Predisposition of Patients with Cannabis-Induced Psychosis to Treatment-Resistant Schizophrenia

CONTENTS

		Page No.
1.	Case History —————————————————————-	2 – 8
2.	Mental State Examination ———————————————-	9
3.	Case Formulation ———————————————————	10 – 15
4.	Discussion ——————————————————————-	16 – 20
5.	References ——————————————————————	21 – 23

 

Word Count excludes figures, headings, quotations and references.

CASE HISTORY

1.1 Patient Details

Initials: BM

RID: 3036085

Age: 37

Date of Birth: 10/09/1980

Gender: Male

Marital Status: Single

Ethnic Group: Irish

Social Class: Homeless

Employment: Unemployed

Date Seen: 03/01/2018

Rotation/Consultant: St Michael’s Ward at Mercy University Hospital (MUH)/Dr. Elaine Dunne

1.2 Reasons for Referral

BM is a 37-year-old single, homeless male who was brought into the Emergency Department (ED) in MUH by ambulance on 26/11/17, called by the Gardaí after bizarre behaviour (masturbating in public), on a background of schizophrenia.

1.3.1 Presenting Complaint

BM claims he had been brought in by ambulance to MUH as he “had an episode and did not eat or sleep for days”, which led to him experiencing a “sharp, shooting pain in heart. It felt like [he] was going to have a heart attack”.

1.3.2 History of Presenting Complaint

Patient’s Recount of Incident

BM’s memory of the sequence of events leading up to his admission is “fuzzy”. He remembers being homeless and losing his bag that contained his clozapine medication. Consequently, he did not take clozapine as prescribed, which he believes triggered this episode. He “slept on the streets, did not eat or sleep for 7 days”, and was outdoors “dressed in just [his] jumper and sweat pants”. He recalls losing his phone but still had his passport and bank card, which his mother cancelled shortly after admission. He believes he was brought in because he was showing symptoms of a heart attack. He is unable to describe the chest pain beyond it being left-sided and sharp.

Upon admission, he tried to leave while his admission into the ED was still being processed, but was stopped by the Gardaí. He misinterpreted their intentions, became agitated and had to be pinned down, struggling to break free when he “thought they were going to do something bad to [him]”. He remembers being given a right gluteal IM Haloperidol injection.

What Happens During an Episode

BM describes this as “a typical episode”, all of which are triggered 2-3 days after he stops taking Clozapine. He notes that this episode lasted the longest of all previous episodes, which usually last about three weeks when he is restarted on his medication. During an episode, he believes everything is real, “like aliens are real”. He feels “very powerful”.

Sometimes he experiences auditory hallucinations, which do not usually cause him distress because “they can’t make me do something if I do not want to”. In this episode, he recalls experiencing second person auditory hallucinations. He reported “God spoke to me, and pronounced me as Jesus Christ.” The voice was external and referred to him in second person.

He also displayed grandiose delusions, believing he is “related to Jesus”, and “God has a direct connection with me, even has my email address”. He believed he was “sent to Earth to heal people”. He did not experience visual hallucinations this time, but recalls jumping out of the window a while ago because he “saw a vision of Christ”.

Sometimes he feels like he is teleporting, which he now believes is because his memory is vague during his episodes and he forgets how he got from place to place. When each episode ends, he feels ashamed and embarrassed for these thoughts, but insists he has not done anything foolish. “I don’t do anything, I’m a good kind of crazy.”

Recent Stressors or Life Events

BM is non-compliant with Clozapine. He has been taking Clozapine for 14 years and does not like it because it makes him drowsy, stating he “would rather take anything else than Clozapine.” He deliberately stopped taking Clozapine while studying for college examinations in 2008, and was awake for a whole week. Since then, he has had periods off Clozapine or changed his dosage as he liked, after which he experiences relapses.

Other Symptoms

BM “feels good”, has no suicidal ideation or intent to self-harm. No reported thought broadcasting, insertion, or withdrawal. He does not feel like an external agent is controlling his feelings and actions.

Patient’s Progress from Admission to Date Seen (Collateral History from MUH Nurse in St Michael’s)

In the first 6 days of admission, BM appeared very thought disordered and pre-occupied at times. He was seen responding to unseen stimuli, laughing to himself and speaking to nobody. He was observed pacing around the ward. He was difficult to engage, and was aggressive at times. He reported second person auditory hallucinations, “God spoke to me again”. There were grandiose delusions, same as detailed above. No visual hallucinations.

His psychotic symptoms resolved by 02/12/17, and he was moved from the Acute unit to the Subacute unit. He was orientated, attended to his personal hygiene, engaged well with peers and staff. No auditory or visual hallucinations have been reported since.

1.4 Past Psychiatric History

BM was diagnosed with Schizophrenia in 2002, since he was 22-years-old.

2001 – 2002	BM began using recreational drugs (refer to Section 1.7.1) frequently. He experienced drug-induced psychosis. He was brought to the UK Mental Health Services by his mother, and was subsequently diagnosed with schizophrenia.
2002 – 2003	BM began a trial of Risperidone and Olanzapine while an inpatient in the UK, for which he was treatment-resistant. BM was started on Clozapine in 2003, and has been on this since.
2003 – 2017	BM’s last hospital admission in the UK was into the Maudsley Hospital in 2013. BM attends the Outpatient Department (OPD) in Lambeth Hospital in the UK. Reviewed every 12 months. Receives monthly monitoring by the Clozapine nurse. A collateral history from Dr Athens (Consultant, Lambeth OPD, SLaM, UK) revealed his last visit was on 08/11/17. He was assessed by the Clozapine nurse and reported as stable in mood. He had been non-compliant with his medication, taking 200mg Clozapine PO nocte instead of the prescribed 350mg Clozapine PO OD. BM has had multiple admissions to St Michael’s Ward in MUH. 17/10/11 – BM was admitted after experiencing an episode secondary to taking 150mg Clozapine PO OD instead of the prescribed 250mg as he had felt it was sufficient. 23/11/15 – BM voluntarily admitted himself after experiencing an episode.

1.5 Past Medical and Surgical History

No history of cardiac problems. Undergoes cardiac review yearly at the OPD in Lambeth Hospital.

• ECG taken on 26/11/17 was normal.

Late 1990s – Testicle Operation

1.6.1 Medication

Medications from Admission to Date Seen

07/12/17  Started on Paliperidone (Invega) 9mg PO OD for a week.

• Plan: To be switched to Paliperidone (Xeplion) 150mg IM Deltoid after, then to 100mg Xeplion IM Deltoid on Day 8.

14/12/17 Lorazepam 2mg PO PRN for anxiety that was disturbing his sleep.

15/12/17  Dosage of Paliperidone (Invega) increased to 12mg PO nocte

• BM showed awareness about his medication, “most people take only 6mg, but I’m taking 12mg.”

19/12/17  Received the Paliperidone (Xeplion) depot (loading dose 150mg IM Deltoid).

27/12/17  Dosage of Paliperidone (Invega) reduced to 9mg PO OD.

29/12/17  Biperiden (Akineton Retard) 2mg BD for lower limb akathisia secondary to Paliperidone.

Current Medications

1.	Paliperidone (Invega)	9mg	PO	Nocte
2.	Lorazepam	2mg	PO	Nocte
3.	Biperiden (Akineton Retard)	4mg	PO	OD

1.6.2 Comments on Concordance

BM is satisfied with his medications, stating he “feels more alert and less sedated on Xeplion”. He mentioned he would consider switching back to Clozapine if his restlessness increases.

1.6.3 Allergies

NKDA.

1.7.1 Drug and Alcohol History

BM smoked cigarettes once or twice in his teens. Does not drink alcohol.

BM abused recreational drugs in his teens.

• He took “many different kinds, whatever I could get my hands on” – mainly cannabis, but also abused MDMA, cocaine and ketamine regularly.
• First tried it in Cork under the peer influence, but it was only after he tried it a second time in London in 2001 that he began regular consumption, at least twice a week.
• The drugs made him “feel warm and fuzzy. I can understand why people like it”.
• BM claims to have stopped since his diagnosis of schizophrenia post drug-induced psychosis in 2002. He denies being addicted, and experienced no withdrawal symptoms. However, collateral history with his mother (refer to section 1.9) revealed he had taken MDMA recently, but is not using it regularly.

BM denies any addictions and gambling problems.

1.7.2 Forensic History

NIL.

 

1.8.1 Family History

BM is the eldest of 3 children in his biological family.

• Both his biological parents were heroin users.
• His parents separated when he was a child. No information on his biological father.
• BM’s mother has depression, for which she attends the mental health services in the UK.

BM’s mother remarried when he was 3-years-old. Since then, he has lived with his stepfather’s family.

• He is the 4^th oldest child, with 2 brothers and 3 sisters.

• All family members are alive and well, and are scattered across London and Ireland.

BM states the home atmosphere was “normal”, but he was not close to his foster siblings, saw them as “strangers in the home, [he] felt like [he] didn’t belong”. BM is not in contact with his siblings. He felt neglected when his mother remarried due to “too many children in the house”. He is “not really close” to his foster parents but is still in contact with them.

1.8.2 Personal History

Early Development and Childhood

BM was born and raised in England (Little Hampton). In view of his parents’ heroin abuse, it is unknown if BM’s mother abused heroin while pregnant with him. Since his biological parents’ divorce, BM moved in with his stepfather’s family when he was 3-years-old, until he moved out when he became independent in 2011. BM “got along fine” with his mother, but does not confide in her.

Education

BM moved to West Norwood (London) where he attended Primary School, which he enjoyed. He attended Secondary School for a while but left. “I’ve always liked art, creativity, that sort of thing. But mixed with drugs, it became a bad kind of crazy. I think I strayed too far.” He mixed with the wrong group of friends who were a negative influence. He “fit in well”, was not bullied, but did not wish to recall unpleasant experiences. BM has been in and out of the UK and Ireland. He resumed studies in London in 2006, and experienced his first episode of non-compliance and relapse in college (detailed in Section 1.3.2).

Employment

BM lived independently from 2011 to 2012, during which he self-reduced his dosage of clozapine and was admitted into MUH after experiencing a relapse. His finances were tight, relying on disability payments, small informal jobs (gardening for his neighbours) and allowance from parents.

Relationship History

BM has never married. He had a girlfriend but is currently single with no children.

1.8.3 Social History and Occupational History

Housing Situation

BM is homeless and lives alone. He has resided in the UK most of his life, entering Ireland 2 weeks prior to admission into MUH. He cannot recall how he entered Ireland from the UK. He prefers to live in Ireland because his mother is Irish (from Dublin), and his cousin lives in Fermoy. He stated his uncle had declared himself homeless when he entered Ireland and obtained housing subsequently. He thought he could do the same, resulting in him “sleeping on the streets” instead of living with his family.

Financial Situation

BM occasionally feels anxious, “I feel a bit stressed thinking about the future.” He looks forward to his discharge, but is unsure of his plans due to lack of funding and housing. He has no access to his bank account because his mother had cancelled his bank card when she thought he had lost it. BM has been looking into getting disability payments in Ireland like how he was receiving it in the UK since 2007. However, he has been unable to get it due to ineligibility (has not lived in Ireland long enough).

1.8.4 Pre-morbid Personality

BM describes himself as self-conscious, often worried about people’s impression of him. He had low self-esteem and poor self-control, “got tempted too easily”. BM’s mother reports he was hyperactive as a child and had a short temper. BM enjoys arts and craft, finds it a “great way to relieve stress and boredom”.

1.9 Collateral History

Collateral History with Simon Community Care Staff (P)

• BM stayed for some nights in Simon Community in the 2 weeks prior to admission.
• Was contacted by family from the UK with concerns that he was non-compliant to his medications.
• BM displayed “strange” and “unpredictable” behaviour – masturbated publicly in the city centre a few days before admission. Gardaí were called. On 26/11/17, BM was again observed masturbating around the premises and behaving inappropriately towards female residents.

Collateral History with BM’s mother (RM)

• BM has been non-compliant to clozapine medication.
• He had entered Ireland to “escape from the voices”. He had returned to the UK 5 weeks prior to admission.  A week before admission, BM had told them he was returning to Ireland and would get a bus home after a few days.
• 4 years ago, he jumped from a height out a window when the Community Mental Health Teams (CMHT) were visiting him as he misidentified their intentions and became scared. He injured his legs. He also swallowed a pen. While in the hospital, he believed that the staff had implanted something in his body to hurt him (persecutory delusions).
• She noticed a deterioration in mental state since he attended the Glastonbury Festival where he took MDMA, but does not think he is using drugs regularly.
• He had been uncontactable in the past few days prior to admission as his phone had been switched off.
• No history of deliberate self-harm.

MENTAL STATE EXAMINATION

2.1 Appearance

BM was dressed in casual attire (jumper and sweatpants). Hair was neat, clothes were clean. He showed good hygiene and self-care, having just showered before the interview.

 

2.2 Behaviour

BM was alert, pleasant and calm, engaged readily, occasionally smiled when talking about his hobbies. Rapport was easily established. He was relaxed, no bizarre gestures or restlessness. Appeared comfortable to share his concerns.

 

2.3 Thought (Form of Speech and Writing)

BM’s answers were normal in tone, flow, rhythm, rate and volume. Conversation was spontaneous. No evidence of speech disorder.

 

2.4 Mood and Affect

Euthymic mood. Reactive affect. No suicidal ideation or intent to self-harm. No ideas of harm to others.

 

2.5 Thought (Content and Possession)

Main thoughts: Looking forward to his discharge. Logical sequence of thoughts. Answers were relevant and coherent. No paranoid thinking. No evidence of disorders of content or possession of thought.

 

2.6 Perception

No psychotic symptoms, no auditory or visual hallucinations.

 

2.7 Cognitive State

BM was oriented in person, place and time. No impairment of concentration or memory noted.

 

2.8 Insight

Showed good self-awareness about his delusions, but insight into his behaviours during his episodes was poor (he claimed, “I don’t do anything”, and is unaware of his bizarre behaviour in his most recent episode). BM showed poor insight into his clozapine medication, “I hate that clozapine makes me sleepy, I’d just rather not take it”, but was willing to try alternative medications.

2.9 Interviewer’s Reaction to Patient

I felt nervous at the beginning, but I calmed down as the interview progressed as it felt like a normal conversation and BM was reciprocally friendly.

FORMULATION

3.1 SUMMARY

BM is a 37-year-old single homeless male, with a 15-year history of schizophrenia and background of multiple hospital admissions following relapses secondary to clozapine non-compliance, brought to the ED in MUH on 26/11/17 by the Gardaí after bizarre behaviour in public. BM had missed his clozapine dose prior to admission. During this period, he was agitated and aggressive, requiring sedation with IM Haloperidol injection. He experienced second person auditory hallucinations and grandiose delusions. No visual hallucinations. No suicidal ideation. BM abused recreational drugs in his teens, and experienced drug-induced psychosis prior to diagnosis with schizophrenia. Collateral report of recent MDMA use. Negative toxicology screen on admission.

 

3.2 DIFFERENTIAL DIAGNOSES

1. Relapse psychosis secondary to clozapine non-compliance on a background of schizophrenia
2. Schizoaffective Disorder, Manic type
3. Drug-Induced Psychosis

3.3 ANALYZING DIFFERENTIAL DIAGNOSES

 

1. Relapse psychosis secondary to clozapine non-compliance on a background of schizophrenia

BM’s presenting symptoms of second person auditory hallucinations, grandiose delusions, disorganized thoughts and decline in personal behaviour (aggressiveness towards the guards on admission, impaired social interaction – difficulty engaging on the ward) fulfil the ICD-10 Criteria for Schizophrenic Psychosis (1). His 22-year history of schizophrenia that is difficult to manage increases likelihood that this is a relapse.

BM has a long history of clozapine non-compliance that resulted in multiple relapses requiring hospitalization. Non-compliance is defined as medication refusal (BM did not take his medication because he had lost his bag in this recent admission), or partial modifications of prescribed dosage (BM was known to take less than the prescribed dosage) (2). Non-compliance to antipsychotics is a major barrier to efficacy of antipsychotics in preventing psychosis (3), increasing BM’s risk of relapse psychosis.

2. Schizoaffective Disorder, Manic type

BM presented with manic symptoms in addition to the schizophrenic symptoms listed above: overactivity (observed pacing around the ward), increased irritability and aggressiveness, impaired concentration, and loss of normal social inhibition (masturbated in public). These fulfil the ICD-10 criteria for Code F25.0 Schizoaffective, Manic type Disorder (4). However, to be diagnosed with schizoaffective disorder, onset of psychosis must not be better explained by direct physiological effects of medications or drug abuse, making this diagnosis less likely for BM, where it is known that he had missed his medication prior to admission.

3. Drug-Induced Psychosis

BM’s vague recall of psychosis onset, history of drug abuse, and recent collateral report of MDMA use raise the possibility that he had misused drugs, triggering drug-induced psychosis. However, this is less likely because there was no evidence of drug abuse present amongst his belongings, with a negative toxicology screen on admission.

 

3.4 DISCUSSION OF AETIOLOGICAL FACTORS

 

BM’s diagnosis of schizophrenia was precipitated by drug-induced psychosis. BM has many risk factors that predisposed him to early drug exposure, schizophrenia and subsequent medication non-compliance. These are summarized in Table 1, and discussed according to familial, individual and environmental factors.

Table 1. Summary of BM’s Aetiological Factors

	Biological	Psychological	Social
Predisposing Factors	Early contact with mental health issues (family history) Parental heroin abuse	Parental divorce in early childhood Poor quality of family relationship	Bad peer influence Single, unemployed (receiving disability payments in the UK)
Precipitating Factors	Drug-induced psychosis Schizophrenia resistant to Olanzapine and Risperidone	Self-conscious of people’s impression of him	Peer pressure to take recreational drugs Dropped out of school Uncle had declared himself homeless and successfully acquired housing in Ireland
Perpetuating Factors	Poor compliance to Clozapine due to side effects Continued recreational drug use	Shows poor insight into medication – thinks he’s fine without his medications	Became independent (started living alone) in 2011 Homeless Lacking funds
Protective Factors	Satisfied with new medication (Paliperidone)	Motivated to look for a job post-discharge Shows good insight into delusions during psychosis	Has hobbies (enjoys art and craft) Still in contact with parents who are currently providing financial support Has family in Ireland to accommodate him

 

1. Familial Factors

Early parental divorce has long-lasting effects on children. Studies report higher rates of anxiety, depression and malaise in adulthood than those from intact families (5, 6). This may have influenced the way he reacts to situations, shaped BM’s premorbid personality – his short temper. This places him at risk of developing mental health problems.

Perceptions of parental care are important predictors of subsequent drug abuse (7). BM was raised in his stepfather’s home when his mother remarried. He was not close to his siblings and felt neglected. Poor quality of parent-child relationships and parental support in childhood increase risk of early drug use (8).

2. Personal Risk Factors

BM fulfils two risk factors for non-compliance: lack of illness insight and drug abuse (2). BM shows poor insight into his medications (long history of non-compliance to clozapine and subsequent hospitalizations following relapses). His thoughts are outlined in Figure 1.

BM had risk factors for early drug abuse (8): male; his premorbid personality of being self-conscious of people’s impression of him made him susceptible to peer early oppositional behaviour; and he had poor self-control. BM also experienced positive effects of early drug use, abusing drugs frequently to seek the “warmth and fuzziness” that these drugs provided. Individuals like BM, who experienced positive effects of adolescent drug use, have increased risk of subsequent drug dependence (9).

3. Environmental Factors

Both BM’s biological parents were heroin users, giving him early drug exposure. Drug-abuse disorders can be inherited through genetics or the environment (10). Moreover, parents who abuse drugs provide substandard parenting because they place family needs behind their addiction, impairing family relationships (11, 12). As this occurred during BM’s early childhood, his attachment to his mother and relationship with his family may have affected.

It is unknown if his mother had abused heroin during her pregnancy. If she had, BM would have received prenatal exposure to heroin. Heroin is detrimental to foetal health (10). Most children exposed to drugs in-utero are raised by parents who provide suboptimal parenting (13).

BM mixed with bad company while schooling, during which he first experimented with recreational drugs. He performed poorly in school, lacked commitment to education – “I’ve always liked art, creativity, that sort of thing. But mixed with drugs, it became a bad kind of crazy. I think I strayed too far.”, and left school at a young age (8). Associating with drug-abusing peers is a major risk factor for adolescent drug use (9, 14).

BM’s mother has depression for which she attends the mental health services in the UK. Early contact with mental health issues increased BM’s risk of developing a mental health disorder. Her mental health disorder may have caused poor parental monitoring, which contributed to the development of problem behaviour outcomes, such medication non-compliance (2).

Financial instability is a risk factor for drug abuse (10). Although BM’s family was financially stable, his finances have been very tight ever since he moved out, relying on informal jobs and disability payments in the UK to get by, which may have been an added risk factor for his recent drug use prior to admission.

 

CORE BELIEFS AND ASSUMPTIONS

BM’s core beliefs and assumptions influencing his emotions and behaviour are summarized below.

Figure 1. Summary of BM’s Thoughts, Behaviours, Bodily Sensations and Emotions

	Thoughts
	Thinks he’s fine without his medications. Thinks he can obtain housing in Ireland by declaring himself homeless, like how his uncle had succeeded. Thinks he can obtain disability payments in Ireland.
Emotions				Behaviours
Scared and upset when held down by the guards when he tried during admission. Feels very powerful and can do anything during his psychotic episodes, but feels ashamed and embarrassed after. Annoyance at being denied disability payments in Ireland. Optimistic about staying in Cork, has unrealistic expectations regarding housing.				Non-compliant with Clozapine. Psychotic episodes (Jumping out of the window after seeing a vision of Christ; swallowing a pen). Continues occasional drug use. Homeless despite having family in Ireland. Unemployed and lacks finances, relies on parents for sustenance.
		Bodily Sensations
		Staying awake (not feeling the need to sleep) for days, neither eating nor sleeping. Feeling the sensation of an impending heart attack prior to hospital admission. Seeks the “warm and fuzziness” that recreational drugs provide.

3.5 MANAGEMENT PLAN

1. Biological Approach

Addressing Non-compliance to Clozapine

BM’s history of non-compliance to clozapine makes him suitable for a ‘depot’ intramuscular antipsychotic formulation, removing the need for daily oral medication (3). He should be trialled on a long-acting, once-monthly Paliperidone injection.

Assessing Side-Effects from Long-Term Use of Clozapine

BM’s recount of sharp, left-sided chest pain must be investigated. BM has been taking clozapine for 14 years, placing him at risk for side-effects such as clozapine-induced agranulocytosis, myocarditis, cardiomyopathy and seizures (15). Clozapine should be discontinued if these side-effects are present. According to the British National Formulary (BNF), he should undergo cardiovascular risk assessment yearly, and receive the following investigations (16):

• Blood Test
  • Full Blood Count (FBC)
    • Monitor neutrophil count, rule out agranulocytosis
  • ESR, C-Reactive Protein (CRP) for inflammation
  • Cardiac enzymes (Creatinine Kinase – MB isoenzyme; Cardiac-specific Troponin I and T)
    • Exclude Myocardial Infarction (MI)
  • Serum Biochemistry and Urea & Electrolytes
    • Check liver function, renal function and albumin levels
  • Lipid profile: monitor triglyceride and cholesterol levels
  • HbA1c, Fasting Plasma Glucose (FPG): monitor serum glucose levels
• Echocardiography (ECG)
• Echocardiogram
  • Rule out myocarditis considering his recent chest pain
  • Check for hypertrophy

Monitoring Side-Effects of Depot Medication

BM should be kept in the ward and monitored for side-effects from Paliperidone depot: akathisia, nausea, weight gain and insomnia (17). A muscarinic antagonist can be prescribed for akathisia secondary to Paliperidone.

2. Psychological Approach

Cognitive-Behavioural Therapy (CBT) for Treatment-Resistant Schizophrenia (TRS)

CBT is effective as an intervention in TRS (18). BM could consider undergoing CBT, which could increase his ability to cope with schizophrenia, improve illness and treatment insight, and reduce onset of auditory hallucinations (18).

3. Social Approach

Addressing BM’s Housing, Employment and Financial Problems

BM should meet a Social Worker to address his unrealistic expectations of staying in Cork and discuss accommodation options post-discharge. The Habitual Residence Condition (HRC) must be explained to BM to help him understand his ineligibility to receive disability allowances. BM’s occupational skills should be assessed by an Occupational Therapist, and he should be encouraged to attend career workshops and seek employment.

4. Post-Discharge Plans / Follow-Up

BM should be followed-up monthly by a Community Mental Health Nurse (CMHN), during which he can receive his monthly Paliperidone (Xeplion) injection and be monitored for side-effects. A yearly review with the Clinical Psychologist should be organized.

3.6 PROGNOSIS

1. Immediate Prognosis

With the Paliperidone IM depot medication, BM should be free from relapse psychosis and experience an improvement in quality of life (QOL), as he no longer experiences sedation caused by clozapine, and his akathisia is well-controlled with Biperiden (Akineton Retard). Hopefully this will reduce his frequency of subsequent hospitalizations.

2. Long-Term Prognosis

TRS has poor prognosis (19). BM fulfils factors that contribute to poor prognosis (19): early age of schizophrenia onset; environmental factors; personality traits – poor self-control, getting annoyed easily; and poor medication insight. BM is also at risk of developing “negative” symptoms in the long-term.

DISCUSSION

4.1 INTRODUCTION

 

CANNABIS ABUSE AND CANNABIS-INDUCED PSYCHOSIS

Cannabis is one of the commonest abused psychoactive drugs in the United States, Australia and Europe (20, 21). Most users, often males, experiment with it in adolescence (20, 21). Cannabis has been associated with psychiatric disturbances, notably cannabis-induced psychosis (20-22). Approximately 15% of cannabis users experience acute psychosis (20). This is defined by the ICD-10 Code F12.5 Criteria as the onset of delusions and/or hallucinations secondary to cannabinoid use, significantly impairing QOL, and is not better explained by a non-medication-induced psychotic disorder (8, 22).

DEFINING SCHIZOPHRENIA AND ITS PREVALENCE

Schizophrenia is a chronic, complex neurodevelopmental disorder caused by disruption or alteration of brain connectivity (20, 23). A range of psychological symptoms arises, outlined in the ICD-10 Criteria (1). Schizophrenia is diagnosed by the persistence for at least one month, of at least one of Schneider’s First Rank Symptoms (auditory hallucinations; delusions of control, influence or passivity; delusions of thought interference – thought insertion, withdrawal or broadcasting; and delusional perception). Or, at least two of: (a) persistent hallucinations; (b) cognitive symptoms such as deficits in working memory and attention, leading to incoherent speech; (c) catatonic behaviour; (d) “negative” symptoms (flattened affect and amotivation); and (e) consistent decline in personal behaviour impacting social interaction (1, 20).

Schizophrenia affects approximately 3,900 people in Ireland (23, 24). Men and women are equally affected. Age of onset in men ranges between ages 15 and 30, and ranges between ages 25 and 30 in women (24).

DIFFERENCE BETWEEN CANNABIS-INDUCED PSYCHOSIS AND SCHIZOPHRENIA

Cannabis-induced psychosis and schizophrenia differ in three aspects: (a) cause of psychosis – cannabis-induced psychosis would only occur secondary to cannabis use unlike schizophrenia which can be precipitated in absence of cannabis (21); (b) duration of symptoms – symptoms of cannabis-induced psychosis are short-lived, wearing off once cannabis use is discontinued; whereas the latter persists regardless of cannabis abstinence (1, 20, 22, 25); and (c) persistent, long-lasting impairment of QOL in schizophrenia compared to improvement of QOL once cannabis-induced psychosis resolves.

This raises two questions that this paper hopes to address: a) how do patients with cannabis-induced psychosis go on to be diagnosed with schizophrenia? and b) are these patients more susceptible to treatment-resistant schizophrenia?

4.2 PROGRESSION FROM CANNABIS-INDUCED PSYCHOSIS TO SCHIZOPHRENIA

MECHANISM BY WHICH CANNABIS INDUCES PSYCHOSIS

When ingested, cannabis is metabolized into both active and inactive metabolites (26). The key psychoactive component is delta-9-tetrahydrocannibinol (THC) (20, 26), which binds to an endogenous, pre-synaptic cannabinoid CB₁ receptor and modulates neurotransmitter release in the brain (8, 20). This G-protein-coupled receptor (GPCR) is present at terminals that release gamma-aminobutyric acid (GABA), dopamine, acetylcholine, glutamate and serotonin (27). Activation inhibits neurotransmitter release from the terminal via coupling inhibitory G_i and G_o proteins (20). It mediates the psychotomimetic effects of THC, as is demonstrated in a randomised controlled trial (RCT) conducted to test the efficacy of a CB1-selective antagonist in preventing the precipitation of acute psychotomimetic effects (28). A dose-response relationship between cannabis use and psychotic symptoms has also been reported (29).

DOES CANNABIS ABUSE CAUSE SCHIZOPHRENIA?

There is much debate over whether cannabis abuse causes schizophrenia. Higher rates of cannabis abuse have been reported in schizophrenic patients, ranging from 19% to 60% (30, 31), compared to the general population (32). Cannabis abuse has also been associated with a younger age of psychosis onset (30). A 2005 study also reported that 50% of participants treated for cannabis-induced psychosis subsequently developed a schizophrenia-spectrum disorder (25).

In 1996, Hambrecht et al reported a significant association between first-episode schizophrenia and drug abuse, but was unable to establish a causal relationship (31). Among schizophrenic patients who abused drugs, 27.5% were diagnosed years after drug abuse; 37.9% began consuming drugs post-diagnosis; and in 34.6%, schizophrenic symptoms occurred in the same month as drug abuse (31).

In 2000, Hambrecht et al again sought to establish a causal relationship between cannabis abuse and schizophrenia (33). While inconclusive, it was noted that cannabis had different effects on different groups of patients: (a) cannabis abuse precipitated psychosis in patients already susceptible to schizophrenia; (b) long-term cannabis usage made these patients more vulnerable to schizophrenia; (c) patients who only abused cannabis post-diagnosis tended to present with “negative” schizophrenic symptoms, and used cannabis as a form of self-medication (20). Cannabis counteracts the hypodopaminergic prefrontal state in these patients, enabling them to cope with their symptoms (33). This is consistent with previous study results (31), and suggests cannabis abuse is a risk factor for the onset of schizophrenia.

CANNABIS ABUSE INCREASES RISK OF SCHIZOPHRENIA

Multiple studies support this conclusion. A 6.0 increased relative risk of schizophrenia in heavy cannabis users compared to non-users was reported (34). There is a dose-response relationship between the frequency of cannabis use and the risk of developing schizophrenia (30, 32, 35-40). This holds particularly true for individuals already predisposed to schizophrenia. These people are more sensitive to the effects of cannabis, experiencing exacerbated symptoms and a worsened schizophrenic prognosis (20, 41).

FURTHER RESEARCH IS NECESSARY

Hall et al provides substantial evidence that cannabis abuse precipitates schizophrenia in susceptible individuals instead of causing it (35). If there were a causal relationship, the incidence of schizophrenia should reflect the same rate of increase in cannabis consumption over a defined period (20, 41).

A 2004 systematic review concluded cannabis abuse as a component cause of schizophrenia (32). This means, while not a necessary cause, it is one factor leading to precipitation of psychosis. This causal relationship could be mediated: (a) directly through neurological pathways; or (b) indirectly through social factors explained in the next section (42). Further research is necessary before conclusions can be drawn.

4.3 PREDISPOSITION OF THESE PATIENTS TO TREATMENT-RESISTANT SCHIZOPHRENIA

DEFINING TREATMENT-RESISTANT SCHIZOPHRENIA (TRS)

Antipsychotics are the mainstay of treatment for people with schizophrenia, yet 20-30% of patients respond poorly to drug treatment, and 7% show “total non-response” (26, 43). Treatment resistance was first defined by Kane et al as persistent illness (more than 5 years) and continuing positive psychotic symptoms refractory to three adequate drug trials (44). It is now most commonly defined as the failure to respond to two or more antipsychotic medications given in therapeutic doses for at least six weeks (26).

ASSOCIATION BETWEEN CANNABIS ABUSE AND TREATMENT-RESISTANT SCHIZOPHRENIA

• Biological Impact of Cannabis Abuse

Early cannabis exposure has a negative effect on neurodevelopment (20). Adolescence is a critical period for brain maturation, such as synapse development and myelination. The endocannabinoid system is vital for modulating multiple neurodevelopmental processes. This system undergoes functional development and modification during adolescence, supported by studies showing transient increased expression of the CB₁ receptor during this period, before normalizing in adulthood (45). Cannabis use during this time could disrupt normal endocannabinoid signalling (20), causing abnormalities in the adult brain.

It is plausible that disrupting neurodevelopment in adolescence via cannabis use could lead to the development of TRS. Determining this requires an understanding of its pathophysiology. Longitudinal studies have reported instances of schizophrenia precipitated from brain lesions incurred during infancy or adolescence, and TRS occurred secondary to a progressive neurodegenerative process that altered treatment response in a progressive manner (19, 46). This progressive development is evidenced by further studies showing increased cortical atrophy on magnetic resonance imaging (MRI), and lower catecholamine levels in the cerebrospinal fluid (CSF) of patients with TRS compared to those with responsive schizophrenia, especially if they had pre-dominantly “negative” symptoms (47). Further evidence is seen in studies where cessation of cannabis abuse led to significant improvements in “positive” and “negative” symptoms, neuropathology and psychosocial functioning (30).

• Psychological Impact of Cannabis Abuse

Cannabis users are more susceptible to treatment-resistant schizophrenia. Cannabis abuse can mask the onset of psychotic symptoms during the early and prodromal stages of schizophrenia. Two psychological factors arise: (a) delay in seeking treatment; and (b) medication non-compliance.

The first-episode of psychosis (FEP) is a “crucial period” that determines the long-term outcome of psychosis (30). Masked psychotic symptoms could exacerbate a delay in seeking treatment, resulting in a longer duration of untreated psychosis (DUP). DUP is defined as the time lag between onset of psychosis and first treatment (19). A longer DUP is associated with increased risk of refractory symptoms, poorer psychosocial functioning and prognosis (19, 26, 30).

Effective management of schizophrenia requires continuous long-term treatment to keep symptoms under control and to prevent relapse (2). Cannabis abuse reduces medication compliance (30), which is a risk factor for treatment-resistant schizophrenia (26). Medication non-compliance involves treatment refusal or ill-advised modification of daily medication doses (as in BM’s case). Cannabis use, lack of illness insight and cognitive impairment are key drivers of non-compliance (2).

• Social Impact of Cannabis Abuse

Cannabis abuse is associated with poorer psychosocial functioning (30). Adolescent cannabis users are at increased risk of poor education outcomes, truancy and decreased academic progress (21). However, it is important to consider these problems as a cause, not a consequence of cannabis use (42), because individuals predisposed to mental health problems may be more inclined to abuse drugs (8, 42).

Schizophrenic patients could be abusing cannabis concurrently as a form of self-medication (20), increasing their risk of treatment-resistant schizophrenia despite adequate treatment (26, 30). Cannabinoid agonists transiently exacerbate symptoms in schizophrenic individuals despite treatment with antipsychotic medications (48). This indicates schizophrenic patients are more susceptible than healthy subjects to the acute behavioural and cognitive effects of cannabinoid agonists.

ARGUMENTS AGAINST CANNABIS ABUSE AS RISK FACTOR FOR TRS

Bias must be accounted for when making this association. This could be explained by chance: Male gender is the most document risk factor for TRS (19). Most cannabis users are male (20, 21), making it a coincidence that patients like BM subsequently developed TRS post-cannabis-induced psychosis. It is also difficult to ascertain if socioeconomic status is a consequence of cannabis abuse or a predisposing factor for cannabis misuse. Further research is necessary.

4.4 CONCLUSION

Cannabis abuse is an important risk factor for schizophrenia and subsequent development of TRS. The individuals most susceptible are those with early cannabis exposure, cannabis-induced psychosis, or high genetic risk of schizophrenia. TRS is a public health problem as these patients are often highly symptomatic, requiring extensive hospitalization and incurring high costs. If a causal relationship exists between cannabis abuse and TRS, reducing cannabis abuse may partially prevent or reverse TRS. Future research could consider the age of cannabis exposure and frequency of cannabis use when exploring this association.

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