Preventive Interventions for schizophrenia: hopes and challenges
Prodromal phase of psychosis is referring to the period from first noticeable symptoms or unusual experiences to the first prominent psychotic symptoms (7). Retrospective studies have shown that the average duration of symptoms before the first admission is between 2-6.5 years (7). During this phase, patients frequently endorse indistinct symptoms such as changes in perceptions, beliefs, cognition, mood, affect and behavior (6) (7). In addition, sleep disturbances, abuse of alcohol or drugs, and social decline (6) (7). These symptoms are not distinguishable to schizophrenia and can be seen in other psychiatric disorders (7). However, studies have shown that poor functioning, high level of depression, reduced attention and family history of psychosis all predict psychosis (5). Risk factors associated with later development of psychotic illness are either parents or close family member having psychotic illness, mental retardation (low I/Q), unfavorable family environment (having major stresses), substance abuse particularly marijuana, distortion in smell, schizotypal personality disorder. Risk of developing psychosis later in life increases with increase in number of risk factors involved in particular case.
Early recognition and treatment of schizophrenia is one of the most important therapeutic goals (1). However, symptoms presented during the prodromal phase of psychosis are often nonspecific and difficult to recognize (2). The positive symptoms include unusual thought content, suspiciousness, grandiosity, perceptual disturbances, conceptual abnormalities, and conceptual disorganization. On the other hand, the negative symptoms include social isolation, avolition, decreased expression and experience of emotions, poverty of thought content, deterioration in functioning. Disorganized behaviors usually appear as odd behavior or appearance, bizarre thinking, trouble with focus and attention, and impairment in personal hygiene. General symptoms such as sleep disturbance, dysphoric mood, motor disturbances, impaired tolerance to stress can emerge.
Therefore, Scale of Prodromal Symptoms (SOPS) (3) and Structured Interview for Prodromal Syndromes (SIPS) (4) are designed to help clinicians identify the prodromal symptoms. A number of clinical studies have proposed the predictive factors and criteria thought to indicate the development of schizophrenia (5). In addition, Comprehensive Assessment of At Risk Mental States Scale (CAARMS) is designed to help recognize individuals at high risk (6). Literature has shown that patients who meet the criteria of the CAARMS and SIPS/SOPS are considered at risk mental states (ARMS) and have high rate of conversion to psychosis (7). Preventive strategies have been suggested for such patients to delay or prevent progression to psychosis i.e psychosocial support, close monitoring of worsening of the symptoms, psychotherapeutic interventions (13),early judicious use of antipsychotics if warranted. Non treatment or delay in treatment can cause rapidly deteriorating course of illness which can lead to difficulties in managing psychotic symptoms and hence improving functioning.
The following case illustrates multiple risk factors and likely presentation of later development of psychosis.
Patient is a 17 year-old female who was born to a mother who, reportedly, had schizophrenia and was adopted at age of 3. Her childhood was unremarkable until when she was 10 years old. At that time, she started having subjective feeling of “not being right”. Early symptoms appears to be feeling depressed, suspiciousness about the others, lack of interest in the usual activities including school work and hence poor school performance, decreased attention concentration, and social avoidance. She also exhibited self-cutting behavior, oppositional and agitated behaviors. She was seen by school counselor more often then not.
Three years later, she was admitted for her first life-time psychiatric hospitalization for worsening depressive symptoms and self-cutting behavior. She was treated with Oxcarbamazepine with some improvement and was discharged to school for emotionally disturbed children. This hospitalization was followed by 4 psychiatric admissions for depression, self-cutting, feeling paranoid that people are watching her. During that time, she was sporadically abusing marijuana, cocaine, alcohol, and Klonopin. Oxcarbamazepine was increased, and Aripiprazole and Quetiapine were added.
At age 16, she was re-admitted for first frank psychotic episode, she believed that she has AIDS and her food is being poisoned, subsequently, she stopped eating and lost significant weight. She did not show clinical response on the previous medication regimen. Olanzapine was started and titrated up to 25mg/d over a 5-week period but she remained psychotic and disorganized. Olanzapine was cross tapered to Clozapine which was titrated up. She showed marked improvement at dose 350 mg/d of Clozapine ( Clozapine level was 360 and Norclozapine level was 141). After 4 weeks, her behavior, thinking, mood, psychosis were significantly improved with no major side effect. She was discharged and referred back to her parents with outpatient psychiatric follow up. After 8 months, she maintained her improvement and compliance with medications.
Patient in case report had multiple risk factors that include strong family history of psychosis, gradually worsening depression, social isolation, declining school functioning, decreased attention concentration, perceptual disturbances, superimposed with self injurious behavior, substance abuse, rapidly deteriorating course of illness. Initial assessment would warrant close monitoring and frequent evaluation to assess the diagnostic clarification. Earlier signs of development of psychosis should have been addressed using available treatment modalities to help establish symptomsfree statesooner then not. Instead she was treated as evolving mood disorder and behavioral problems (Although CAARMS was not used, patient seemed to meet the criteria of at risk mental state). After her first psychiatric admission her psychotic symptoms became more pronounced and social functioning was rapidly declining at which point she was treated with trileptal and klonopin which seemed to be not helpful and she developed treatment resistant psychosis.
Literature has shown that patients who meet the criteria of the CAARMS and SIPS/SOPS are called being at risk mental states (ARMS) (6) (7). Therefore, a number of interventions for preventing psychosis in ARMS patients have been described and recommended. These interventions include monitoring mental status, providing psychosocial treatment including family support and psychoeducation, and even initiating neuroleptic medications (5).
CAARMS is a diagnostic tool for the prodromal phase using a combination of 7 symptoms domain (Positive symptoms, Cognitive change/Attention concentration, Emotional disturbance, Negative symptoms, Behavioral change, Motor/ Physical changes, General Psychopathology), change in functioning and family history (6) (7). In a study of 45 patients who met the criteria of the CAARMS, there was a 42% rate of conversion to psychosis within 12 months (6) (7). Another tool called SIPS/SOPS is designed to help assess severity of the prodromal phase (3) (4) (7). In a study of 29 patients, SIPS/SOPS helped differentiate the prodromal from non-prodromal symptoms in 93% of the patients, and the conversion rate to psychosis was 46% at 6 months and 54% at 12 months in the prodromal patients (7). .
Two randomized controlled medication trials for prevention of onset of psychosis have been reported. The first trial randomized 59 ARMS patients to either low dose of risperidone and cognitive-behavioral therapy (31 patients) versus need-based treatment (28 patients) (8). It was found that 9.7% (3 patients) of specific treatment group converted to psychosis versus 35.7% (10 patients) in the need-based treatment group after 6 months of follow up, but there was no significant difference between the 2 groups after another 6 months of observation (8). The second trial randomized 60 ARMS patients to either olanzapine (31 patients) or placebo (29 patients) (9). It was reported that 16.1% (5 patients) of olanzapine group versus 37.9% (11 patients) of placebo group converted to psychosis after one year (9).
Moreover, one open trial used low dose of antipsychotic (haloperidole or risperidone) together with supportive therapy and psychoeducation in 42 ARMS patients. They found that only 7.1% (3 patients) progressed to psychosis during the 6-month of treatment and no new psychotic episodes were reported during the 6-month follow-up (10). In addition, studies that examined the cognitive-behavioral therapy in ARMS patients have proven its effectiveness in lowering the rate of conversion to psychosis and improving overall functioning (11) (12).
Although the results of above mentioned studies are encouraging, N value is low, results are not robust, psychopharmacologic treatment is not free from side effects immediately and in the long run and risk of treating and exposing them to medications when it is not needed can not be ruled out. Each case should be assessed on its merits and demerits to choose the treatment options.
In conclusion, case discussed represents example of emerging schizophrenia. Although patient displayed multiple risk factors including genetic vulnerability, decline in functioning, depressed mood, substances abuse, social withdrawal, disorganized thoughts; Treatment seems to be unsuccessful to cease or slow down the process of psychosis. On the other hand, clinicians and psychiatrists are facing dilemma to initiate treatment when there is no decisive data to support type of treatment modality. Case in discussion probably throw some light how an adolescent presenting with vague symptoms of depression, cognitive deficits, social awkwardness, etc can progress in many different ways, therefore be vigilant about many different possibilities of emerging adolescent symptoms. Had the above mentioned patient was treated with early multiaxial approach including psychosocial support, cognitive-behavioral therapy, group therapy and appropriate use of efficacious antipsychotic might had resulted in different out come.
Adolescent years are crucial for personality development, career building, self image in the society and step to achieve high end goals. These challenges put adolescents at increased level of stress, and appropriate intervention ranging from control of symptoms to achieve best level of functioning can make huge difference for incoming years. Clinical staging of the of the psychotic illness according to the progression of the disease creates a preventive framework for early interventions (13).. Multimodal approach should be considered, ranging from close monitoring, psychoeducation, supportive family therapy, appropriate psychotherapy, and use of antipsychotics if warranted. Severity of illness, level of functioning, and course of illness could help the clinician formulate and individualize the appropriate treatment intervention. Moreover, each case should be evaluated for risk of introducing the antipsychotics and long term side effects of medications should be considered against the risk of not treating the adolescent. The case also raises a question of the benfits of early treatment with Clozapine in a first episode of psychosis.
A combination of ARMS with risk factors may yield to increased number of at risk mental states who truly can benefit from early intervention of multiple treatment modalities. Preventive trials in ARMS patients have shown promising results in delaying or preventing onset of psychosis (711). More clinical research is needed to set forth guidelines when to treat and what treatment modality should be used. However, does identifying individuals who are at high risk of developing psychosis and initiating therapeutic interventions targeting the prodromal symptoms improve the prognosis? Research is also needed to examine the effectiveness of the preventive interventions on the course of illness and long-term outcome.
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4 Miller TJ, McGlashan TH, Rosen JL et al. Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry. 2002 May;159(5):863-5.
8 McGorry PD, Yung AR, Phillips LJ et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry. 2002 Oct;59(10):921-8.
10 Kéri S, Kelemen O, Janka Z. et al. Therapy of mental states at high risk for psychosis: preliminary results fromHungary. Orv Hetil. 2006 Feb 5;147(5):201-4.