Pharmacological Treatment of Early Onset Schizophrenia: A Review

INTRODUCTION

A substantial proportion of patients with Schizophrenia experience the onset of their illness by the age of 18 years (Kumra and Schulz, 2008). Four percent of all schizophrenics have their onset of illness before 15 years of age (Findling et al., 2007). Data from phenomenological, cognitive, neuroimaging and genetic studies suggest a similar profile of clinical and neurobiological abnormalities between early and adult onset schizophrenia patients. However, children and adolescents with schizophrenia have been found to have more severe neurodevelopmental abnormalities (Rutter and Taylor, 1984), worse long term outcome, more cytogenetic anomalies and potentially greater loading of family histories for schizophrenia than their adult counterparts (Kumra and Schulz, 2008). Various researches support the view that’ Early Onset Schizophrenia’ (EOS) shows continuity with the adult form of the disorder at the level of symptoms, clinical course and underlying neurobiology (Werry and Taylor, 1994). Since the time Krapelin used the term Dementia Praecox in 1919 (Srivastava, 2009), till date the treatment guidelines have not been revised for treating EOS (Campbell and Cueva, 1995) and the treatment recommendations are extrapolated from adult literature (Campbell and Cueva, 1995), however, the pharmacokinetic and pharmacodynamic parameters of different antipsychotic medications differ in childhood and adolescent age group (Remschmidt and Schulz, 1995).

AVAILABLE TREATMENT OPTIONS

The severe cognitive impairment and resultant poorer prognosis of EOS calls for early diagnosis, treatment and ultimately prevention before onset of psychosis. Current approach to the treatment of EOS is multipronged (McClellan and Werry, 1994), involving pharmacotherapy, family ‘psycho educational’ intervention, individual psychotherapy, social skills training, cognitive remediation, rehabilitation and assertive community treatment (McClellan and Werry, 1994), although pharmacotherapy is the mainstay of treatment (Campbell and Cueva, 1995).

Various drug trials which have been conducted on this population, have shown efficacy for the following medications:

Table 1 given above has tried to simplify a huge piece of data and an analysis of the table shows that haloperidol and clozapine are much more efficacious. Several multi center trials are also available which shows that quetiapine, ziprasidone and aripiprazole (Findling et al., 2007), may also be useful in EOS, though in lesser doses. Previous studies are also available on trifluoperazine but they were conducted on autism, ADHD and mental retardation. Thioridazine is not recommended currently because of its poor adverse effect profile (Green, 2009). Haloperidol (AMA, 1994) the starting age was 13-12 years age, the usual dose was 0.5 mg day^-1 or 0.15 mg/kg/day, the response was as per the adult response. The other drug which has been extensively studied is resperidone, this medication has been found to be effective at 3 to 4 mg day^-1, the usual response is highly efficasious. The other significant aspect highlighted in the table is the efficacy of clozapine and molindone both these drugs are useful but as 2nd line treatment choice. In nutshell the above table highlights that resperidone tops the list of drugs in efficacy and body of research followed by haloperidol followed by molindone then clozapine and olanzapine. Thiothixane, loxapine and pimozide have shown to be less efficacious.

Ethical Issues in Treatment
It is important to understand that there are certain important ethical considerations while treating childhood schizophrenia. In very young patients only parent’s consent is adequate (Clark and Lewis, 1998), valid consent is required from the older patients, patients have to be explained about the nature of illness, available treatment options and side effect profiles, outcome of treatment and prognosis of the illness. For consent to be valid patient must understand the information given to him/her and must be in a mental state, such that he/she would be capable of exercising the choice. They can also be treated against their consent either on the basis of consent of their parents or by involving mental health legislation, or the treating team finds it urgent for treatment initiation to save the patient or others (Clark and Lewis, 1998; Clark, 2001).

Table 1:	Drug trials

When consent is not at all available and treatment has to be started urgently, help of appropriate child care or mental health legislation is sought (Clark and Lewis, 1998).

Available Studies
These can be divided according to the type of antipsychotic administered.

Typical Antipsychotics

Atypical Antipsychotics
The studies are summarized in a tabular form. The studies have been mainly done on resperidone, clozapine, olanzapine and very few on aripiprazole, although there is no marked benefit of one over the other. Resperidone has the largest data back up.

In nutshell the above, Table 2 has shown that the maximum studies (4 out of 5) have been conducted to compare the efficacy of various atypical antipsychotics and have clearly shown favourable response for resperidone. Remschmidt et al. (1994) and Levkovitch et al. (1994) have shown a good response for clozapine, while Sikich et al. (2004) and Haas et al. (2007) have gone in favour of resperidone only one study has gone in favour of aripiprazole (Findling et al., 2007). Thus a clear consensus has emerged showing promising results for resperidone. Some important studies are being summarized below;

Clinical Antipsychotic Trial of Antipsychotic Effectiveness Study (CATAIE), which is a direct, randomized, double blind trial compares multiple second generation antipsychotics with mid potency first generation antipsychotics and found modest effectiveness advantage of olanzapine as compared to perphenazine, risperidone and quetiapine but no advantage of other second generation antipsychotics over perphenazines, olanzapine however, was associated with more adverse effects, particularly weight gain (Sikich et al., 2004).

Treatment of Early Onset Schizophrenia Spectrum Disorder Study, (TOESS) which is a 8 week, flexible dose, randomized, double blind clinical trial comparing risperidone and olanzapine with molindone in equivalent doses in 8-18 year age group finds significant reduction in positive symptoms with all the three but adequate response in only less than 50 % patients, with olanzapine showing most troublesome side effects e.g., weight gain at one year follow up (McClellan, 1998; Findling et al., 2007).

Table 2:	Studies on atypical antipsychotics

A clinical retrospective chart review of 172 hospitalized children with EOS treated by clozapine for 8 months showed hematological side effects in 16.1% patients which was higher than that obtained in adult studies, but agranulocytosis was found in only 0.99% cases which was similar to that found in adult studies (Gerbino-Rosen et al., 2005).

Conclusions from above Studies
There are some significant conclusions emerging from these studies:

Difficulties in Conducting Studies in EOS
There are considerable hurdles when studies in EOS are conducted, because of certain specific reasons e.g., the relative rarity of the illness (Campbell and Cueva, 1995). Only 4% of the schizophrenics have their onset of illness before the age of 15 years (Knapp, 1997)and ethical difficulties in establishing trials in young people (Campbell and Cueva, 1995). Due to these reasons one cannot ignore the lacuna of previous studies, like small sample size, inadequate control group or lack of it, longitudinal follow-ups are lacking and economic feasibility is not established. Hence, it becomes difficult to formulate guidelines for an optimal treatment of EOS. The previous studies did not have a homogeneous sample (they included autism, ADHD and MR under the broader rubric of EOS), longitudinal effects on measures like cognitive status, side effects, treatment adherence, relapse prevention are lacking in most of the studies comparison of different antipsychotics in EOS and adult onset schizophrenia are lacking (Clark, 2001), many of the studies are conducted by the pharmaceutical companies and may be biased and very few conclusive studies are available.

Assessment Before Starting Treatment
Practice parameters have been developed by the American Academy of Child and Adolescent Psychiatry (McClellan et al., 2001), but it is not widely accepted because of difference in cultural parameters and treatment settings in various countries, hence the available practice guidelines are extrapolated from the adult literature. A few parameters are to be rigorously assessed before treatment is initiated. Baseline assessment of weight, BMI, waist circumference at umbilicus; personal and family history of diabetes, dyslipidemia, obesity, hypertension, cardiovascular disease; BP, fasting blood sugar, lipid profile, urea, electrolytes, CBC, LFT; EEG and CT-Brain if neurological dysfunction is anticipated (Clark and Lewis, 1998; Clark, 2001). Regular monitoring of urea, electrolytes, CBC, LFT to be checked yearly after baseline assessment. For clozapine, specifically CBC to be evaluated weekly for first 18 weeks, then every 2nd week for 1 year, then monthly. After baseline assessment lipid profile and fasting blood sugar to be reevaluated at 3rd and 4-6th month respectively and then yearly. Weight to be measured frequently for 3 months and then yearly.

TREATMENT

Currently there is no clear consensus about choice of antipsychotics in EOS (Clark and Lewis, 1998; Clark, 2001). Some authors suggest starting with a first generation antipsychotic (FGA), which may be substituted after 6-8 weeks with a second generation antipsychotic (SGA), only if the FGA is found to be ineffective or intolerable (Clark and Lewis, 1998). The treatment can be divided according to the phase of illness (Somsubhra, 2008).

In Acute Phase
A standard oral antipsychotic should be started the dose in children is usually lesser than that in the adults (Sachdev, 1995). In young age metabolism of drugs is faster, hence they tend to metabolize antipsychotic more efficiently therefore older children and adolescents require same dose as those recommended in adults (Sachdev, 1995). Additional sedation may be considered with shorter acting benzodiazepines (lorazepam 2-4 mg orally or parentally). Parenteral neuroleptics may be considered in only those in whom benzodiazepines are ineffective (Clark, 2001). Propranolol may be considered in cases of akathesia (Green, 2009).

Antiparkinsonians may be used in the treatment and prophylaxis of dystonia and parkinsonism like symptoms. For 6-8 weeks adequate doses of medicines are given if they are well tolerated, or a trial of another antipsychotic may be considered (Clark and Lewis, 1998; Clark, 2001). The treatment differs substantially in the special age group like the elderly (Parakh and Srivastava, 2010).

Recuperative Phase
This phase persists up to 4-6 weeks after the acute symptoms are controlled (Clark and Lewis, 1998). In this phase antipsychotic should be continued in same doses despite reduction in positive symptoms/disorganization/confusion. Dose reduction is considered only when high doses were administered in acute phase for rapid control of symptoms or if intolerable side effects develop (Clark and Lewis, 1998). In case of reduction of doses, close monitoring is needed to assess further relapse of symptoms (McClellan et al., 2007).

Recovery Phase
In this phase antipsychotics have been documented to prevent relapse (65% relapse rate as opposed to 30% relapse rate with neuroleptics in 1st year) (Kumra et al., 2008). Indefinite medication is needed if the patient relapses, or if the patient shows chronic symptoms, or in newly diagnosed cases that show persistent psychotic symptoms. In these cases maintenance is requires with minimum effective dose with longitudinal regular follow up.

If in any phase two antipsychotic from different classes are proved to be ineffective or intolerable the diagnosis has to be reviewed and compliance to be checked and if compliance is found to be questionable depot preparations of antipsychotic are used (haloperidol deaconate injection, risperidone depot, the long acting risperidone injection) (Shapiro and Shapiro, 1989). Lithium may be considered for affective symptoms (Clark and Lewis, 1998). Clozapine may be considered as a last resort in the doses considered safe, for atleast 6-12 months (Clark and Lewis, 1998; Sachdev, 1995). If even clozapine fails to improve the symptoms all the ineffective medications are to be withdrawn, the most effective drug used previously is to be considered in lowest effective dose (Clark and Lewis, 1998). Another depot antipsychotic may be considered if poor compliance is anticipated (Clark, 2001). Cognitive behavioral interventions may also be considered to improve some symptoms (Clark, 2001).