Prodromal Schizophrenia

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Prodromal schizophrenia: To treat or not to treat?

Rupert Kelly PrizeAlhafidz Hamdan, MRes (Neuroscience)

Stage 4 MBBS, Newcastle University


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Rupert Kelly Prize Prodromal schizophrenia: To treat or not to treat?

Alhafidz Hamdan, Stage 4 MBBS 1

Content

Introduction.. 2

The ethics of early interventions in prodromal schizophrenia. 3

Principles of prodromal schizophrenia.. 3

The potential benefits of being at risk.. 5

Pharmacological interventions. 5

Nonpharmacological interventions

7

The potential risks of being at risk 7

False positives 7

Stigma. 8

Issues regarding confidentiality and autonomy 9

Prodromal intervention: A clinical equipoise 10

References. 11

Cover illustration:Louise Wain (5 Aug 1860 4 July 1939) was an English artist best known for his drawings,

which consistently antropomophised large-eyed cats and kittens. In his later years he suffered from

schizophrenia which, according to some psychologists, can be seen in his works. The image on the cover

illustrates his differing perceptions of a cat as he progressed through the spectrum of schizophrenia from the

premorbid (top left), prodromal (top right), acute (bottom left) and chronic (bottom right) phases.


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Prodromal schizophrenia: To treat or not to treat?Alhafidz Hamdan, MRes (Neuroscience),

Fourth year medical student, Newcastle University.

Introduction

Sarah* was a 17-year-old student when she first developed a gradual and distinct change in personality in

1964. She was a bright young girl prior to the deterioration, leading the schools cheerleading team to win the

Nationals and being awarded the Best Performing Student at her high school. However, when she entered

university, things started to become different; she was no longer the centre of attention nor the high achieving

teachers pet and this deflated her self-confidence. Little did she know that her life was going to be taken over

by a relentless disease, stripping off her sanity. She began to hear external voices for brief periods of the day

once a week and these voices relentlessly called out her name Sarah, Sarah, Sarahand instructed her to do

things. At times her surroundings would seem unreal to her, she would avoid sunlight which she found

excessive and unbearable and she would experience an unusual sensation in her head a brainstorm,

according to her. She would weep when she was not sad, laugh when not happy. She was understandably

frustrated and decided to quit university, preferring to spend time at a college nearer to home, where she

could seek solace from her parents. Retrospectively it was clear that she was exhibiting prodromal symptoms

of schizophrenia. Back then in the 1960s, it was not so. When she saw a psychiatrist a few months later, he

attributed the symptoms to stress and anxiety and told her to go on a holiday.

Fast-forward 48 years later, Sarah was 65 years old, diagnosed with schizophrenia and living in a psychiatrichospital. She was one of the patients I was privileged to interview during my mental health rotation. As I sat in

front of her for the first time, listening to her talking about faces that she can see behind me, I cannot help

but wonder if something could have been done to prevent the development of her illness. What if she was

identified early on, still a 17-year-old precocious teenager, as having prodromal symptoms and then treated?

Would this have prevented the deterioration or would this label contribute to another potentially equally

devastating downward social trajectory? What if we had an effective treatment for prodromal schizophrenia

without any significant side effects? Do we have enough evidence to conclude that treating patients with

prodromal symptoms is ethically acceptable, beneficial and not detrimental?

In this essay, I will attempt to answer these questions. I begin by introducing the concept of prodromal

schizophrenia and then go on to explore the benefits and the risks of identifying and treating patients with

prodromal schizophrenia.

*The actual name of the patient has been changed to protect her identity


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The ethics of early interventions in prodromal schizophrenia

Principles of prodromal schizophrenia

Schizophrenia has been conceptualised as a chronic disease with lasting cognitive, social and functional

impairments since dementia praecox was first described at the dawn of the twentieth century. Up until the

1950s Sarah would probably have just been born then those with psychotic illnesses were locked away,

entrapped by the notion that life could not exist beyond the desolate walls of hospitals. With

deinstitutionalisation, while many patients with psychotic illnesses relished the newfound freedom, others

were relegated to lives of poverty, homelessness and loneliness. In the past three decades, schizophrenia

researchers have challenged this notion of inevitable decline, postulating that early interventions may mitigate

deteriorations in psychotic illness and improve functional outcome, providing hope for patients and families.1

Despite the more favourable prognosis for patients with psychotic illness compared to Kraeplins time, the

majority of patients with schizophrenia nowadays never return to their previous state of normal functioning

after the first psychotic episode. Sarahs symptoms were initially intermittent and mild but then progressed to

become constant and severely disabling, which warranted actual disease diagnosis. Indeed, studies have

shown that significant functional deficits present in the psychotic episode may have been inoculated even

before the illness began.2-4

Therefore, it is clear that schizophrenia cannot be defined to begin with the onset of frank psychosis; it is

rather a continuum characterised by premorbid, prodromal, acute and chronic phases. The premorbid phase

encompasses a period of stable social and cognitive deficits, alongside frequent subtle neurological

abnormalities, long preceding the first psychotic episode.5

On the contrary, the prodromal phase is

characterised by its lack of stability, worsening positive and negative symptoms and deteriorating trajectory of

psychosocial impairment, culminating in the onset of frank psychosis.6

After the first psychotic episode, there

comes a period of recurrent exacerbations and remissions as well as ongoing functional decline until an

individual settles into the chronic phase of illness where deficits and symptoms stabilise. While in the latter

two phases (acute and chronic) symptoms are more easily identifiable, the subtle nonspecific symptoms that

first emerge during the prodrome are often overlooked (as in Sarahs case). The failure to recognise these early

changes is particularly concerning as the duration of untreated psychosis (DUP) corresponds significantly to

further functional decline.7

As the prodromes can only be accurately identified retrospectively, research efforts have focussed on

developing measures to predict future psychosis risks with high sensitivity and specificity. The Comprehensive

Assessment of At-Risk Mental State (CAARMS)(Table 1)8

and the Structured Interview of Prodromal Symptoms

(SIPS)9

defined three similar at-risk criteria, which can predict conversion to psychosis at rates as high as 50-

54% over the course of 6 months to 1 year, implying increased sensitivity. In addition, the North American

Prodromal Longitudinal Studies (NAPLS)

10

revealed that individuals who were most likely to convert topsychosis had a family history of psychosis, symptoms of suspiciousness or delusional-like experiences, a


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decline in social functioning and/or a history of drug abuse; any three combination of these criteria increased

the positive predictive probability up to 80%, suggesting that an algorithm for treatment for those who are at

the highest risks may be developed.

A few months after the first onset of her psychotic symptoms, Sarah presented to the local psychiatrist, who

then attributed her symptoms to stress and anxiety. Had the CAARMS/SIPS/NALPS criteria be applied to her,

she would have qualified for the diagnosis of prodromal schizophrenia. However, the existence of these

criteria would be of little use to her or other patients if early interventions that ensue prove to be ineffective

or worse, detrimental. In Sarahs case, this is unknown since she was not managed prodromal ly. Studies

elucidating the effectiveness of early interventions are thus important; some of them will be discussed in the

next section.

Table 1. Prospective diagnostic criteria for three schizophrenia prodomes.8-10


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The potential benefits of being at risk

Classifying an individual as being at risk for schizophrenia may usher in possible therapeutic interventions.

Various studies have highlighted the potential of intervening in the early phases of the disease with both

pharmacological and psychosocial treatments. However, relatively few psychopharmacological studies have

assessed patients meeting the prodromal criteria.12-15

Reasons for this include: the short history of prodromal

research, difficulties in sufficient subjects willing to enter a clinical trial for nonspecific symptoms, the majority

of at-risk patients are adolescents and there are many ethical issues associated with performing such studies.

Pharmacological interventions

In 2002, the Personal Assessment and Crisis Evaluation (PACE) study11

randomised 59 individuals meeting the

at-risk criteria with low dose risperidone and cognitive behavioural therapy (CBT) vs needs -based

intervention (NBI) and found that individuals who received the specific treatments were significantly less

likely to develop psychosis at 6 months than those who received NBI only (10 out of 28 people receiving NBI

converted to psychosis compared to 3 of 31 from the intervention group)(Figure 1). However, the difference

was no longer significant at 12 months. Interestingly, during the subsequent 6-month follow-up period, it

appeared that those who did not adhere to risperidone treatment were those who were most likely to convert

to psychosis.

Figure 1. Rate of transition to psychosis in the PACE study.11

NBI: needs-based intervention, SI: specific intervention (low

dose risperidone and cognitive behavioural therapy), SI-NC: SI with no or partial drug compliance and SI-C: SI with full

compliance.


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The Prevention through Risk Identification, Management and Education (PRIME) study,12

conducted in 2003 to

further evaluate the benefit of interventions in prodromal schizophrenia, is the only placebo-controlled

double-blinded study of an antipsychotic for the prodromal illness. Olanzapine vs placebo was compared in 60

at-risk individuals over the course of 1 year with subsequent 1-year follow-up. In the placebo group, 38% of

patients converted to psychosis compared to 16% in the olanzapine group and the hazard of conversion

among placebo patients was 2.5 times that of olanzapine-treated patients. However, these were not

statistically significant, probably due to the small sample size. It is interesting however, that all of the

psychoses in the olanzapine group occurred in the first 4 weeks of clinical trial when doses of olanzapine were

relatively low, implying that perhaps those who converted may not have had sufficient time on olanzapine for

it to affect the active processes leading to psychosis. The Global Assessment of Functioning (GAF) score, an

observer rated scale for measuring overall severity of functional impairment, was also non-significant.

Another study from the PRIME clinic (2007)13

included 15 participants in an open-label trial with fixed-flexible

dosing of aripiprazole (5-30 mg/day) for 8 weeks. There was improvement from baseline in the total number of

prodromal symptoms and none of the participants converted to psychosis. While the results are promising, the

significance of these findings is complicated by small sample size and lack of control group and blinding.

Figure 2. Time to onset of psychosis among patients with prodromal psychotic symptoms during 1 year of treatment with

olanzapine or placebo (PRIME study).12


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Nonpharmacological interventions

In the three studies mentioned above, the benefits of nonpharmacological interventions were either not

assessed (in the case of the PRIME studies12,13

) or insufficiently analysed (in the PACE study,11

the relative

contributions of risperidone treatment and CBT were not investigated). Perhaps, some patients could betreated with psychological therapy alone as a first-line therapy. The Early Detection and Intervention

Evaluation (EDIE) trial14

randomised 58 people with prodromal symptoms to 6 months of CBT or a monitoring

group. The CBT group had a lower risk for conversion to psychosis at 1-year follow-up and displayed fewer

indicators toward conversion on all outcome measures. However, an analysis of the EDIE data in the Cochrane

report15

stated that of the outcomes reported, the rate of psychotic conversion was not significantly different

between the groups.

As rigorous trials involving nonpharmacological interventions conducted in at-risk youths are limited, those

conducted in the first episode patients may also be examined because of their applicability in this age-specific

population. One example is the OPUS-Scandinavia study16

which included 547 people with a diagnosis of first

episode schizophrenia; 275 were randomly assigned to integrated treatment (consisting of an assertive

community treatment, family therapy, social skills training, and modifications of medication regime) and 272

to standard treatment. The results show that the GAF symptom score significantly favoured integrated

treatment by 1 year, but neither group differed significantly at 2-year follow-up. Two patients committed

suicide, one from each group. While psychosocial interventions often complement pharmacological

treatments in chronic schizophrenia, further studies are necessary to validate such strategies in the

prodromes.

The potential risks of being at risk

The results of the intervention studies while being positive in some cases are still preliminary, requiring

large-scale collaborative efforts with sufficient sample power and rigorous statistical analyses for more

adequate validation. Nonetheless, it is worth noting that success in treating the prodromal population as

described will not serve to clarify the issues of who to treat. If outcome can be affected by pre-emptive

interventions, there will be a great incentive to expand the profile of eligible candidates likely to benefit from

treatment; this may include increasingly younger patients or even those without symptoms. Hence, strict

scrutiny of possible ethical concerns arising from unintended consequences of false positives (those who

would not have developed the disease even without the intervention), stigma, and loss of confidentiality and

autonomy is crucial. These will be discussed in turn in the sections below.

False positives

There is no method of screening a population for susceptibility to schizophrenia existing or envisaged that can

eliminate the issue of false positives. The current range of specificity of the at-risk criteria is 71-74%, reflecting

a substantial false positive rate.9 One apparent problem for false positives is the risk of over-treatment. The

use of antipsychotic medication for those who have not yet developed frank psychotic symptoms is


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controversial as the data regarding the efficacy and safety are inconclusive. Investigators from the PACE and

PRIME studies11,12

believe that the newer atypical agents, such as risperidone and olanzapine provide a safer

alternative than previous neuroleptic medications while others argue that this is questionable, particularly in

this population, which are primarily young adults and teenagers.15,17

Taking an example from the PRIME study

(2003),12 patients who were given olanzapine had higher increases in weight gain (mean weight gain of 8.79

kg) compared to those taking placebo (0.30 kg) at 1-year follow-up. This supports other recent reports of

olanzapines association with weight gain.15,18

The issue of weight gain should be taken seriously as it poses

threat not only to self-image and social functioning but also adds to serious long-term health risks of obesity

and diabetes mellitus, especially as these medications have been associated with insulin resistance and

metabolic syndrome.18

Stigma

Beyond the issue of side effects of treatments, it is worth considering whether there are any ethical

considerations specific to the idea of participating in a programme designed to study and prevent incipient

psychosis. Prodromal research subjects could feel that they are labelled as at risk for psychosis in a way that

could cause negative repercussions. This does not necessarily imply that researchers would use such a label, or

that the idea of being considered at risk for psychosis is inherently pejorative. Nonetheless, it raises the issues

of stigma. In a population that is not immediately at risk or impaired, the idea of being vulnerable for psychosis

could leave the false positives with a lasting sense of being fragile or damaged. It might alter their goals or

make them less likely to achieve; it could be harder to find motivation for a future threatened by impending

illness. Families might well reorganise their priorities in the light of this information. Sarahs family was very

supportive of her predicament especially after she stopped going to university even when the actual

diagnosis of prodromal schizophrenia was not made. Indeed, some families, like Sarahs, tend to be

protective, allowing them to protect at-risk individuals from stress and redefining behavioural problems as

illness rather than character flaws. In others, the protective impulse might in effect, result in discouragement

of growth or achievement.

The issues of stigma surrounding false positive results should be viewed in context of the stigma associated

with actually suffering from the disease, the true positives. Is there a risk of stigma if we do not identify

individuals early? If we do not, and a person becomes schizophrenic, he or she may violate societal norms in a

situation that may be detrimental or embarrassing. Which is more stigmatising? For the true positives

identified early, the potential of effective treatment must be balanced against heightened anxiety and

medicalisation of their presymptomatic years, a period of time that could represent their best shot at

normalcy in the face of what might be a lifelong struggle with mental illness. Sarahs early psychotic symptoms

were severe enough to warrant her quitting university and she had only worked for two years as a secretary

before being forced into retirement, due to her cognitive instability. Would knowing and treating the

prodromal symptoms make her lifes trajectory any better? As we have seen in the studies above, this is

unlikely. Would the stigma associated with being labelled as at risk be less severe than that linked with the


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disease itself? This is unknown. Nonetheless, the stigma associated with schizophrenia is widely recognised,

creating challenges for sufferers and discrimination in society. This demonstrates the need for education

concerning mental illness amongst family members and society. The importance of addressing stigma, along

with early detection and treatment of schizophrenia may help to reduce the morbidity associated with

schizophrenia.

Issues regarding confidentiality and autonomy

At-risk individuals should also have concerns about whether intervention for susceptibility will make them

unemployable or uninsurable and whether it will constitute a diagnosis in the eyes of employers or insurers,

meaning that from this point forward they will have on record a pre-existing condition. Confidentiality is an

important tool for protecting the at-risk population from this discrimination. It includes not only who is told

and what is told but what type of language is used and what sort of messages are implied. The PACE (Personal

Assessment and Crisis Evaluation) study11 was named deliberately as such (i.e. using neutral language) to avoid

frightening the at-risk population of youths and to prevent suggestion of diagnosis of schizophrenia/psychosis

to the observers. The PACE clinic was situated in a teen centre within a shopping mall rather than in a hospital

setting to further minimise association with mental illness. Even with such a sensitive and thoughtful

approach, confidentiality issues regarding prodromal interventions may still arise. One problem is that it relies

on the discretion of parents and families. It is not reasonable to assume that patients and families will keep

information to themselves even if that is in their best interests. It is safest to assume that any information

given to patients could become available to their community, schools, employers, insurers and other potential

third parties, by virtue of what the families choose to share.

One potential solution that has been debated by researchers is that it might be possible to just limit the

information given to patients and families using language that is neutral and avoiding specific mention of

schizophrenia/psychosis as a risk. This circumvents the problems of relying on the discretion of the patient and

family members. However, filtering information is not compatible with our understanding of patient autonomy

or the requirements of informed consent. Indeed protecting patient autonomy in medicine has come to be

synonymous with informed consent. In the prodromal period, patients are on the cusp of competence both in

terms of age and mental status. Interventions at an earlier stage imply that patients will be less compromised

by the disease, in terms of cognition and insight, but will also be younger and thus less able to participate in

the decision-making process. Presumptively, parents/guardians will often be very much involved in any

decision to pursue treatment. Most of the time, the best interests of the child and the best interests of the

family converge. However, family members, as potential caregivers, may at times have an agenda that

deviates from the best interests of the patient. Psychosis can place an enormous burden on family members;

they may feel that with regard to treatment, limiting unnecessary risks is more important than any treatment

goal. Cultural issues, educational inadequacies and geographic or economic barriers might be at play in

influencing decisions. Doctors should therefore then take an active role in guiding the decision-making

process.


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Prodromal intervention: A clinical equipoise

Exploring the ethical and social implications of early interventions in schizophrenia at this stage of the game

affords us a moment to consider the impact of schizophrenia has on public health. The estimated overall cost

of schizophrenia in the US is $62.7 billion, with total indirect cost of unemployment of $32.4 billion.

19

Althoughthe cost of early identification and intervention may initially appear to be higher, it is suggested that early

identification may be cost-saving.19

As a result, there has been an increase in the number of studies on

prodromal schizophrenia reported recently. The ED:IT programme20

in the UK targets engagement and

intervention for at-risk youths and improved access to care for at-risk populations and communities. Such

clinical research has led in the Department of Health funding a five-year public health programme to reduce

the rates of transitions to psychosis and the DUP.20

Nonetheless, in my opinion, current circumstances encourage but do not dictate intervention, as there exists a

state of clinical equipoise regarding evidence related to treatment efficacy and safety. Furthermore, the ethical

issues are complex and multifaceted, involving the issues of side effects in the false positives, significant stigma

associated with involvement in prodromal research and the unresolved aspects of confidentiality and

autonomy. As such, early intervention for prodromal schizophrenia is still very much in the realms of research

and the decision-making process on who to treat requires an individualised strategy rather than the one -size-

fits-all approach. However, as more trials are being conducted worldwide, this might change in the near

future.

During my first SSC earlier this year, I had the opportunity to visit Sarah again at the psychiatric hospital. She

recognised me, to my delight, but then proceeded to talking about another delusion she was having; this time

it was about nurses who tried to kill her whilst she was asleep. Much research has been done about

schizophrenia, but none is more important than those that contribute to the prevention of the disease, after

all, prevention is better than cure. But for now, most patients with schizophrenia would have followed a

disease course similar to that of Sarah: prodromal symptoms went unnoticed, schizophrenia diagnoses made

late into the disease progression, subsequent schizophrenia symptoms inadequately treated. Like Sarah, these

patients will end up imprisoned in their own body. Much effort needs to be done to prevent the onset of this

devastating disease.

(3495 words excluding headings and legends)


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Prodromal Schizophrenia