to experience a high likelihood of depression and suicidal behavior during the early course of their illness. Controlled trials are underway showing initial promising results (Power et al., 2003). Noncompliance rates are high in the first episode of psychosis, perhaps related to high rates of poor insight. Motivational enhancement therapies may help improve compliance as shown in controlled trials in patients with psychotic disorders (Kemp et al., 1998). An uncontrolled study showed a lack of efficacy of this treatment in patients with schizophrenia or schizoaffective disorder (Byerly et al., 2005). Results from controlled studies in early schizophrenia are awaited. Finally, cognitive remediation studies have also begun to provide encouraging results in regard to improvements in functional outcome when introduced early in the course of schizophrenia (Hogarty et al., 2004).

Conclusion

In summary, the evidence base of early interventions in schizophrenia is rapidly gaining acceptance in the field. However, as the field matures, it will be necessary to more extensively replicate the findings of the handful of early prevention studies, more conclusively validate the criteria currently defining the prodrome, further extend the range of potential interventions to include treatments other than antipsychotics, and to target specific prodromal and possibly premorbid phases of illness. Evidence-based demonstrations of cost-effectiveness of such interventions are critically needed if this field of research is to sustain and solidify this paradigm shift.

References:

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