Ryan is a 21-year-old male brought to the clinic by his parents after his teachers expressed concerns that he was failing his university examinations and had poor attendance. Over the past six months, Ryan had accused his classmate of inserting thoughts into his head and controlling his actions. He reported this as true because he heard ‘the voices’ warning him. His friends noticed that Ryan was more withdrawn, and he was seen talking to himself. Ryan denied taking recreational drugs, and a routine drug screen performed last month revealed no abnormalities.
Question 1: What are the diagnosis and differential diagnoses?
Ryan accused his classmate of working for a sinister network of aliens called ‘The Organisation.’ They reference him on the radio whenever the radio uses a word that starts with ‘R’. When these ideas were challenged, he rebuffed your assertions that perhaps he might be mistaken.
Question 2: What type of delusion is being demonstrated?
You ask Ryan about the voices that he hears. He describes a male voice coming from outside his head, which talks to him throughout the day. The voices occasionally comment on his actions, for example ‘Ryan is drinking the cup of coffee now’ and at other times suggest that his classmate is going to hurt him ‘They are coming to get you’. There had been times when he heard his thoughts spoken out loud, which bothered him greatly.
Question 3: How would you describe his hallucinations?
With the constellation of symptoms presented, you diagnose Ryan with schizophrenia. Ryan’s cousin (Jake) was also diagnosed with schizophrenia, but had a very different presentation. Jake was found to be increasingly quiet, and when he did speak, he was often incoherent. He refused to leavehis room and did not appear to be excited over anything, often giving a blank stare with little emotion shown.
Question 4: How will you explain Jake’s seemingly different presentation of schizophrenia?
Ryan’s parents suspect that he might have used recreational drugs in the past and wonder if that might have contributed to the development of his psychotic episode.
Question 5: Which illicit substance has a known association with the development of schizophrenia?
Now that he has been diagnosed with psychosis, Ryan’s parents want to know what investigations will be done.
Question 6: How will you investigate Ryan’s first presentation of psychosis?
Having heard his conspiracy theories, you ask Ryan if he feels safe currently. Ryan replies that he is worried “The Organisation” is plotting to abduct him and states that he would rather die than be abducted. He intends to hurt himself and shows you a kitchen knife he has hidden in his bag.
Question 7: What is the next step of management?
Ryan is admitted, and investigations return as unremarkable. You explain to Ryan’s parents that early intervention may improve cognition and will be in his best interest. His parents cautiously accept the treatment plan. However, his parents mention that Ryan was previously bullied for his heavy weight, and are worried about the side effects.
Question 8: Which antipsychotic medications would you avoid for Ryan?
Ryan was started on haloperidol. Unfortunately, despite treatment with haloperidol and subsequently risperidone for six weeks each at a therapeutic dose, he remains symptomatic. He is diagnosed with treatment-resistant schizophrenia (TRS).
Question 9: What is the definition of TRS?
Question 10: What are the potentially life-threatening side effects of clozapine ?
Ryan’s condition stabilises on clozapine and he reports compliance with his medications. While the risk of extrapyramidal side effects (EPSEs) with clozapine is low, he remains concerned about the side effects of antipsychotics.
Question 11: What are EPSEs and what are the different types?
Answers to Case 1
Answer
Schizophrenia
Apart from organic causes, the main differentials to consider for symptoms of psychosis without prominent affective symptoms would be:
Explanation
At least two of the following symptoms must be present (by the individual’s report or through observation by the clinician or other informants) most of the time for a period of 1 month or more. At least one of the qualifying symptoms should be from items (1) to (4) below:
1. Delusions
2. Hallucinations
3. Disorganised thinking
4. Passivity phenomenon
5. Negative symptoms
6. Grossly disorganised behaviour
7. Psychomotor disturbances (e.g., catatonia)
Specify if the first episode or multiple episodes, are continuous or in remission.
The onset of schizophrenia generally occurs in late adolescence or early adulthood. Auditory hallucinations are the most common form of hallucination, with an estimated prevalence of 40–80% [Reference Thomas, Mathur, Gottesman, Nagpal, Nimgaonkar and Deshpande1, Reference Andreasen and Flaum2].
A diagnosis of delusional disorder is less likely as there is impairment in functioning with odd behaviour and prominent hallucinations. The history given in the vignette suggests an acute deterioration, which is not typically seen in personality disorders. Acute and transient psychotic disorder often lasts for a few days up to a month and does not exceed three months. Schizotypal disorder persists for at least two years and the individual must not have fulfilled the criteria for schizophrenia.
First-rank symptoms are commonly seen in schizophrenia:
Hearing thoughts spoken aloud
Third-person hallucinations
Auditory hallucinations in the form of a ‘running commentary’
Thought withdrawal or insertion
Thought broadcasting
Delusional perception
Passivity (feelings or actions felt as influenced by external forces)
Schneider’s first-rank symptoms of schizophrenia – ABCD
◦ Auditory hallucinations
◦ Broadcasting, insertion, withdrawal
◦ Control, passivity
◦ Delusional perception
There are two age peaks of schizophrenia: early 20s and 40s
Late-onset schizophrenia: aged 40 to 60 years
Very late-onset schizophrenia: > 60 years
Although first-rank symptoms are highly prevalent in patients with schizophrenia, they should not be used as a sole diagnostic tool due to their higher specificity but lower sensitivity
While auditory hallucinations are more common, visual hallucinations are also present in schizophrenia. The visual hallucinations experienced are often unformed, such as glowing orbs or flashes of colour
If the patient presents with predominant non-auditory hallucinations (e.g., visual, olfactory, gustatory), it is important to rule out organic causes (e.g., epilepsy, encephalitis, brain tumours)
Question 2
What type of delusion is being demonstrated?
Explanation
A delusion is defined as a firmly maintained false belief contradicted by reality; idiosyncratic, incorrigible and preoccupying. Delusion of reference is characterised by the erroneous belief that innocuous events have strong personal significance, with complete conviction. Approximately 80% [Reference Andreasen and Flaum2] of people with schizophrenia have delusions.
Impairment of insight is common and a delusional explanation for their hallucinations is often elicited. Bizarre delusions are implausible and absurd to same-culture peers and do not derive from ordinary life experiences (e.g., the belief that one’s organ has been replaced entirely with another’s, although there are no scars or evidence of such). A non-bizarre delusion is one that, while not true, can be derived from ordinary life experience with the possibility of it being true (e.g., believing that valuables have been stolen).
Features of delusion can be remembered as three ‘U’s:
◦ Untrue
◦ Unshared
◦ Unshakeable
The differences between a delusion and an overvalued idea lie in the degree of conviction and how it is being derived
Question 3
How would you describe his hallucinations?
Answer
Second- and third-person auditory hallucinations in the form of a ‘running commentary’ with the presence of a thought echo.
Explanation
Perception is the organisation, identification and interpretation of sensory information to represent and understand the presented information or environment. Hallucinations are false perceptions that are not in any way distortions of a real perception but spring up on their own as something quite new and occur simultaneously with and alongside real perception. They may take the form of noises, music, single words, brief phrases, or whole conversations.
Approach to hallucinations should include:
1. Where?
The first distinction is between hallucinations and pseudohallucinations. Ask where the voices are from and assess the degree of insight lost.
| Hallucination | Pseudohallucination | |
|---|---|---|
| Space | External space | Inner subjective (not seeming to the patient to represent external reality, being located within the mind) |
| Insight | Impaired | Intact |
| Control | Cannot be willfully modified | Can be modified by will (initiated or interrupted) [Reference Jaspers and Jaspers3] |
2. Who?
Assess who the voice(s) have been identified as.
3. How?
If it is an auditory hallucination, distinguish between the second person (voice speaking to the person addressing him as ‘you’) and the third person (voice talking about the person as ‘he’ or ‘she’). Third-person auditory hallucinations are part of the first-rank symptoms in schizophrenia.
4. What?
Examine the content of the hallucinations and determine if they are mood congruent or incongruent. Auditory hallucination may come in the form of a running commentary or voices arguing etc.
A thought echo refers to a form of auditory hallucination where the person hears his or her thoughts aloud after thinking them.
Check for the presence of command hallucinations and passivity as part of the risk assessment – higher risk if the patient has both
Question 4
How will you explain Jake’s seemingly different presentation of schizophrenia?
Answer
Jake has predominantly negative symptoms of schizophrenia, whereas Ryan presents with predominantly positive symptoms of schizophrenia.
Explanation
Positive symptoms are characterised by delusions and hallucinations.
Negative symptoms are characterised by deficit symptoms leading to the absence or diminution of normal processes and functioning. They are often listed as the six ‘A’s: anhedonia (inability to feel pleasure), apathy (disinterest in daily activities), avolition (decreased motivation), alogia (decreased spontaneous speech), affective flattening (lack of emotional expressivity, but not depressed) and asociality (social withdrawal).
Patients may present in a varied manner, with features consisting of both positive and negative symptoms.
6 ‘A’s of negative symptoms:
◦ Anhedonia
◦ Apathy
◦ Avolition
◦ Alogia
◦ Affect flattening
◦ Asociality
Differentials for apathy include:
◦ Schizophrenia (negative symptoms)
◦ Depression
◦ Parkinsonism
◦ Behavioural-variant frontotemporal neurocognitive disorder
◦ Drug-induced (e.g., amotivation syndrome from chronic cannabis use)
◦ Drug withdrawal (e.g., ‘crash’ from cocaine or stimulant use)
Question 5
Which illicit substance has a known association with the development of schizophrenia?
Explanation
Cannabis use has been associated with a two- to threefold increased prevalence of schizophrenia and schizophrenia spectrum disorders [Reference Gage, Hickman and Zammit4]. The reverse causation hypothesis also postulates that schizophrenia risk itself predicts the likelihood of cannabis initiation and a genetic predisposition for schizophrenia was associated with increased use of cannabis [Reference Gage, Jones, Burgess, Bowden, Davey Smith and Zammit5, Reference Power, Verweij, Zuhair, Montgomery, Henders and Heath6].
While other drugs do not have as clear an association with the development of schizophrenia, their use can still precipitate an acute psychotic episode:
| Recreational drugs |
|
| Medications |
|
Cannabis users who have homozygous VAL/VAL alleles in the COMT genotype have a higher risk of more severe psychosis [Reference Nieman, Dragt, van Duin, Denneman, Overbeek and de Haan7]
The lifetime prevalence of co-morbid substance use disorder in patients with schizophrenia is 74% [Reference Boland, Verduin, Ruiz, Shah and Sadock8]
The risk of schizophrenia increases with the younger onset of cannabis use [Reference Van Winkel and Kuepper9]
Question 6
How will you investigate Ryan’s first presentation of psychosis?
Answer
| Category | Investigations |
|---|---|
| Point-of-care test | Electrocardiogram |
| Biochemical |
|
| Imaging |
Explanation
Psychosis can be a symptom of an underlying acute medical illness or chronic condition. Hence it would be prudent to rule out medical causes and medication and substance-related causes before considering primary psychiatric causes of the psychosis.
Symptoms suggestive of organic causes:
Sudden onset
Predominant non-auditory hallucinations (visual, gustatory, olfactory)
Fluctuating altered mental status
Autonomic instability
Abnormal neurological examination
For very young and old patients, investigations should be done to rule out organic causes.
In individuals with an acute medical illness, delirium is a common cause of psychosis
Consider urine and blood toxicology screen if high suspicion of drug-induced psychosis but the urine drug screen is negative
New synthetic psychoactive substances may not be picked up by conventional drug screens
Symptoms suggestive of drug-induced psychosis:
Question 7
What is the next step of management?
Answer
Inpatient admission and initiation of antipsychotic medications in the absence of an organic cause.
Explanation
The patient poses a high suicide risk and has demonstrated a concrete plan to hurt himself. His delusions severely impair insight into his condition, and one should not treat his threats lightly. The harm he poses to himself warrants an inpatient admission and early intervention for his psychosis. Antipsychotic drugs are the first-line treatment for schizophrenia.
Question 8
Which antipsychotic medications would you avoid for Ryan?
Answer
Antipsychotics with a high propensity to cause weight gain, such as olanzapine, quetiapine, clozapine (although weighing of the risk–benefit ratio in patients with TRS is required).
Explanation
The side effects of each antipsychotic medication vary. As a rule of thumb, second-generation atypical antipsychotics are serotonin 2A/dopamine 2 antagonists with a lower risk of extrapyramidal side effects (EPSEs) and a higher risk of metabolic side effects (weight gain, insulin resistance, impairment of glucose tolerance, development of hyperlipidaemia, etc.).
Side effects of antipsychotic medications include:
Metabolic (including weight gain and diabetes)
Extrapyramidal (including akathisia, dyskinesia and dystonia)
Hormonal (including increasing plasma prolactin)
Others (including unpleasant subjective experiences)
Below are different concerns which arise with antipsychotic use:
| Concerns | Antipsychotic(s) to avoid | Preferred antipsychotic(s) |
|---|---|---|
| Typical antipsychotics (haloperidol, chlorpromazine) |
|
| EPSEs |
|
|
| Weight gain |
|
|
Elevated prolactin levels |
|
|
| Sedation |
| Aripiprazole |
| Seizure |
|
|
First- and second-generation antipsychotic medications are comparable in their clinical efficacy [Reference Jones, Barnes, Davies, Dunn, Lloyd and Hayhurst10]
The latter have a better effect on negative symptoms and have mood stabilisation properties [Reference Németh, Laszlovszky, Czobor, Szalai, Szatmári and Harsányi11]
Clozapine, a second-generation antipsychotic, has proven superior efficacy in TRS (response rates between 40% and 54% [12, 13])
The NICE guidelines [14] suggest that the choice of antipsychotic medication should be jointly made by the patient and healthcare professional
Irish guidelines [Reference Fitzgerald, O’Connell, Keating, Hynes, McWilliams and Crowley15] recommend the use of metformin as an adjunct in the treatment of antipsychotic-induced weight gain in adults with psychosis
Question 9
What is the definition of TRS?
Answer
Based on the 2017 Treatment Response and Resistance in Psychosis (TRRIP) Working Group [Reference Howes, McCutcheon, Agid, de Bartolomeis, van Beveren and Birnbaum16] definition of TRS, there are two consensus-based criteria, minimal and optimal:
Diagnosis – DSM-5 diagnosis of schizophrenia [17]
Symptom severity – at least moderate symptom severity (> 3 in psychotic symptom items) as rated using a standardised scale (e.g., Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS))
Functional impairment – at least moderate impairment measured using a validated scale (e.g., Social and Occupational Functioning Assessment Scale)
Prior treatment – at least two trials of ≥ 6 weeks at a therapeutic dose (equivalent to ≥ 600 mg chlorpromazine) with adherence ≥ 80% of prescribed doses
The minimal criteria (above) with the addition of:
Prospective evaluation of symptom severity using a standardised scale (e.g., PANSS or BPRS) confirming < 20% symptom reduction over six weeks of treatment
One of the two antipsychotic trials should be a long-acting injectable antipsychotic
Antipsychotic adherence should be confirmed by ≥ 2 antipsychotic plasma levels
Explanation
There are varying definitions of TRS and the TRIPP working group was formed in 2017 to establish the consensus criteria to standardize the definition of TRS. The previous 2014 NICE guideline [14] definition of TRS was clinically defined as failure to respond to two trials of different antipsychotics, one usually an atypical antipsychotic, of adequate dose and duration.
Question 10
What are the potentially life-threatening side effects of clozapine?
Answer
Explanation
Clozapine is initiated with close monitoring of the FBC for blood dyscrasias. Based on the NICE guidelines [14], the FBC must be repeated at weekly intervals for 18 weeks and then fortnightly until one year with a subsequent monthly FBC. Other side effects include:
| System | Description of side effects [Reference Fitzgerald, O’Connell, Keating, Hynes, McWilliams and Crowley15] |
|---|---|
| Haematology |
|
| Cardiology | The risk of fatal myocarditis or cardiomyopathy is estimated to be up to 1:1,300 patients treated |
| Neurology | Associated with a dose-dependent seizure risk at a rate higher than that seen in most other antipsychotic drugs. Seen in 4.4% of patients prescribed with 600 mg/day or more. Caution required when used with lithium due to increased risk of neuroleptic malignant syndrome |
| Anticholinergic |
|
| Anti-adrenergic |
|
| Others |
|
Possible causes of TRS include non-compliance to treatment, misdiagnosis, ongoing psychosocial stressors, high EE, co-morbid affective disorder and organic causes.
One important side effect of clozapine is agranulocytosis, which may worsen with co-prescription with other medications, such as valproate or carbamazepine. Lithium has been used to increase the neutrophil count and total white cell count in patients taking clozapine
High expressed emotion (EE) is an adverse family environment and is one of the more robust predictors of relapse in schizophrenia. The construct of EE comprises of
◦ Criticism
◦ Hostility
◦ Overinvolved emotionally
Consider checking the clozapine level and review medications the patient may be on (e.g., fluoxetine) that may increase the clozapine level, if the patient develops side effects
Clozapine reduces mortality in schizophrenia due to a lower risk of suicide [Reference Semple and Smyth18]
Good prognostic factors:
◦ Female
◦ Older age at the first episode
◦ Rapid (versus insidious) symptom onset
◦ Predominant positive (rather than negative) symptoms
◦ Presence of mood symptoms
◦ Good pre-morbid functioning
Poor prognostic factors include (in addition to the reverse of positive factors above):
◦ Positive family history of schizophrenia
◦ Early illness onset
◦ Structural brain abnormalities
◦ Prominent cognitive symptoms
Answer
EPSEs consist of acute dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia.
Explanation
Refer to the table on the next page for more elaboration.
Tardive dyskinesia has an insidious onset and is observed in 10 to 20% [Reference Meltzer, Alphs, Green, Altamura, Anand and Bertoldi19, Reference Novick, Haro, Bertsch and Haddad20] of patients who are treated for more than a year. It persists for at least a month after discontinuation of the offending agent and may be irreversible. Akinesia and rigidity develop more frequently than tremors.
Clozapine, quetiapine, aripiprazole, brexpriprazole and lurasidone are antipsychotic medications that cause the fewest EPSEs
Patients starting an antipsychotic medication should be evaluated for the following EPSEs weekly until the medication dose has been stable for at least two weeks:
| Acute dystonia | Akathisia | Pseudoparkinsonism | Tardive dyskinesia | |
|---|---|---|---|---|
| Incidence | 10% | 25 to 50% | 20% |
|
| Risk factors |
| Rapid anti-psychotic dose increment |
|
|
| Onset | Few hours |
| Gradual | At least six months after initiation, usually seen after many years |
| Symptoms | Involuntary contractions of major muscle groups, characterised by:
|
| Mimics Parkinson’s disease:
| Oro-bucco-lingual and facial dyskinesia (e.g., ‘Fly-catching’ , tongue protrusion)
|
Acute dyskinesia (involuntary movements):
| ||||
| Management |
|
|
|
Over a lifetime, about 1% of the population will develop schizophrenia. Schizophrenia affects more than 24 million people worldwide, and more than two out of three people with psychosis in the world do not receive specialist mental healthcare for the disease [Reference Ortí-Pareja, Jiménez-Jiménez, Vázquez, Catalán, Zurdo and Burguera21].
The heritability of schizophrenia is between 60% and 80% [17]. Twins, family and adoption studies have consistently demonstrated familial aggregation of schizophrenia, largely attributed to genetic factors. The concordance rate for monozygotic twins is approximately 45%, and for dizygotic twins is approximately 10% [22].
Children of patients with schizophrenia have a 13% risk of developing schizophrenia:
Children of BOTH patients with schizophrenia have a 46% risk of developing schizophrenia
Grandchildren of patients with schizophrenia have a 4% risk of developing schizophrenia
Parents of children with schizophrenia have a 6% risk of developing schizophrenia
Siblings of patients with schizophrenia have a 17% risk of developing schizophrenia
The rate of suicide is higher in patients with schizophrenia than in the general population. Antipsychotic medications may decrease long-term suicide mortality with the risk of suicide attempts increasing fourfold with non-adherence to antipsychotics [Reference Puri, Hall and Ho23].
Inadequate response to clozapine alone is not uncommon and the augmentation of clozapine to treat TRS is increasingly common. If there are no clear benefits with augmentation, the medication should be discontinued after three to six months to reduce polypharmacy burden and adverse drug effects. Commonly used augmentation agents include antipsychotics for positive symptoms, antidepressants for negative symptoms and mood stabilisers for suicidal ideation or aggression. The Maudsley guidelines [Reference Puri, Hall and Ho23] have suggested the consideration of the following agents for augmentation of clozapine: amisulpride, aripirazole, haloperidol, lamotrigine, omega-3-triglycerides, risperidone, sulpiride, topiramate, valproate and ziprasidone.
The term ‘at risk mental state’ (ARMS) was first coined by Yung et al. [Reference Taylor, Barnes and Young24, Reference Yung, McGorry, McFarlane, Jackson, Patton and Rakkar25] and described patients in the prodromal phase before the onset of psychotic symptoms. These individuals have changes in well-being and psychosocial functioning, often associated with cognitive decline or subthreshold psychotic symptoms. Recognising individuals with ARMS allows the healthcare team the opportunity for early intervention, which could delay, ameliorate or even prevent the onset of frank psychosis. The Comprehensive Assessment of At-Risk Mental States (CAARMS) [Reference Yung, Yuen, McGorry, Phillips, Kelly and Dell’Olio26] is a widely used semi-structured assessment tool to identify patients with ARMS. The CAARMS includes the following subscales: disorders of thought content, perceptual abnormalities, conceptual disorganisation, motor changes, concentration and attention, emotion and affect, subjectively impaired energy and impaired tolerance to normal stress. Depending on the severity scale score under each subscale, patients are: Group 1, Attenuated psychosis group; Group 2, Brief limited intermittent psychotic symptoms; and Group 3, Vulnerability; or they are diagnosed with psychosis.
Management of patients with ARMS is dependent on the local healthcare systems in place but typically includes a form of early intervention in psychosis (EIP) services. Such EIP services may offer cognitive behavioural therapy (CBT)-focused interventions along with case management and treatment of psychiatric co-morbidities. More than half of patients with ARMS will not develop a psychotic illness and therefore antipsychotics, which are not without adverse effects, are not typically used as a first-line treatment as suggested by both the 2014 NICE guidelines [14] and the Early Psychosis Guidelines Writing Group [27].
