psychopathology and addiction

Question 1

Introduction

Answer 1

People who abuse or are dependent on alcohol and/or other drugs are at higher than normal risk of suffering from a range of other psychiatric conditions. This is true both for concurrent diagnoses (i.e. occurring at same time as SUD) and for lifetime risk (i.e. at any point before or after SUD). According to the UK National Household survey 2001, many people suffer from psychiatric disorders comorbid with nicotine dependence 22%, alcohol dependence 30%, drug dependence 45%. Research has suggested that chronic substance use can lead to the development of psychosis. However, there are also lines of evidence which suggest that people with a mental health disorder develop SUD through self-medication of illicit and elicit substances to alleviate or as a negative reinforcer for systems that are part of the other disorder (e.g. anxiety and alcohol). Therefore the element of causality can go both ways. This essay will present evidence in order to show that there are circumstances under which SUD’s can have a causal influence on psychosis, but that associations are not always of this nature.

Question 2

What is amphetamine

Answer 2

• Amphetamine (contracted from alpha methylphenethylamine) is a potent central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity.
• Amphetamine, through activation of a trace amine receptor, increases monoamine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrineand dopamine.
• At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increasedwakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.

Question 3

Concern about amphetamines as a cause of psychosis arose around the time that Connell (1958) showed evidence of psychosis related symptoms of prescribed users in a series of case studies and issues around dependancy. There are many much more recent studies which have found an association. Angrist et al (1970) who gave 9 healthy volunteers around 50mg amphetamine and all became psychotic within 7-45 hours. Fortunately, all recovered within 6 days of abstinence. Therefore, these acute affects support what research was finding in more chronic usage.
However this does not establish causality of schizophrenia, as the symptoms found here were transient. In order to establish causality, a longitudinal study would be needed to show that methamphetamine use precedes and predicts mental illness.

Name one longitudinal study

Answer 3

• McKetin et al 2016 We use data from a longitudinal cohort study to examine the profile of psychiatric symptoms that are acutely exacerbated by methamphetamine use. Methods: 164 methamphetamine users, who did not meet DSM-IV criteria for a lifetime primary psychotic disorder, were followed monthly for one year to assess the relationship between days of methamphetamine use and symptom severity on the 24-item Brief Psychiatric Rating Scale. Symptoms exacerbated by methamphetamine loaded on three factors: positive psychotic symptoms(suspiciousness, unusual thought content, hallucinations, bizarre behavior); affective symptoms (depression, suicidality, guilt, hostility, somatic concern, self-neglect); and psychomotor symptoms (tension, excitement, distractibility, motor hyperactivity).
Limitation- no evidence of specificity. Produced a range of psychotic symptoms, need to assess whether effects of methamphetamine influence development of a particular disorder. Scale used have many items that rely on self-report (others on clinician rating), if methamphetaimine does produce delusions, may not be the most reliable account of their habits over the month.

Question 4

Define schizophrenia

Answer 4

a long-term mental disorder of a type involving a breakdown in the relation between thought, emotion, and behaviour, which can lead to inappropriate actions and feelings, withdrawal from reality and personal relationships, paranoia and delusions.

Question 5

In order to address causality, there are 4 things that need to be addressed

Answer 5

1. Association
2. Temporal priority
3. Specificity- one drug –> one psychotic illness
4. Strength (i.e. dose-response)

Question 6

Issues with longitudinal studies that investigate the causal role of cannabis use on psychosis

Answer 6

• One issue complicating all of this, particularly in longitudinal studies, is the composition of cannabis itself, evolutionary speaking over time evidence has shown that the THC (the key psychoactive ingredient) has increased over time. The THC content around the world was relatively stable then increased significantly from 2000 (from around 5% to 10% in 2008; National Institute of drug abuse, 2008).
• Lab studies have found the higher the THC, the greater the risk of psychosis at least in the acute reactions.

Question 7

THC content study

Answer 7

D’Souza et al (2004)
On three test days at least a week apart, the researchers administered THC to 22 test subjects—including Yale medical students and undergraduates and other volunteers. All had used cannabis previously but none had ever been diagnosed with cannabis abuse disorder or a major psychiatric disorder. On each test day the subjects received one of three injections, a placebo or a low or medium dose of THC, before taking a series of behavioral and cognitive tests. The subjects reported how they felt, using a scale of feeling states associated with cannabis effects—high, calm, relaxed, tired, anxious and panicked. THC induced temporary responses similar to the three domains of schizophrenia: positive symptoms such as paranoia and disorganization of thinking, negative symptoms such as blunted affect and reduced spontaneity, and cognitive deficits such as memory lapses. Some subjects experienced schizophrenia-like symptoms lasting between half an hour and an hour. In addition, THC induced euphoria and raised levels of cortisol and prolactin, biological markers for activity of cannabinoid receptors. In further support of causality, the behavioural and neurochemical effects tended to be dose dependent, i.e. 5mg of thc produced stronger effects than 2.5mg thc.
Limitations- The tests relied on self-reporting and the observations of trained researchers, which at times differed from those of the subjects. “We had a subject who refused to complete some of the cognitive testing because she was convinced we were trying to trick her,” said D’Souza. “But when we asked if she felt paranoid, she said ‘no.’ ”

Question 8

Issues with short term studies on the effects of addiction on psychopathology

Answer 8

Importantly, these studies show that symptoms produced by short term cannabis use are transient. Cannabis can give rise, in experimental conditions, to feelings of de-realisation, depersonalisation and paranoia, sometimes some cannabis users even report hallucinations and/or delusions without insight, but these disappear within a month of abstinence (and usually within a few days). Persistent toxic psychosis for single doses is very rare, instead it’s an issue of longer term habitual patterns of large scale use that may be relevant to development of exacerbation of psychosis. Therefore longitudinal studies are needed to assess causality.

Question 9

Issues with longitudinal studies

Answer 9

• A problem with this, is that research showing that THC content of cannabis has increased over time, when considered in light of research showing that amount of THC influences the extent of psychotic symptoms, means that when comparing longitudinal data, it is likely that the cannabis compared is significantly different (apples and oranges). Therefore, the longitudinal study loses validity.
• However, increases in THC content of cannabis smoked over long time periods is unlikely to confound results beyond useful interpretability. In other words, whilst the assumption that THC consumption remained stable over the time period of interest is likely not met, these studies still provide valuable insight into long term use.

Question 10

Longitudinal study- cannabis and SZ

dose-dependency

Answer 10

Zammit et al (2002) the Swedish (Military) Conscript data base, followed up 50,000 military conscripts over a long period of time. There was cannabis use at baseline (between 18-20 years) and found a 2.4 – 6.0 fold increase in risk for schizophrenia in those who used marijuana at baseline.
However- Schizophrenia is rare and only 1.4% of 50,000 developed schizophrenia. In the crude odds, a person who had used cannabis up until 18-20 baseline, they were 2.2 time more likely to develop schizophrenia. Adjusted odds: SES, IQ, etc. resulted in a decrease in the odds to 1.5. Overall risk for sz still remain very small. However, there was still a significant relationship.
By investigating the dose dependency aspect of cannabis and sz, again they provide some information about the nature and causality of the relationship. Risk was found to be dose dependent i.e. higher risk for greater usage of cannabis more frequently prior to the age of 18-20.once people imply use of more that 5 times to more than 50 times (times of use before baseline), the odds rations increase significantly. For more than 50 times, the risk ratio is 6.7times greater, in that 28 of the 731 of individuals who have used cannabis more than 50 times prior to baseline develop schizophrenia. Conversely, when variables (SES, development, etc.) are controlled for, risk goes down to 3.1. However, the pattern is pretty robust across longitudinal research, in that using cannabis prior to the age of 18, increases risk in dose dependant way.

Question 11

Longitudinal study- cannabis and SZ

Specificity

Answer 11

Arseneault et al., (2002) The authors analysed data from a representative group of 759 (74%) living study members from the Dunedin Longitudinal study, divided into 3 groups based on cannabis use at ages 15 and 18. The 494 controls (65.1% of the sample) had reported using cannabis “never” or “once or twice” at both ages; cannabis users by age 18 (236; 31.1%) first reported using cannabis “three times or more” at age 18; and cannabis users by age 15 (29; 3.8%) had reported using cannabis “three times or more” at age 15 (all of whom continued to use cannabis at age 18). Multiple linear regression analyses showed that cannabis users by age 15 and by age 18 had more schizophrenia symptoms than controls at age 26. These results remained significant after psychotic symptoms at age 11 were controlled for. The effect was stronger with earlier use. The risk is magnified if the individual had psychotic symptoms by age 11. Therefore, according to this study, cannabis appears to be specific to schizophrenia. Logistic regression analyses showed that people who used cannabis by age 15 were more than 3 times as likely to have a diagnosis of SZD at age 26 than controls. (age 15 users (3/29= 10.4%), compared to rest of cohort (22/730 = 30%). Difficult to know if this is the result of usage during a sensitive period or greater cumulative exposure. After psychotic symptoms at age 11 were controlled for, the risk for adult SZD remained higher among those who used cannabis at age 15; however, this risk was reduced by 31% and was no longer significant. Other substances were also investigated and it was confirmed that risk for schizophrenia was specific to cannabis, as opposed to other drugs.
Limitiations- It must be considered that it is unsure what the THC content of the cannabis was amongst these people. Furthermore, these studies are relying on what people recall from memory was is also fallible. In the short term, cannabis can impair various aspects of working memory. It is also unknown if the cannabis use problems are from fuelative exposure which is small steady exposure to cannabis over a long period or whether single, shorter, acute forms of cannabis use.

Question 12

Are all individuals who take drugs equally vulnerable?

Gene-environment interaction study

Answer 12

• Caspi et al. (2005) examined the moderating effect of the COMT gene (chemical involved in the transformation of dopamine which has been suggested to be involved in schizophrenia and it seems to be implicated in dopaminergic transmission, particularly in the prefrontal cortex) on cannabis use as a risk factor for psychosis in the Dunedin cohort. They looked at the polymorphism for the COMPT gene (VAL or a MET). Compared effects across adolescent-onset users and adult-onset users and found the COMT gene did interact with adolescent- onset which predicted various facets of psychosis. Earlier usage combined with VAL/VAL genotype confers more risk for psychosis. MET/MET, Heterozygous: MET/VAL, Homozygous: VAL/VAL. Those with VAL/VAL have a much greater risk of schizophreniform particularly if they had used cannabis at age 15. However for MET/MET, it seems that cannabis use in adolescence has little affect in comparison. There is a slight increase in risk in those that have the VAL/MET gene in cannabis use in adolescence. Therefore, genetic research suggests that adolescence cannabis use is not a prerequisite of schizophreniform, instead there are people who have a genetic vulnerability to contain predisposition. Therefore, its a combination of risk factors which may result in schizophreniform.
Limitations- this particular finding has not been replicated all that well (for example Zammit et al 2007 used 500 sz cases who had a history of cannabis use and failed to find any influed of COMT variant) but this is a difficult process as single genes of small effect sizes need very big sample sizes for a small effect to prove to be significant and the effect may not be hugely robust.

Question 13

Summary of findings from longitudinal studies

Meta-analytic review

Answer 13

Meta-analysis- what is the summary of these findings
• Moore et al. (2007) meta-analysis systematic review of risks for psychosis and depression. Suggest that ‘The evidence is consistent with the view that cannabis increases risk of psychotic outcomes independently of confounding and transient intoxication effects, although evidence for affective outcomes is less strong. The uncertainty about whether cannabis causes psychosis is unlikely to be resolved by further longitudinal studies such as those reviewed here. However, we conclude that there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life’. The review found that as frequency of cannabis use increases, so does the risk of psychosis associated. Moore et al. (2007) estimated that heavy use of cannabis for adolescents and young adults is 40%, the pooled odds ratio in 1.4 which means 14% of psychotic episodes reported in the UK, would not have occurred without the use of cannabis.
• Limitations- This extrapolation between the results, assumes causal link between the two, however, this is far from clear.
• It is always possible that those with tendencies towards psychosis may simply have a tendency towards substance use and cannabis use exacerbates psychosis.

Question 14

Evidence for bidirectional causality of cannabis use and szhizophrenia

Answer 14

• Griffith-Lendering et al (2013) assessed 2120 adolescents at ages 13, 16 and 19. They assessed past year cannabis use and psychosis related problems. They found that cannabis and psychosis significantly related at each time point, cannabis use at age 16 predicted psychosis vulnerability at age 19 and that psychosis vulnerability at ages 13 and 16 predicted cannabis use at, respectively, ages 16 and 19. Therefore suggesting that cannabis use increases the risk of subsequent psychosis and it also appears that psychosis vulnerability also increases the risk of using cannabis. Therefore, suggesting the link between cannabis use and psychosis may be bidirectional and there is likely to be a complex set of interrelated reasons why aspects are related together.

Question 15

What are the underpinnings of the association between cannabis and schizophrenia

Answer 15

Genetic liability
Dopamine
Brain structure abnormalities

Question 16

How does dopamine underpin the association between cannabis and schizophrenia

Answer 16

Dopamine has been linked specifically to both substance use and sz and may therefore be an underlying neurobiological mechanism for the link between sz and cannabis use. With regards to cannabis use in adolescence, it is suggested that as neurotransmitter systems are developing in the adolescent brain, there is a disruption of the endogenous endocannabinoid system due to the large intake of exogenous cannabinoids, • The endocannabinoid system plays an important role in fundamental brain developmental processes such as neuronal cell proliferation, migration and differentiation, therefore, changes in endocannabinoid activity during this specific developmental phase induced by THC might lead to subtle but lasting neurobiological changes.
• The cannabinoid systems has a dense distribution of GABAergic neurons and plays a central role in inhibiting the GABAergic neurons.
•Secretion of GABA usually inhibits the release of dopamine from other neurons.thus a disruption to this system during development may affect GABAergic and dopaminergic functioning long term.
Altered dopaminergic function is regarded by many as key causal element in sz (although causality is always debatable). Dopamine hypothesis. Therefore as disrupted dopaminergic functioning results from cannabis use, this disruption may contribute to the development of sz in ways outlined by the dopamine hypothesis of sz. Suggests that cannabis use has the causal influence in the association.

Question 17

Dopamine hypothesis

Answer 17

• Classic Dopamine hypothesis of Schizophrenia- states that sz is caused by overactive dopamine secretion in the brain. Dopamine is a neurotransmitter which is synthesised in nerve cells in the midbrain substantia negra and ventral tegmental areas. Dopamine if transmitted to three main areas of the brain- 1) prefrontal cortex (thinking and working memory) 2) striatum (movements) 3) limbic system (including nucleas accumbens which is the reward centre).
o EVIDENCE
o Seeman et al (2006) Review papers such as that conclude that an increase in D (2)-high-receptors is a necessary basic requirement for the development of a psychosis that correlates with dopamine super-sensitivity.
o CRITIUQE
o However, the classic dopamine hypothesis is no longer accepted as a satisfactory explanation of Sz, as antipsychotic medication which reduces the effects of dopamine in the brain often leads to a reduction in poisitive symptoms, but negative symptoms tend to persist.
• This led to the reformation of the dopamine hypothesis. It is currently understood that there are two dopamine pathways in the brain which contribute to sz syptoms. It is believed that overactivity in the mesolimbic dopamine pathway leads to the positive symptoms of sz, whereas underactivity in the mesocortical dopamine pathway leads to negative and cognitive symptoms.
• The effects of early cannabis use on the development of brain functions also explain why psychotic symptoms differ according to age of onset of use, as in short term use after adolescence the disruption of neurochemical processes likely to last only until drug wears off.

Question 18

How does genetic liability underpin the association between cannabis use and schizophrenia

Answer 18

• Although considerable evidence implicates cannabis use as a component cause of schizophrenia, it remains unclear whether this is entirely due to cannabis directly raising risk of psychosis, or whether the same genes that increases psychosis risk may also increase risk of cannabis use.
• Power et al 2014 In a sample of 2,082 healthy individuals, we show an association between an individual’s burden of schizophrenia risk alleles and use of cannabis. This was significant both for comparing those who have ever vs. never used cannabis (p=2.6×10−4), and for quantity of use within users (p=3.0×10−3). While directly predicting only a small amount of the variance in cannabis use, these findings suggest that part of the association between schizophrenia and cannabis is due to a shared genetic aetiology. This form of gene-environment correlation is an important consideration when calculating the impact of environmental risk factors, including cannabis use.

Question 19

Do brain structure abnormalities underlie the association between cannabis use and schizophrenia?

Answer 19

• Campbell et al 191 a controversial report was published in the Lancet concluding that cannabis caused cerebral atrophy as evidenced by pneumoencephalography in a small group of male users.
• This was followed by several refutes and CT studies in the later 1970’s and 80’s that failed to confirm significant effects of marijuana on the brain (e.g. Co and Goodwin et al 1977).

Question 20

Why are schizophrenic patients more likely to smoke cigarettes?

Answer 20

Self-medcation.
• Leon and Diaz (2005) conducted a meta-analysis of studies comparing smoking in psychiatrically healthy adults vs people with mental illness. Forty-two studies across 20 nations consistently demonstrated an association between schizophrenia and current smoking. This showed that patients are up to five times more likely to smoke and schizophrenic patients are particularly likely to smoke (70 - 88%) compared to patients with other forms of mental disorder (c. 50%) and the general population (c. 25%), they smoke more heavily, extract more nicotine from each cigarette and are less likely to succeed in attempts to quit. This suggests that those with SZ also have risk factors for smoking nicotine.
Nicotine has stimulant properties which are associated with arousing and alerting effects.
Research has shown that smokers report smoking in part to enhance their alertness/cognitive function, and there is evidence that they do perform faster/more efficiently immediately after smoking than when acutely abstinent. As schizophrenics suffer from impaired cognitive function (i.e. memory, delusions, inhibitory control), it has been suggested that schizophrenics use nicotine as means of self-medication to relieve symptoms. This essay will review evidence for nicotine use as self-medication in shizophrenia.

Question 21

2 studies showing that nicotine enhances cognitive functioning

Answer 21

• Andrews et al gave participants the N back task, in which the person maintains a number of steps behind in their head. Participants were given a nicotine nasal spray, gum patch etc. and performance improved significantly from ingestion of the nicotine. Therefore, it is theorised that part of what maintains nicotine addiction is the improved cognitive functioning.
• However, this may reflect their dependence rather than a ‘normal’ benefit of smoking as there is very little evidence that non-smokers show performance improvements when given nicotine via routes such as patch or gum (Kassel, 1997).
• Gurpegui et al (2007) asked 173 Szs and 100 non- psychiatric smokers about benefits of smoking. Schizophrenics consistently reported more so than the controls to greater levels of calmness, cheerfulness, alertness, concentration and agility. Sociability differed only slightly. Probability of reported calming/ cheerfulness effects related to patients’ levels of depression and anxiety.

Question 22

Studies showing that nicotine enhances cognitive functioning in schizophrenia

Answer 22

With respect to schizophrenia, nicotine has been reported to reduce impairments in visuospatial working memory (e.g. Sacco et al, 2005), ‘sensory gating’ and smooth pursuit eye movements (Kumari and Postma, 2005) and inhibitory control of anti-saccadic eye movements (Larrison-Faucher et al, 2004).

Question 23

Kumari and Postma (2005)- smoking can also medicate schizophrenia in terms of gene-environment interactions.

Answer 23

Nicotine acts through a family of nicotinic receptors with either high or low affinity for nicotine. The loci for several of these receptors have been genetically linked to both smoking and to schizophrenia. Smoking changes gene expression for more than 200 genes in human hippocampus, and differentially normalizes aberrant gene expression in schizophrenia. The α7* nicotinic receptor, linked to schizophrenia and smoking, has been implicated in sensory processing deficits and is important for cognition and protection from neurotoxicity. Nicotine, however, has multiple health risks and desensitizes the receptor. A Phase I trial of DMXB-A, an α7* agonist, shows improvement in cognition, suggesting that further development of nicotinic cholinergic drugs is a promising direction in schizophrenia research.

Question 24

• The interaction of schizophrenia and nicotine various dependant on the medication. One kind of medication that largely blocks DA receptrs, and one that does this far less, have differential effects.

Describe these medication and how smoking varies according to medication.

Answer 24

Typical antipsychotics such as haloperidol block DA receptors and when the doses increase, patients electively increase the amount of nicotine they consume (Dawe et al, 1995). Atypical antipsychotics such as clozapine or risperidone do not block DA transmission to the same extent and patients smoke less heavily (e.g. George et al, 1985). Therefore there appears to be a relationship with the side effects/ nature of the antipsychotics used. Nicotine may address some of the aversive side effects that antipsychotic medication have.