adolescence is a period of profound changes in the brain structure with a complex interplay between biological , psychological , and social factors .
mental health problems commonly emerge in adolescence and many adolescents have enduring disorders rather than simply a transient  teenage  emotional turmoil . individuals who develop psychosis often experience a prodromal phase ( also known as  at - risk mental state  ) , which typically involves changes in perception , behavior , cognition , mood , and physiology ( yung and mcgorry , 1996 , mcgorry et al . , 2001 ) .
this phase is ambiguous because of the non - specificity of symptoms that are commonly observed during development in adolescence , and the low predictive power in identifying individuals who make a transition to psychosis ( mcgorry and killackey , 2002 ) .
structured instruments , such as structured interview for prodromal syndromes ( sips ; mcglashan et al . , 2001 ) , scale of prodromal symptoms ( sops ; miller et al . , 1999 ) , the bonn scale for the assessment of basic symptoms ( bsabs ; gross et al . , 1987 ) , the personal assessment and crisis evaluation ( pace ; phillips et al . , 2002 ) , and the comprehensive assessment of at risk mental states ( caarms ; yung et al . , 2004 )
, can help better characterize the prodromal phase although these lack  predictive  value . in recent years
, better characterization of the prodrome phase of the disorder and improved prediction algorithms have shown to be effective in informing the timing and management process of early intervention ( cadenhead et al . , 2010 ) .
( 2004 ) conducted a 12-month follow - up on individuals with ultra high - risk , proposing a  four - or - more 
algorithm for risk identification , including poor functioning , long duration of symptoms , high levels of depression , and reduced attention .
the algorithm showed a positive predictive value of 80% , with heightened specificity and sensitivity values ( yung et al . , 2004 ) . in the north american prodrome longitudinal study ( napls ) cohort , cannon et al .
( 2008 ) followed up 291 treatment - seeking patients with prodromal symptoms at regular intervals for up to 2.5  years .
the study showed conversion rates to be 35% at follow - up , with baseline characteristics predictive of psychosis to include a genetic predisposition of schizophrenia alongside reduced overall functioning , heightened levels of abnormal thought content , greater psychosocial impairment , and a history of substance abuse ( cannon et al . , 2008 ) .
similar findings have been reported in the european prediction of psychosis ( epos ) study ( ruhrmann et al . , 2010 ) .
however , there is a paucity of  biomarkers  for this phase with good predictive value either for course or treatment response .
although the identification of biomarkers for schizophrenia is in its early stages , some attempts have been made to discover biomarkers in eos ( taurines et al .
there is limited evidence that management and symptom specific treatment of help - seeking prodromal patients may delay or prevent the onset of psychosis ; however the uncertainty of course prediction adds to the risk of stigmatization and heightened anxiety in individuals and their families .
additionally , the eos cases tend to be insidious , non - episodic , and typically result in rapid deterioration ; providing a limited chance to study and intervene during this window .
the identification of biomarkers would improve the ability to intervene during the prodromal period or earlier .
the search for clinically relevant biomarkers is a challenging task in a heterogeneous disorder like schizophrenia but studying eos provides a unique opportunity as the phenotype is relatively homogenous , associated with less risk of secondary influences from disease associated alterations of environment ( e.g. , marijuana , smoking , hospital admissions , etc . ) and typically shows more salient genetic loading ( vyas et al .
for example , a neurocognitive deficits in schizophrenia is considered a core feature of the illness ( meta - analysis , heinrichs and zakzanis , 1998 ; heaton et al . , 2001 ;
keefe and fenton , 2007 ) and studies on ultra high - risk cohorts suggest that impairments in olfactory identification and spatial working memory ( measures targeting the dorsolateral prefrontal cortex and cortical physiological processes ) , may have a strong predictive value for conversion to psychosis ( brewer et al . , 2006 ) .
neurophysiological measures such as electroencephalography , event - related potentials , prepulse inhibition , and mismatch negativity , also show promise as potential biomarkers ( javitt et al .
2012 ) but further work to elucidate the relationship of such measures with specific clinical expression ( e.g. , negative symptoms , cognitive functioning ) is needed .
neuroimaging studies have shown relatively less predictive value despite consistent reports of progressive structural brain abnormalities associated with schizophrenia ( gogtay et al . , 2004 ; rapoport and gogtay , 2011 ) , and non - psychotic siblings of cos patients ( gogtay et al . , 2003 ; greenstein et al . , 2011 ) .
some studies have suggested that high - risk individuals that go on to become psychotic show less gray matter volume in the right medial temporal , lateral temporal , inferior frontal cortex , and in the cingulate cortex bilaterally , while individuals who do not develop psychosis show changes restricted to the cerebellum ( pantelis et al . , 2003 ) .
there is a relative dearth of evidence - based studies of antipsychotic ( both typical and atypical ) efficacy in eos , partly because of the rarity of the population and partly because it is difficult to do treatment trials in children with severe illness ( gogtay and rapoport , 2008 ) . taken together
, these studies suggest that although first - generation antipsychotics ( fgas ) improve positive symptomatology , they elicit significant extra pyramidal side effects , tardive dyskinesia , and prolactin elevations ( pool et al . , 1976 ; realmuto et al . , 1984 ; spencer et al . , 1992 ; findling et al . ,
, second - generation antipsychotics ( sga , or atypical antipsychotics ) have become the mainstay of therapy in the treatment of eos , because of their potential for lower propensity to induce extrapyramidal symptoms and reduced risk of tardive dyskinesia ( madaan et al . , 2008 ;
however the cochrane review identified 6 ( clinical trials ) studies with a total of 256 children and adolescents , to examine the effects of antipsychotic medication for eos ( kennedy et al . , 2007 ) .
the authors concluded that there was limited data that supported one antipsychotic medication over another for the treatment of eos .
there was no superiority of sgas over fgas , given the evidence showing small differences in effect size for alleviating positive and negative symptoms .
furthermore , an 8-week , government - funded , randomized double - blind trial on eos entitled  treatment of early - onset schizophrenia spectrum  ( teoss ) showed that sgas , risperidone and olanzapine , were not superior to fga , molindone , in symptom improvement .
risperidone and olanzapine were associated with high degrees of weight gain ( risperidone additionally showed elevated prolactin concentration ) in comparison with molindone , while individuals prescribed to molindone showed akathisia ( sikich et al . , 2008 ) .
clozapine remains the gold standard treatment for schizophrenia , and has been shown to have a more favorable profile of clinical response compared with haloperidol and olanzapine in treatment - refractory eos ( spencer et al .
, 1992 ; mozes et al . , 1994 ; towbin et al . , 1994 ; kumra et al . , 1996 , 2008 ; mcevoy et al . ,
however , clozapine remains as the last resort choice limited by its significant side effect profile on the hematopoietic system ( agranulocytosis ) , cardiovascular system ( myocarditis ) , central nervous system ( seizures , akinesia , myoclonic jerks ) , and liver function , along with other side effects such as severe movement disorders , hypersalivation , hyperglycemia , diabetes , and weight gain , which are particularly problematic for children and young adults ( connor et al .
, 2001 ; vyas et al . , 2011b ) . clearly , there is an ongoing debate about the efficacy of atypical medications accounting for the long - term side effects profile , and therefore there is a pressing need for larger randomized control trials ( rcts ) , to delineate the best available antipsychotic agents , and provide a platform for novel drug discovery .
to date , there are no published rcts of psychosocial treatments for children with schizophrenia .
however , the adult literature has supported adjunct psychosocial and individualized psychological treatments ( eack et al . , 2009 ; review , vyas et al . , 2012 ) . a review concluded that psychosocial therapies ( cognitive behavioral therapy , cbt ) , family intervention , social skills training , and cognitive remediation ) are effective adjuncts to pharmacological interventions in adults with schizophrenia ( mcgurk et al . , 2007 ; patterson and leewenkamp , 2008 ) .
for example , cbt addresses dysfunctional beliefs , coping strategies ,  tuning  of cognitive abilities , and behavior modification , by linking and then re - evaluating thoughts and feelings about the presentation of clinical symptoms , which in turn aims to improve the mental states of patients .
cognitive enhancement therapy has also shown to be effective in improving neurocognitive functioning in outpatients with eos or schizoaffective disorder ( eack et al . , 2009 ) . indeed , family therapy , psycho - education , and social skills training
have also shown improvement in clinical symptoms of newly diagnosed patients with schizophrenia ( petersen et al . , 2005 )
. a recently published multicenter rct was conducted on young people with an early initial prodromal state of psychosis , to investigate the effectiveness of integrated psychological intervention ( including cbt , group skills training , cognitive remediation therapy , and multifamily psycho - education ) and supportive counseling on prevention of psychosis ( bechdolf et al . , 2012 ) .
the results showed that the integrated psychological intervention was more effective in delaying the onset of psychosis over a 24-month follow - up period ( bechdolf et al . , 2012 ) .
these studies suggest that psychotherapeutic interventions may thus be an important platform to alleviate psychotic relapse , re - admission , and medication compliance ; systematic validation of such measures however is warranted .
early onset schizophrenia is a rare , severe , and treatment - refractory form of the adult - onset illness .
although antipsychotic treatment , in addition to psychotherapeutic interventions , provides some symptom relief , there are a very high percentage of residual psychotic symptoms and cognitive deficits .
existing medication treatments do not result in adequate response and the side effects in children remain daunting . hence , there is a dire need for early characterization of symptoms and biomarkers , better understanding of the pathophysiology and progression of the illness , and exploring novel and  outside the box 
treatment options such as transcranial magnetic stimulation ( tms ; tanaka and watanabe , 2009 ) , or transcranial direct current stimulation ( tdcs ) trials , which are well tolerated in pediatric populations ( mattai et al . , 2011 ; vercammen et al . , 2011 )
non - invasive neurostimulation techniques such as these have been shown to ameliorate cognition and negative symptoms in schizophrenia ( levkovitz et al . , 2011 ; minzenberg and carter , 2012 ) ,
features commonly reported in early onset cases ( vyas et al . , 2011a ) .
however , new treatment strategies should be informed by advancing knowledge from neurochemical and neuroanatomic studies , which may provide more specific targets in the brain .
recent advances in neuroimaging methodologies , particularly those that provide a window into brain functioning and circuitry , may provide a blueprint for identification of novel biomarkers for schizophrenia .
for instance , resting - state and task orientated functional mri or magnetoencephalography ( meg ) analyses show abnormal brain synchrony and neural networks in schizophrenia ( reite et al . , 1999 ; banaschewski and brandeis , 2007 ; ford et al . , 2007 ; brookes et al
2011 ) . an ongoing meg study from our nimh cos cohort showed abnormal oscillatory patterns in cos patients compared to healthy controls ( n. s. vyas , unpublished data ) .
treatment strategies could be ideally designed ( e.g. , regionally specific neuromodulation using tdcs ) to  normalize  these abnormal brain circuitries or evaluate efficacy of new compounds .
research and implementation of novel treatments coupled with advances in genome - wide microarray technology may lead to the identification of genes that are relevant not only in the pathophysiology of schizophrenia , but also in providing an insight into treatment response , or course prediction .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 early onset schizophrenia ( onset before adulthood ) is a rare , severe , and chronic form of schizophrenia . 
 the clinical presentation of schizophrenia at this unusually early age of onset has been associated with premorbid developmental abnormalities , poor response to neuroleptic treatment , greater admission rates , and poor prognosis . 
 this is a brief , condensed review of current treatment strategies for the early onset population highlighting the need for novel treatment strategies for these generally treatment - refractory cases . 
 based on the current literature , second - generation antipsychotics remain the mainstay of treatment , although current medications provide suboptimal response at best . 
 based on the adult literature , combining antipsychotic treatment with psychotherapeutic intervention may be a more comprehensive treatment strategy . 
 indeed , early detection , identification of relevant biomarkers , coupled with advancing knowledge of the neurochemical and neuroanatomic pathways may help design informed and novel treatment strategies . 
Early Detection and Management of Psychosis
Pharmacological Treatment in EOS
Psychotherapeutic Interventions
Conclusion and Future Directions
Conflict of Interest Statement