Unmet needs in treatment of schizophrenia’s negative symptoms – Part 1

Ray is 20 and the youngest of three brothers. He grew up in suburban Dublin and both parents work in business.

Relatively popular throughout secondary school, Ray always socialised well and had a solid circle of friends.

He enjoyed rugby training on Saturdays, supported the Leinster rugby team and attended matches at the Aviva Stadium with friends when the opportunity arose. A good student with a keen intellect, he worked hard academically and ultimately achieved 570 points in his Leaving Certificate. This was enough points to pursue the architecture course he had always dreamed of.

But college is not working out as planned. Ray is a moderate drinker, but he has been smoking cannabis intermittently for the past few years – although crucially never around exam time. As Ray’s first year at college has progressed, his parents have noticed a change of demeanour. His face seems less expressive than normal, his actions are less spontaneous, and he makes less eye contact. When asked a question, he now typically leaves a gap before he answers, while his conversation generally seems more stilted and perhaps lacks the depth that it used to.

Previously a smart dresser (perhaps even a little vain), he now has to be reminded to take a shower or change his clothes. He has given up rugby training and does not bother watching the television coverage either. The family soon realise that Ray has not been to college in months, that he has drifted from his friends and that he has stopped returning his girlfriend’s phone calls. Towards his end-of-year exams, he drops out of college completely with a vague plan to get a job instead.

In time, Ray begins to hear voices talking about him, remarking that he will never amount to anything in life. He tries hard to get rid of these voices using distraction techniques, loud music and even alcohol, but nothing seems to work. What is initially irritating soon becomes frightening, as the voices are ever more sinister and threatening. His thoughts sometimes seem mixed up and he finds it hard to express himself.

As he reverts to watching more and more television, he begins to feel a strong connection with the events happening on the news. Indeed, he wonders if the newscaster is trying to communicate directly with him to offer a warning. Ray experiences a similar sense of foreboding while on the internet and suspects his email account is being hacked by the Gardaí. He increasingly switches off his phone so that he cannot be tracked and unplugs electronic equipment at his home.

Part 1
This is the first of two articles about the negative symptoms of schizophrenia (those outlined in the paragraphs two and three above). The first article will deal mostly with diagnosis; the second will discuss treatment.

Schizophrenia generally presents for the first time between the ages of 15 and 40, while the lifetime risk is around 1 per cent. Approximately 20 per cent of psychiatric admissions in Ireland are for the treatment of schizophrenia, making it second only to depressive disorders, while psychosis remains the commonest reason for involuntary admissions. Schizophrenia is both profoundly debilitating for the individual and costly for society.

Behan and colleagues (2008) estimated the (direct and indirect) expense of schizophrenia to the Exchequer to be over €460 million in 2006.(1) This sum is likely to have increased significantly in the intervening 14 years.

Aetiology of schizophrenia
What is the aetiology of schizophrenia? Unfortunately, there is no single easy answer. Clinicians still emphasise the stress-vulnerability model, a theory in which biological factors (a complex interaction between genetics and disrupted early development of the nervous system) predispose people to developing psychosis as they mature and encounter the rigours of life.

Obstetric factors, stressors in childhood and adolescence (leading to dopaminergic dysregulation), and social adversity (leading to negative cognitive biases in relation to everyday experiences) all increase the risk of emerging psychosis. This risk is further heightened by the use of illicit substances, especially cannabis, which can increase the lifetime risk of schizophrenia by six or more times. Relapse of psychosis is more likely with interpersonal conflict and high expressed emotion in the family setting.

Diagnosis as a whole
Before considering negative symptoms, we could review the diagnosis of schizophrenia as a whole. According to the World Health Organization’s International Classification of Diseases 10th Edition (ICD-10, 1993), schizophrenia is a severe psychotic illness that is not attributable to: (a) organic brain disease; (b) substance intoxication, dependence or withdrawal; or (c) diagnosable mania or depression.(2)

A formal diagnosis dictates that psychotic symptoms must be present on most days for at least a month, and must include one or more of the following: (a) thought echo, insertion, withdrawal or broadcast; (b) passivity delusions (in which the individual believes their actions, impulses or feelings are controlled by an outside force) or delusional perception (in which a delusion is triggered by the perception of something real); (c) auditory hallucinations (usually third-person or running commentary); and (d) persistent delusions not already mentioned.

Less specific symptoms
Even if a patient does not fulfil the criteria above, they can still be diagnosed with schizophrenia if they have two or more from a longer list of less specific symptoms. These include: (a) other types of hallucination; (b) thought disorder (where the link – or “association” – between one thought and the next becomes loosened); (c), catatonic behaviours (for example, unconscious physical posturing or mutism); and (d) negative symptoms (which we will outline in detail below). An updated classification system – ICD-11 – is currently being finalised and is due for adoption on January 1, 2022.

A set of criteria
The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5, 2013) describes schizophrenia in a slightly different manner.(3) Again, schizophrenia is seen as a severe psychotic illness, but it must meet a set of criteria to qualify for the diagnosis. Criterion A requires the presence of at least two from a list of symptoms that includes delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour, and negative symptoms (again, outlined below). At least one of these symptoms must come from the first three items on the list.

Criterion B requires that the individual’s level of social and occupational functioning for a significant proportion of their time since onset must fall short of their normal level.

Criterion C requires that the symptoms meeting Criterion A must be present continuously for at least six months, with at least a month of active symptoms (or less if successfully treated). This may include a prodrome or residual symptoms.

Criteria D, E and F primarily involve exclusions such as schizoaffective disorder, depression, bipolar disorder, substance misuse and medical conditions, and allowances for autistic spectrum disorder.

Two sets of symptoms
The concept that schizophrenia could be divided into two sets of symptoms was originally proposed by Hughlings-Jackson in 1931. Essentially, positive symptoms are those which are there when they should not be (like hallucinations, delusions and so forth), while negative symptoms are those that are not there when they should be (like fluent speech, social interaction and so forth).

In 1982, Andreasen and Olsen devised a set of validated diagnostic criteria allowing for the subdivision of patients into those with positive, negative, or mixed schizophrenia.(4) They asserted that, while patients with positive-symptom schizophrenia typically demonstrate adequate premorbid adjustment and global functioning, normal cognition and no evidence of cerebral atrophy, patients with negative-symptom schizophrenia tend to exhibit poor premorbid adjustment, poorer global functioning, impaired cognitive function and evidence of cerebral atrophy.

The negative symptoms are in five domains and are as follows:

Affective flattening or blunting
• Unchanging facial expression;
• Decreased spontaneous movement;
• Paucity of expressive gesture;
• Poor eye contact;
• Affective non-responsivity;
• Lack of vocal inflection.

Alogia
• Poverty of speech;
• Poverty of the content of speech;
• Blocking;
• Latency of response to questions.

Avolition-apathy
• Poor grooming and hygiene;
• Impersistence at work or school;
• Physical anergia.

Anhedonia-asociality
• Few recreational interests or activities;
• Reduced sexual interest or activity;
• Inability to experience intimacy or closeness;
• Impaired relationships with friends and peers.

Attention
• Social inattentiveness;
• Inattentiveness during mental state examination.

These five domains feature in Nancy Andreasen’s Scale for the Assessment of Negative Symptoms (SANS) which (along with the subsequently-developed Scale for the Assessment of Positive Symptoms, or SAPS) is commonly used in early intervention services to identify evolving psychotic symptoms and reduce the duration of untreated psychosis (DUP).(5)

Within each domain of the objectively rated SANS, each symptom is marked from 0 (absent) to 5 (severe), while each domain is given a global rating to yield the overall score.

Meanwhile, the other commonly used inventory, especially in research, is the Positive and Negative Syndrome Scale (PANSS).(6)

This was first published in 1987 by Kay, Fiszbein and Opler. During the course of an interview that usually takes under an hour, the patient is rated from 1 to 7 on 30 different symptoms – seven on the positive scale, seven on the negative scale and 16 on the general psychopathology scale. The negative scale items are as follows:
• Blunted affect;
• Emotional withdrawal;
• Poor rapport;
• Passive or apathetic social withdrawal;
• Difficulty with abstract thinking;
• Lack of spontaneity and flow in conversation;
• Stereotyped thinking.

Because 1 is the lowest score for any item, all PANSS scores range between 30 and 210. As negative symptoms can sometimes be harder than positive symptoms to pin down in individuals such as Ray (from our vignette above), inventories such as the PANSS and the SANS can be useful adjuncts to clinical assessment, if used properly. So, what happens to Ray?

Therapy
Ray’s parents are naturally worried, and they call the family GP, who refers him to a psychiatrist. With some difficulty, Ray is persuaded to keep this appointment, whereupon the psychiatrist diagnoses psychosis and admits him to a local psychiatric hospital. Ray resides there for a few weeks, and receives a combination of medication, occupational therapy, and some group psychological work. His subjective experiences gradually begin to normalise.

Positive symptoms like his hallucinations become fainter and less frequent and he no longer feels paranoid. But the family believe the “Ray” they used to know, has yet to fully return. In truth, his negative symptoms are harder to ameliorate. In this regard, the next and concluding article will allow us to examine the pharmacological and non-pharmacological management of negative symptoms and its effect on unmet needs and prognosis.

References
1. Behan C, Cullinan J, Kennelly B, Turner N, Owens E, Lau A, Kinsella A, Clarke M. Estimating the Cost and Effect of Early Intervention on In-Patient Admission in First Episode Psychosis. J Ment Health Policy Econ (2015). 18(2):57-61.
2. World Health Organization (1993). The ICD-10 Classification of Mental and Behavioural Disorders.
3. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorder 5th Edition (DSM-5).
4. Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry (1982). 39(7):784-8.
5. Andreasen NC. Scale for the Assessment of Negative Symptoms (SANS). Iowa City, University of Iowa (1984).
6. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome scale (PANSS) for schizophrenia. Schizophr Bull (1987). 13(2):261-76.