Understanding the schizophrenia prodrome.

Schizophrenia is a neurodevelopmental disorder and its course is said to have an onset much before the presentation with psychotic symptoms. Even though the concept of prodrome in schizophrenia has been accepted, there is still an existence of a diagnostic dilemma. Various imaging studies and biomarkers have also been studied for confirmation of this diagnosis. The critical period of intervention when identified clarifies the doubts about faster and better outcomes.

INTRODUCTION

The evolution of the concept of schizophrenia dates back to the 1850s when Kraepelin delineated symptomatology which shared a common course and outcome and called it as dementia precox. Later, Bleuler coined the term “schizophrenia” describing it as a group of psychosis having a variable and chronic course.[123] There is extensive evidence that schizophrenia is a neurodevelopmental disorder and its course unfolds throughout life. Starting from genetic and environmental factors, it will eventually lead to deficits in neural systems hampering the functions of substrates critical for assessment of sensory input, cognitive functions, and information processing.[34] The widespread acceptance of the neurodevelopmental model of schizophrenia has not been able to throw light on the much debated prodromal phase of the illness.[5]

It was Bleuler in 1911, who first gave the concept that changes in a person who develops schizophrenia can be identified as a prodromal phase.[6] Accurate depiction of the prodrome can help identify individuals who may be at risk of impending psychosis. Appreciating the first manifestations of the subtle changes and intervening at the particular state with antipsychotic medication may be associated with a better prognosis in the long-term outcome of the disease. Several other studies have suggested the use of antidepressants or anti-anxiety drugs to alleviate symptoms in a person who may be at risk. According to recent developments, a prodromal state may be identified based on the current symptoms with reliability and predictive validity. Appreciation is growing that these patients and their families experience substantial current distress.[7] Thus, current symptoms provide another rationale for intervention research in addition to the need for research targeting the prevention of schizophrenia.

THE CONCEPT

Prodrome in clinical medicine refers to the early symptoms and signs of illness preceding the characteristic manifestations. In psychiatry, it is referred to as “the initial prodrome” and “relapse prodrome.” The widely accepted definition of prodrome was given by Keith and Matthews in 1991 as a “heterogeneous group of behaviors temporally related to the onset of psychosis. Loebel et al. (1992) defined it as the time interval from the onset of unusual behavioral symptoms to onset of psychotic symptoms[8] and Beiser et al. (1993) defined it as the period from first noticeable symptoms to first prominent psychotic symptoms.[9] The concept of prodrome does not refer to a hardbound set of signs and symptoms. It is an evolution over time. Docherty et al. in 1978 described it as a “moment to moment march of psychological changes.” The evolution of prodrome has been categorized into two main patterns. Pattern 1 was described as certain nonspecific changes, followed by specific prepsychotic symptoms, and then eventually leading to psychosis. Pattern 2 explains the evolution to begin with early specific changes followed by neurotic symptoms as a reaction to these and then psychosis. Chapman in 1978 described 5 patterns of disturbances which are disturbances in attention, perception, speech production, motor functions, and thought block. From the above-mentioned symptoms, disturbance in motility occurs secondary to disturbance of attention and perception.[10] Huber et al. coined the term “basic symptoms” which can be subjective complaints of emotional, cognitive, or autonomic impairment. Another consideration was “symptomatic psychosis at-risk state” which finally paved way to the ultrahigh risk (UHR) criteria which was set at a high threshold in an attempt to reduce misdiagnosis among psychiatrists.[1112] This is in contrast to at-risk mental state (ARMS) which defines a syndrome that may or may not develop into psychosis. A person at ARMS may manifest symptoms such as depressed mood, anxiety, and psychosis but may not necessarily meet UHR criteria. The finding of duration of untreated psychosis and early intervention at this particular point has provided a new insight into the etiopathological progress of the illness.[13] Studies have indicated better socio-occupational functioning in patients who have received intervention.[131415] Although the boundary between the ARMS and actual psychosis might be narrow and vaguely demarcated,[16] “close-in” follow-up strategy, which involves shortening the periods of follow-up helps us to observe the transition to psychosis.

CRITERIA FOR THE DIAGNOSIS

The Diagnostic and Statistical Manual (DSM)-III-R (American Psychiatric Association 1987) focuses mainly on observable behavioral changes in its description of the prodromal features of schizophrenia. It provides an operationalized criteria of nine symptoms for schizophrenic prodrome:[17]

Marked social isolation or withdrawal

Marked impairment in role functioning

Markedly peculiar behavior

Marked impairment in personal hygiene and grooming

Blunted or inappropriate affect

Digressive, vague, overelaborate or circumstantial speech, or poverty of speech, or poverty of content of speech

Odd beliefs or magical thinking

Unusual perceptual experiences

Marked lack of initiative, interests, or energy.

This list of criteria has been dropped from the DSM-IV (American Psychiatric Association 1994). The International classification of diseases (ICD)-10 (World Health Organization 1994) acknowledges a prodrome as part of the schizophrenic syndrome; prodromal symptoms are not included in its description of schizophrenia (Keith and Matthews 1991). The whole picture of this prodromal phase should also be compared to the DSM-IV concepts of fully psychotic disorders that have not been present for long enough to meet the criteria for schizophrenia or schizoaffective disorder. These DSM-IV concepts are psychotic disorders not otherwise specified, brief psychotic disorders, and schizophreniform disorders. Yung et al. in 1996 gave the criteria for the diagnosis of schizophrenia and divided it as three main categories.[18]

Category 1, the patient should have at least one of the following attenuated (i.e., subthreshold) positive symptoms: ideas of reference, odd beliefs, or magical thinking; perceptual disturbance; odd thinking and speech; paranoid ideation; and odd behavior or appearance.

Category 2 consists of participants who have experienced transient psychotic symptoms, which have spontaneously resolved within a week.

Category 3 is a combination of genetic risk (i.e., being the first-degree relative of an individual with a diagnosis of schizophrenia) with changes in functioning. The patient must have undergone a substantial decline in the previous year. The criteria in the first two categories have been largely derived from positive symptoms, and that negative signs and symptoms were not utilized as the basis of any of the categories.[67]

VARIOUS ASSESSMENT MEASURES FOR PRODROME

The recent resurgent interest in the field of prodromal research has led to the development of various assessment tools. These tools can identify symptoms in the phase which calls for intervention. The various tools include:

Instrument for the retrospective assessment of onset of schizophrenia developed by Hafner et al. 1992

Bonn Scale for the assessment of basic symptoms by Huber et al. 1980

Structured Interview for Prodromal Symptoms (SIPS) by McGlashan 1996[8]

Scale for prodromal symptoms (SOPS) also by McGlashan 1996[8]

Multidimensional assessment of psychotic prodrome by Yung and McGory in 1996[67]

Comprehensive assessment of ARMS (CAARMS) by McGory et al. 2003.

Structured interviewing technique was followed in all these scales. The SIPS and SOPS to rate the prodromal symptoms were developed by research team from Yale University called The Prevention through Risk Identification, Management, and Education. Among these, the most widely used measure is the SIPS. It enhances positive predictive power, thus increasing the true-positives.[19] The SIPS is a diagnostic interview used to diagnose the prodromal syndromes and similar to the structured clinical interview for DSM-IV. The CAARMS defined the at-risk criteria and included in it the vulnerable groups, attenuated positive symptom groups, and the brief limited intermittent psychotic symptoms.[20] The other symptoms and syndromes which are measured in these scales include genetic risks and deterioration, brief-limited psychotic symptoms, and attenuated positive symptoms; brief limited psychotic symptoms includes transient psychotic symptoms at a specified frequency over a given period. Unusual perceptual experiences and ideations that do not meet the level of conviction and severity required for hallucinations and delusions are characterized as attenuated positive symptoms. These are vital in UHR criteria and charted by all of these measures.

PROGRESSION TO SCHIZOPHRENIA

It was reported that 75% of the patients with schizophrenia passed through the stages of prodromal symptoms. Subthreshold psychotic symptoms were reported 1 year preceding the onset and nonspecific anxiety and affective symptoms much before this.[2122] Only a proportion goes on to develop psychotic disorder. Current estimates suggest that 1 in 4 of the patients who can be categorized as high risk will convert to schizophrenia and hence warrant intervention. According to different studies, only 20%–40% of those who meet UHR criteria convert to psychosis within 2–4 years. Studies conducted in both Australia and the United States showed that young people with “subthreshold” psychotic symptoms and some evidence of functional decline with a history of genetic risk for schizophrenia were ascertained and followed longitudinally for the development of psychosis.[212223] In a few earlier studies, it was seen that prodromal status was associated with a 40%–50% rate of conversion to psychosis in 1–2 years. A more modest rate of transition was explained by a group of researchers in North America. In Australia, 1-year transition rates for patients have steadily decreased over time 50% in 1995, 32% in 1997, 21% in 1992, and 12% in 2000.[23]

CLINICAL FINDINGS

Cognitive deficits including memory, attention, and concentration are the most commonly documented clinical findings. This may incorporate relative disturbance in speed and verbal memory, social reasoning, and emotional processing. Various mood changes such as anxiety, depression, mood swings, sleep disturbances, irritability, anger, and suicidal ideas are reported as part of prodromal symptoms. Patient may also present with spectrum of conditions including obsessive-compulsive phenomenon and dissociative disorders. Even subtle changes such as social withdrawal, school refusal, deterioration in school work may be considered as part of prodrome and may require intervention if the person is under UHR category.

IMAGING STUDIES AND BIOMARKERS

Much of the work on imaging and biomarkers was done by Pantelis et al. in 2003. Their studies focused on structural changes in the gray matter and following up these individuals at a later phase after they developed psychosis. The structures affected include right medial temporal, lateral temporal bilateral cingulated cortex, and inferior frontal cortex. On rescanning the individuals who developed psychosis, there was a reduction in gray matter in the left parahippocampal, fusiform, orbitofrontal, and cerebellar cortices whereas longitudinal changes were restricted to only cerebellum in those who did not become psychotic. This progressive change which was studied in adolescence was considered to be due to a combination of several factors. Genetic factors like those resulting from altered expression of genes are critical for neurodevelopmental processes such as glutaminergic N-methyl- D-aspartate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor expression or altered dynamics of dopaminergic or GABAergic neurotransmitter systems.[24] Hormonal changes such as reproductive steroids could modulate brain maturational processes such as synaptic pruning or myelination. Psychosocial and environmental factors also have a role in dendritic arborization. Biomarkers which have a role in early identification of psychosis have also been evaluated in studies by Schoebel et al. in 2009. Different categories of biomarkers representing inflammation, oxidative stress, endocannabinoids, glucocorticoids, and biogenic amine systems are dysregulated and interact with each other in the early phase of schizophrenia. Biomarkers for impending psychosis might identify high-risk individuals and thus help in halting the progression of aberrant neurodevelopmental processes.[25] This was also studied in researches in mouse models of maternal immune activation which revealed that interventions directed at maternal inflammatory cytokines protected against neurodevelopmental abnormalities in the offspring.[26] Targeting risk genes and environmental factors in the signaling pathway are found to restore functionality in a more efficacious way in these individuals. Studies have also indicated that treatments which reduce molecular deficits produced by genetic variants like folate supplementation in people with certain risk alleles have actually caused a decline in relapse rates.[27] Drugs which act on Val 158 and decreases catechol-o-methyl transferase activity when given at an early stage have improved the socio-occupational functioning in affected individuals.[28]

MANAGEMENT

The importance of early detection focuses on prevention of the psychological and social disruption which results from psychosis. Minimizing the delay between the onset of psychosis and treatment is the primary objective for this diagnosis. Medications that decrease the stress levels have been found to reduce clinical deterioration in individuals with biological susceptibility for schizophrenia. Anti depressants, anxiolytics and mood stabilizers might in some cases enhance At Risk individual's ability to tide over stressful situations.[29] Studies have shown that combination of low dose Risperidone together with cognitive behavior therapy or supportive psychotherapy have shown a conversion rate of 9.7% (3/31) over 6 months in the experimental group compared to 35.7% (10/28) in the control group. Over a 12 month follow up period it was seen that 20 subjects became psychotic. Therefore, the 12 month transition rate was 40.8% (20/49). Similar placebo controlled and double blind trial of olanzapine focusing on symptoms over 8 weeks, also showed improvement in prodromal patients primarily limited to the SOPS and PANSS scales. In this study it was seen that there was a higher transition rate in the group where olanzapine was discontinued.[30] 15 patients were observed over 8 weeks in an open label study administering Aripiprazole. Significant improvement was seen in symptomatology in these patients.[31] The prevalence of sub-threshold psychosis was higher in subjects at genetic risk.[32] Antipsychotic medications for such people seem to be a logical extension for treatment protocol as a whole.[333435] In a double blind, randomized, placebo controlled treatment study; patients were supplemented with omega 3 fatty acids. They carried out the trial on 81 ultra high risk individuals. The experimental group was given 1.2g/day omega 3 fatty acids. It was observed that after 40 weeks monitoring period 2 of the 41 in the experimental group and 11 of the 40 in the placebo group had converted to psychosis. The patients materialized improvement in positive, negative and general symptoms with betterment in functioning in comparison to the placebo group.[36] Besides pharmacological interventions, study of the effect of psychosocial modification on the vulnerable individuals helps the young person to regain their capacity for psychological well-being and improved quality of life. Psycho education assists the young person and their family in understanding psychosis as a brain disorder rather than a mental illness. Individuals should be taught about the coping and problem solving skills to better help the people deal with the manifestations of the illness.

IMPLICATIONS FOR DAILY PRACTICE

It is mandatory on clinicians to exercise caution before labeling a person for early intervention. The symptoms of prodrome are subtle and often missed by family members and primary care physicians. Hence, it is important to observe the patient at frequent intervals and monitor the progress over the course of time. It is equally important to communicate the concept of prodrome to the primary care physicians and primary health-care staff so that early recognition and referral is done, as they are the point of first contact for the individual. Even at this low threshold sufficient referral guidelines must be present for faster, better, and appropriate care. Promotion of mental health services is essential for people to understand about possible stress-coping strategies which can also act as a prophylaxis against impending psychosis.[33]

CONCLUSION

A danger is undoubtedly exists that early conclusions may lead to widespread use of antipsychotic medications as standard care in the treatment of symptoms which appear prodromal. The extent to which an intervention will work is actually difficult to assess. Naturalistic studies establishing the base rates of eventual illness are, therefore, critical for evaluating the successfulness of early treatment. The research community of all times have put forth significant amount of data to identify and predict vulnerability of individuals who might develop psychosis. The critical period of intervention if identifiable clarifies the doubts about faster and better outcomes. Time should be spent to explore the ethical and social implications at this stage, and the juncture gives us a moment to consider what measures might be taken to minimize liabilities but does not preclude the opportunity for patient to receive treatment and improve the quality of living. Of course, much discretion should be warranted in introducing the idea that an individual may be at risk in developing psychosis. However, quintessential diagnosis is facilitated by exposure to all the risks involved together with accurate information about the array of therapies that may have a significant impact in the course of schizophrenia.

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Conflicts of interest

There are no conflicts of interest.