Nature - Does Cannabis Cause, Exacerbate Psych. Disorders?

Abstract: The purpose of this circumspectives piece is to discuss evidence of cannabis’ effects on two psychiatric conditions: post-traumatic stress disorder and psychotic disorders. Dr Haney and Dr Evins will discuss two viewpoints regarding the benefit and harm of cannabis use for these conditions, while outlining what remains unproven and requires further testing to move the field forward.

PSYCHOTIC DISORDERS - Eden Evins
It is clear that THC can cause acute psychotic symptoms, such as paranoia, in a dose-dependent manner (D'Souza et al, 2004; Murray et al, 2013), and those with a psychotic illness who do not stop using cannabis have a poorer prognosis on average than those who do (Tarricone et al, 2014; Alvarez-Jimenez et al, 2012), controlling for other substance use (Foti et al, 2010).

What is somewhat controversial is whether to draw causal inference from the now well-replicated finding from large, prospective, longitudinal, epidemiologic studies that cannabis use, particularly heavy adolescent use of high potency cannabis, is associated with increased odds of developing schizophrenia (Andreasson et al, 1987; Arseneault et al, 2002; Di Forti et al, 2009, 2013; Fergusson et al, 2003; Giordano et al, 2014; Large et al, 2011; van Os et al, 2002; Zammit et al, 2002; Stefanis et al, 2014).

There is a well-replicated dose effect, such that daily use and use of high THC potency cannabis further increase odds of developing a psychotic illness and of earlier onset of psychosis (Di Forti et al, 2009, 2013, 2015). Galvez-Buccollini and colleagues (2012) found a direct association between age of onset of cannabis use and age of onset of psychosis.

While presence of schizophrenia prodrome confounds establishment of precise onset of schizophrenia illness, and those in the prodrome may be more likely to use intoxicants (Giordano et al, 2014; DeLisi et al, 1991), strong evidence that cannabis exposure preceded onset of psychosis by up to 7 years has been reported in several large studies, controlling for or removing those with other drug use (Andreasson et al, 1987; Di Forti et al, 2009; Fergusson et al, 2003).

Control for familial risk of schizophrenia attenuates but does not eliminate the association between cannabis use and schizophrenia, further supporting the hypothesis that cannabis exposure, particularly early, frequent exposure to high THC potency cannabis is a causal factor in the development of schizophrenia (Giordano et al, 2014). Interactive effects between genotype, cannabis use, and psychosis suggest that cannabis use confers far greater risk of psychosis for some, in some cases a five- to sevenfold greater risk among daily users.

[...]

There is evidence that individuals with or vulnerable to psychosis have a neurobiological response to THC that renders them more vulnerable to psychotogenic effects of cannabis. Those with psychotic disorder and their siblings are more sensitive than matched controls to the psychotogenic effects of acute THC administration (D’Souza et al, 2005; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). This may explain why even among those taking medications for psychotic disorders, cannabis use is associated with an increased risk of relapse into psychotic symptoms (Alvarez-Jimenez et al, 2012).

Inhalation of vaporized THC (8 mg) by cannabis users with a psychotic disorder (not on medication) and those with first-degree relatives with a psychotic disorder showed significantly greater striatal Dopamine release following THC administration than control cannabis users without psychiatric illness, despite having a similar subjective response to THC (Kuepper et al, 2013). Therefore, although a common argument against causality is that cannabis use has risen considerably in the past 40 years, whereas rates of schizophrenia have not (eg, Frisher et al, 2009; Degenhardt et al, 2003; but see Hickman et al, 2007), its impact in the general population would be expected to be modest if cannabis precipitates psychosis preferentially in those with specific genetic vulnerability (Hall, 2014).

Thus, although schizophrenia etiology is multifactorial, and the majority of people who use cannabis do not develop schizophrenia, these findings, taken together, support the hypothesis that cannabis use, particularly frequent use of high THC content cannabis, increases the risk for development of psychosis, particularly in those with genetic susceptibility that influences vulnerability to environmental exposures. This warrants serious consideration from the point of view of public health policy (Radhakrishnan et al, 2014)

PSYCHOTIC DISORDERS - Meg Haney
Although heavy cannabis use by individuals with a psychotic disorder or vulnerable to one is largely associated with a poorer prognosis, there are sufficient reasons to question the causality of this relationship. To start, it is important to emphasize that although meta-analyses show a consistent association between cannabis use and psychotic disorders, the odds ratio is small. For those ever using cannabis, the association with psychotic disorders is 1.41 (95% CI 1.20–1.65), whereas the odds ratio is 2.09 (95% CI 1.54–2.84) for those using cannabis frequently (Moore et al, 2007). As noted by Moore et al (2007), larger effect sizes have been reported in other analyses, but these were based on cross-sectional data or were not adjusted for factors such as cumulative cannabis use, presence of psychiatric illness at baseline, other concurrent drug use, or cannabis use at least once vs dependence (Arseneault et al, 2002; Henquet et al, 2005, Semple et al, 2005). Thus, an association between cannabis and psychosis exists, but, at best, it is only one small factor in a much larger constellation of factors associated with this disorder.

So why might a diagnosis of schizophrenia be associated with higher rates of cannabis use relative to the general population (Foti et al, 2010)? As noted above, the apparent dose–response relationship between amount of cannabis smoked and the likelihood of a disorder is one piece of evidence consistent with causality. The more cannabis used at baseline in large prospective studies, the greater the risk of developing schizophrenia or psychotic symptoms (Zammit et al, 2002; van Os et al, 2002; Fergusson et al, 2003) and the greater likelihood that psychotic symptoms at baseline persist (Henquet et al, 2005).

Yet, psychotic disorders rarely emerge without warning. Even when cannabis use unequivocally predates a diagnosis, schizophrenia is a neurodevelopmental disorder with origins in early development. Those destined to develop schizophrenia exhibit unusual thoughts and behaviors years before they develop delusions and hallucinations (Schiffman et al, 2005). This presents the possibility that, prior to a diagnosis of psychotic disorder and perhaps even prior to the prodrome phase of schizophrenia, those who have unusual thoughts or behaviors smoke more cannabis than those without these features; if this is the case, then a dose–response relationship, ie, heavier cannabis use prior to a diagnosis, does not support a causality association but could reflect heavier use by those neurodevelopmentally vulnerable to developing a psychotic disorder.

Why would individuals at clinical high risk of psychosis or those with schizophrenia smoke cannabis? One reason may be to attenuate negative symptoms (eg, social withdrawal, anhedonia) poorly managed by antipsychotics. This hypothesis of self-medication has been disputed because there is no correlation between early symptoms of the disorder and cannabis use (Malone et al, 2010) or between cannabis use and psychotic symptoms or negative mood (Henquet et al, 2010). Yet, if patients are self-medicating negative or subtle mood symptoms, this correlation could be missed by retrospective reports or prospective monitoring of positive psychotic symptoms.

Another argument levied against the self-medication hypothesis is that individuals seeking treatment for a psychotic episode are more likely to smoke cannabis high in THC and low in CBD, a cannabinoid with potential antipsychotic effects (Leweke et al, 2012) as compared with control volunteers (Di Forti et al, 2013). The authors suggest that since high THC can worsen psychotic symptoms, patients with schizophrenia would not choose a type of cannabis high in THC to self-medicate their symptoms.

Yet, whether cannabis worsens or ameliorates certain symptoms of schizophrenia, it remains a drug of abuse, producing positive subjective and reinforcing effects regardless of psychiatric diagnosis. In fact, there is evidence that cannabis produces greater positive subjective effects in patients with schizophrenia or those prone to a psychotic disorder than in healthy controls. A study tracking mood each day using momentary assessments reported that those with schizophrenia were more sensitive to both the mood-enhancing (lower negative affect) and the psychosis-enhancing (auditory hallucinations) effects of cannabis than healthy controls (Henquet et al, 2010). Similarly, we found that participants who were clinically at high risk for developing schizophrenia showed larger increases in both intoxication and anxiety and paranoia following controlled cannabis administration relative to matched healthy controls (Vadhan et al, 2013). Although symptoms of psychosis were worsened by cannabis, mood was elevated to a greater extent than in controls, and this elevated mood might contribute to the consistent association between psychotic disorders and cannabis use. Thus, evidence that individuals who develop schizophrenia are more likely to smoke cannabis with high THC concentration than those who do not develop schizophrenia may simply demonstrate that this population favors more potent and reinforcing strains of cannabis, regardless of CBD content.

In terms of the interaction between genetic vulnerability and cannabis use, the link between COMT alleles and vulnerability to psychosis (Caspi et al, 2005; Henquet et al,2006) has been deemed ‘very weak’ upon subsequent analysis (Moore et al, 2007). A comparison of relatives of individuals
with schizophrenia who smoked cannabis versus those relatives who did not did smoke cannabis showed that both groups were more likely to develop the illness compared with relatives of healthy controls regardless of cannabis use (Proal et al, 2014), which does not support the hypothesis that cannabis worsens outcome in individuals genetically vulnerable to psychosis. It may be that rather than a causal link, there are shared genetic and environmental risk factors for schizophrenia and cannabis use or for drug use in general. An association between schizophrenia risk alleles and cannabis use has been reported (Power et al, 2014), supporting a shared genetic etiology, and there are a number of demographic risk factors in common for cannabis use disorder and schizophrenia, such as being male with low socioeconomic status and educational attainment (DeRosse et al, 2010).

At last, in assessing the interaction between cannabis and psychotic disorder, it is useful to consider tobacco cigarette smoking in this population, as tobacco is more strongly linked to schizophrenia than cannabis. In a meta-analysis assessing tobacco use among patients with first-episode psychosis, there was a strong association (OR=6.04; 95% CI, 3.03–12.02) compared with healthy controls (Myles et al, 2012). Similar to the data with cannabis, patients with first-episode psychosis usually smoked tobacco cigarettes for some years prior to the onset of psychosis, have high prevalence of tobacco use when presenting for treatment, and are more likely to smoke than aged-matched controls (Myles et al, 2012). Also similar to cannabis, some suggest this association reflects the underlying neurobiology of psychotic disorders, which may enhance nicotine reinforcement; or those with schizophrenia use cigarettes to moderate the effects of the illness and the antipsychotic medications (eg, Dalack et al, 1998). Conversely, Kendler and colleagues (2015) recently presented evidence supporting the idea that tobacco use prospectively increases the risk of schizophrenia. These authors thoughtfully considered the same factors argued to support a cannabis–schizophrenia link, but acknowledge that the data support but do not prove causality. They also demonstrate that familial/genetic factors contribute to the association between tobacco use and schizophrenia.

To conclude, public perception and popular media often interpret associations shown in longitudinal studies as demonstrating causation, so the scientific community has to consistently emphasize the distinction between association and causation. Given the low odds ratio and evidence that schizophrenia is a neurodevelopmental disorder, the most scientifically conservative stance is that the association between cannabis and psychotic disorders is not causal. As described by Dumas et al (2002), there are three possible models explaining the cannabis–schizotypal link: (1) cannabis use increases risk for schizotypal traits; (2) schizotypal traits increase risk for cannabis use; (3) a third causal variable underlies both cannabis use and schizotypal traits. The data do not demonstrate causality but may reflect self-medication or a shared risk factor.

Haney and Evins: Moving the Field Forward
Despite differing on their interpretation of the evidence-supporting causality, the authors agree on the biological plausibility of a causal relationship between adolescent cannabis use and negative psychiatric outcome. CB1 cannabinoid receptors are the most common G-coupled protein receptors in the brain, at concentrations 10-fold higher than opioid receptors, for example, and endocannabinoids are an abundant CNS neuromodulatory system (Passie et al, 2012). Further, adolescence is a critical time of synaptic and circuit development, and CB1 receptors are ubiquitous in the prefrontal cortex, a brain site heavily impacted by schizophrenia (Malone et al, 2010; Hill, 2014). Exogenous cannabinoid use could disrupt endocannabinoid-directed brain organization during this period of rapid development, impacting neurobiological and therefore psychiatric outcome. The authors therefore agree with those (eg, Moore et al, 2007) who argue that even without data to demonstrate causation, the potential for long-term brain changes by regular cannabis exposure during adolescence is sufficient to warn the public against the risk of adverse psychiatric outcomes with adolescent cannabis use.

The authors also share concern about the impact of extraordinarily high THC concentrations in new routes of THC administration, such as marijuana e-cigarettes and dabbing (>60%THC), which may heighten the likelihood of adverse psychiatric consequences, particularly if regular use begins in adolescence. Cannabis smokers typically adjust their inhalation patterns and smoking topography as a function of cannabis strength (eg, inhaling more forcefully on low potency than high potency cannabis cigarettes; Heishman et al, 1989; Cooper and Haney, 2009), but this titration would be difficult with new routes of very potent THC administration.

In terms of moving the field forward: further study of the gene–environment interaction could improve our understanding of the association between cannabis use and schizophrenia. Polygenic effects (Pan et al, 2015) from large genome-wide association studies (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) could be calculated for those who do or do not use cannabis to potentially clarify some of the shared genetic risks that may underlie the association. Prospective, longitudinal studies, with assessments commencing in youth prior to initiation of drug use that include family history, prospective and ongoing psychiatric evaluation, genetics and neuroimaging such as the upcoming ABCD study would contribute understanding of how cannabis use influences the onset of schizophrenia (albeit not definitively demonstrating causality). Given that intellectual and neuromotor abnormalities in childhood are evident long before a diagnosis of schizophrenia (Larson et al, 2010), it would be useful to capture these symptoms early in development to observe whether those who later smoke cannabis have a worse prognosis than a group with comparable childhood symptoms who do not smoke cannabis.

Naphtha schreef:maar ik heb het zelf nooit als anitpsychotisch ervaren

• In 2014 lag de mediaan van het CBD gehalte in de nederwiet op 0,3%, in de geïmporteerde wiet op 0,2%, in de nederhasj op 3,5% en in de geïmporteerde hasj op 7,2%.
• Er zijn aanwijzingen dat CBD sommige effecten van THC tegengaat, zoals acute psychotische symptomen, angst, verslechtering van het geheugen en belonende effecten (Niesink en Van Laar, 2012).
• Vooral de verhouding tussen THC en CBD lijkt belangrijk te zijn. De nederwiet bevat relatief veel THC en weinig CBD. Voor buitenlandse hasj is deze verhouding ‘gunstiger’.

CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ(9)-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis.

Naphtha schreef:Valt me op dat blowers lui zijn als ergste bijwerking, ook apatisch in die zin. 19/20 jaar non stop gedaan. Krijg meer gedaan zonder, en rook het nog steeds soms met veel plezier.

The evidence for an "amotivational syndrome" among adults consists largely of case histories and observational reports (e.g. Kolansky and Moore, 1971; Millman and Sbriglio, 1986). The small number of controlled field and laboratory studies have not found compelling evidence for such a syndrome (Dornbush, 1974; Negrete, 1983; Hollister, 1986)... (I)t is doubtful that cannabis use produces a well defined amotivational syndrome. It may be more parsimonious to regard the symptoms of impaired motivation as symptoms of chronic cannabis intoxication rather than inventing a new psychiatric syndrome.

Naphtha schreef:Psychotisch zit m in de definitie overigens. Klinisch psychotisch is wel ver van een normale psychoot z'n bed.

Naphtha schreef:Daarnaast als je het afstreept tegen drinkers, denk ik dat die dan weer een hele lage kans hebben op psychotische trekjes. Maar in de klinische psychoses weer breed vertegenwoordigd zijn.

Claviceps schreef:Wietjes zoeken met hogere concentraties CBD en stoppen met het roken van Haze, Kush, en andere varianten die gegroeit zijn om hun hoge concentraties THC waarbij CBD vaak maar in zeer beperkte gehaltes aanwezig is.

Claviceps schreef:CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models.

Naphtha schreef:Psychotisch zit m in de definitie overigens. Klinisch psychotisch is wel ver van een normale psychoot z'n bed.

Naphtha schreef:Daarnaast als je het afstreept tegen drinkers, denk ik dat die dan weer een hele lage kans hebben op psychotische trekjes. Maar in de klinische psychoses weer breed vertegenwoordigd zijn.

Naphtha schreef:"atypical"

Naphtha schreef:De meesten zijn wantrouwig tegen de medische wetenschap, en zullen dus niet zo gauw opgenomen worden. Als je kwaliteit van leven nog goed is dan kan niemand je vertellen dat je ziek bent. Ookal heb je constant last van psychotische ideeën. Je omgeving zal ook zijn best doen om dit te ontkennen zeker als je jong bent, en zich vastklampen aan het beeld wat ze van je hebben. Een opname zal pas plaatsvinden als mensen aangeven dat je er rijp voor bent. Of als je zelf aangeeft dat je er niet meer mee kunt leven.

Naphtha schreef:Ik heb dit wel eens zien gebeuren irl. Van verdrietig naar overmatig alcohol gebruik/hulp behoevendheid naar de grip kwijtraken op het doel van opname naar diagnose+ medicatie.

Gezien de beperkte leefomgeving van veel mensen komen anekdotische drogredenen bijvoorbeeld veelvuldig voor. De persoon haalt in zijn betoog dan voorbeelden uit de directe leefomgeving aan om zijn standpunt (op een incorrecte manier) te onderbouwen

Naphtha schreef:

Naphtha schreef:Ik heb dit wel eens zien gebeuren irl. Van verdrietig naar overmatig alcohol gebruik/hulp behoevendheid naar de grip kwijtraken op het doel van opname naar diagnose+ medicatie.

Anekdotisch bewijs. In termen van wetenschappelijkbewijs of onderbouwing geen sterk argument. Voor de mensen in jouw omgeving geldt dit mogelijk (of juist alleen specifiek voor de persoon in jouw voorbeeld) maar de wereld populatie is groter dan alleen de mensen die jij kent.

Gezien de beperkte leefomgeving van veel mensen komen anekdotische drogredenen bijvoorbeeld veelvuldig voor. De persoon haalt in zijn betoog dan voorbeelden uit de directe leefomgeving aan om zijn standpunt (op een incorrecte manier) te onderbouwen

Argumentum ad hominem (Latijn voor "Argument op de man") is een logische drogreden die de positie van de opponent in diskrediet brengt. Het is een tegenwerping die betrekking heeft op de persoon die een bewering doet, niet op de bewering zelf.

Naphtha schreef:Maar het liquifyen melden dat je gaat werken is zo interessant als een natte dwijl

davy jones schreef:Hoor vaak dat 1 op de 4 luitjes t schizofrenie gen meedraagt en dat maryuana smoken chronische psychoses in werking zet. flippen als dat klopt.

davy jones schreef:Hoor vaak dat 1 op de 4 luitjes t schizofrenie gen meedraagt en dat maryuana smoken chronische psychoses in werking zet. flippen als dat klopt.

Bokkie schreef:

davy jones schreef:Hoor vaak dat 1 op de 4 luitjes t schizofrenie gen meedraagt en dat maryuana smoken chronische psychoses in werking zet. flippen als dat klopt.

Ik hoop niet dat je dat te vaak hoort, straks heb je er ook last van.

Schizofrenie is dacht ik een chronische ziekte, dus dan kunnen de psychoses inderdaad ook blijvend zijn. Maar 1 op de 4? Dat lijkt me erg veel. Gevoeligheid voor psychose lijkt me dan eerder, maar schizofrenie lijkt me dan een stapje verder..

Ik heb het artikel verder niet gelezen hoor, zover rijkt mijn vocabulaire nog niet vooral zo'n lange Lap. Dus wie weet?

Maurits schreef:Op dit moment heeft de wetenschap -voor zover ik weet- nog geen specifiek schizofrenie-gen ontdekt. Ondanks de toename van het gebruik van cannabis in de afgelopen 10-tallen jaren is de prevalentie van schizofrenie niet toegenomen. Vanuit epidemiologisch perspectief vind ik dit een goed argument tegen de stelling dat cannabis langdurige psychotische stoornissen zou veroorzaken.

Among cannabis users and daily cannabis users, respectively, carriers of the DRD2, rs1076560, T allele had three- and fivefold increased odds of developing a psychotic disorder compared with cannabis users who were GG carriers (Colizzi et al, 2015). Carriers of the COMT valine158 (Val) allele were more likely to develop schizophreniform disorder if they used cannabis in adoles- cence, although cannabis use had no influence on individuals homozygous for the methionine (Met) allele (Caspi et al, 2005).

Maurits schreef:Ongeveer 10% pleegt zelfmoord, ongeveer 25% is (zwaar) chronisch ziek, ongeveer 30% heeft geregeld last van psychotische, cognitieve en negatieve symptomen en ongeveer 35% herstelt voldoende van zijn of haar schizofrenie.

Bokkie schreef: Hoever is voldoende?

Bokkie schreef:Ongeveer 10% pleegt zelfmoord, ongeveer 25% is (zwaar) chronisch ziek, ongeveer 30% heeft geregeld last van psychotische, cognitieve en negatieve symptomen en ongeveer 35% herstelt voldoende van zijn of haar schizofrenie.

Maurits schreef:De meta-studie van Menezes, maar ook die van de World Health Organisation laten zien dat een relatief flink percentage (volledig) herstelt van schizofrenie of aanverwante psychotische stoornis.

Multiple relapses characterise the course of illness in most patients with schizophrenia, yet the nature of these episodes has not been extensively researched and clinicians may not always be aware of important implications.

Results: Relapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse; many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs; once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode; while most patients respond promptly to re-introduction of antipsychotic treatment after relapse, the response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients. These observations are consistent with contemporary thinking on the dopamine hypothesis, including the aberrant salience hypothesis.

Conclusions: Given the difficulties in identifying those at risk of relapse, the ineffectiveness of rescue medications in preventing full-blown psychotic recurrence and the potentially serious consequences, adherence and other factors predisposing to relapse should be a major focus of attention in managing schizophrenia. The place of antipsychotic treatment discontinuation in clinical practice and in placebo-controlled clinical trials needs to be carefully reconsidered.

[...]

Taken together, these results suggest that even after a single episode of psychosis the vast majority of patients will experience symptom recurrence if followed up for a sufficient period of time.

It could be argued that a substantial proportion of patients remain relapse-free even 12 months after treatment discontinuation, and that these patients may not require continuous antipsychotic treatment. This may be an option if such patients could be identified prior to considering treatment discontinuation. However, while Chen et al. found pre-morbid schizoid and schizotypal traits, level of functioning, and a diagnosis of schizophrenia to significantly predict relapse after 12 months of treatment discontinuation, we were unable to identify any predictors of early relapse in our own study [10].

Remember, in complex disorders such as this, researchers are not looking for a “schizophrenia gene” or genes. Instead, researchers try to find basic processes that contribute to the behaviors or symptoms of the disorder and then find the gene or genes that cause these difficulties—a strategy called endophenotyping (Braff et al., 2007)

• Schizophrenia is generally chronic, and most people with the disorder have a difficult time functioning in society. This is especially true of their ability to relate to others; they tend not to establish or maintain significant relationships, so many people with schizophrenia never marry or have children. Unlike the delusions of people with other psychotic disorders, the delusions of people with schizophrenia are likely to be outside the realm of possibility. Finally, even when individuals with schizophrenia improve with treatment, they are likely to experience difficulties throughout their lives.
• Worldwide, the lifetime prevalence rate of schizophrenia is roughly equivalent for men and women, and it is estimated to be 0.2% to 1.5% in the general population (Mueser & Marcello, in press), which means the disorder will affect around 1% of the population at some point. Life expectancy is slightly less than average, partly because of the higher rate of suicide and accidents among people with schizophrenia.
• Although there is some disagreement about the distribution of schizophrenia between men and women, the difference between the sexes in age of onset is clear. For men, the likelihood of onset diminishes with age, but it can still first occur after the age of 75. The frequency of onset for women is lower than for men until age 36, when the relative risk for onset switches, with more women than men being affected later in life (Mueser & Marcello, in press). Women appear to have more favorable outcomes than do men.

DEVELOPMENT:

• The more severe symptoms of schizophrenia first occur in late adolescence or early adulthood, although we saw that there may be signs of the development of the disorder in early childhood (Murray & Bramon, 2005). Children who go on to develop schizophrenia show early clinical features such as mild physical abnormalities, poor motor coordination, and mild cognitive and social problems (Schiffman et al., 2004; Welham et al., 2008).
• Unfortunately, these types of early problems are not specific enough to schizophrenia—meaning they could also be signs of other problems, such as the pervasive developmental disorders we review in Chapter 14—to be able to say for sure that a particular child will later develop schizophrenia.
• Up to 85% of people who later develop schizophrenia go through a prodromal stage—a 1- to 2-year period before the serious symptoms occur but when less severe yet unusual behaviors start to show themselves (Murray & Bramon, 2005; Yung, Phillips, Yuen, & McGorry, 2004).
• Once the symptoms of schizophrenia develop, it typically takes 1–2 years before the person is diagnosed and receives treatment (Woods et al., 2001). Part of this delay may be the result of hiding symptoms from others (sometimes because of increasing paranoia). Once treated, patients with this disorder will often improve. Unfortunately, most will also go through a pattern of relapse and recovery (Harvey & Bellack, 2009).
  
  

CULTURAL FACTORS:

• We now know that people in extremely diverse cultures have the symptoms of schizophrenia, which supports the notion that it is a reality for many people worldwide. Schizophrenia is thus universal, affecting all racial and cultural groups studied so far.
• However, the course and outcome of schizophrenia vary from culture to culture. For example, the stressors associated with significant political, social, and economic problems that are prevalent in many areas of Africa, Latin America, and Asia may contribute to poorer outcomes for people with schizophrenia in these countries (Burns, 2009). These differences also may be the result of cultural variations or prevalent biological influences such as immunization, but we cannot yet explain these differences in outcomes.
• The differing rates of schizophrenia, therefore, may be partially the result of misdiagnosis rather than to any real cultural distinctions. However, an additional factor contributing to this imbalance may be the levels of stress associated with factors such as stigma and isolation (Pinto, Ashworth, & Jones, 2008). There also may be genetic variants unique to certain racial groups that contribute to the development of schizophrenia (Glatt, Tampilic, Christie, DeYoung, & Freimer, 2004).

GENETIC INFLUENCES:

• Family studies
• Kallmann showed that the severity of the parent’s disorder influenced the likelihood of the child’s having schizophrenia: The more severe the parent’s schizophrenia, the more likely the children were to develop it. Another observation was important: All forms of schizophrenia (for example, catatonic and paranoid) were seen within the families. In other words, it does not appear that you inherit a predisposition for, say, paranoid schizophrenia. Instead, you may inherit a general predisposition for schizophrenia that manifests in the same form or differently from that of your parent. More recent research confirms this observation and suggests that families that have a member with schizophrenia are at risk not just for schizophrenia alone or for all psychological disorders; instead, there appears to be some familial risk for a spectrum of psychotic disorders related to schizophrenia.
• For example, you have the greatest chance (approximately 48%) of having schizophrenia if it has affected your identical (monozygotic) twin, a person who shares 100% of your genetic information. Your risk drops to about 17% with a fraternal (dizygotic) twin, who shares about 50% of your genetic information. And having any relative with schizophrenia makes you more likely to have the disorder than someone without such a relative (about 1% if you have no relative with schizophrenia).
• Twin Studies
• In one of the most fascinating of “nature’s experiments,” identical quadruplets, all of whom have schizophrenia, have been studied extensively. All four shared the same genetic predisposition, and all were brought up in the same particularly dysfunctional house- hold; yet the time of onset for schizophrenia, the symptoms and diagnoses, the course of the disorder, and, ultimately, their out- comes, differed significantly from sister to sister.
• The case of the Genain quadruplets reveals an important consideration in studying genetic influences on behavior—unshared environments (Plomin, 1990).
• Adoption Studies
• The largest adoption study is currently being conducted in Finland (Tienari, 1991). From a sample of almost 20,000 women with schizophrenia, the researchers found 190 children who had been given up for adoption. The data from this study support the idea that schizophrenia represents a spectrum of related disor- ders, all of which overlap genetically. If an adopted child had a biological mother with schizophrenia, that child had about a 5% chance of having the disorder (compared to about only 1% in the general population). However, if the biological mother had schizophrenia or one of the related psychotic disorders (for ex- ample, delusional disorder or schizophreniform disorder), the risk that the adopted child would have one of these disorders rose to about 22% (Tienari et al., 2003; Tienari, Wahlberg, & Wynne, 2006).
• Even when raised away from their biological parents, children of parents with schizophrenia have a much higher chance of having the disorder themselves. At the same time, there appears to be a protective factor if these children are brought up in healthy supportive homes. In other words, a gene– environment interaction was observed in this study, with a good home environment reducing the risk of schizophrenia (Gilmore, 2010; Wynne et al., 2006).
• The Offspring of Twins
• Twin and adoption studies strongly suggest a genetic component for schizophrenia, but what about children who develop schizophrenia even though their parents do not?
• The data clearly indicate that you can have genes that predispose you to schizophrenia, not show the disorder yourself, but still pass on the genes to your children. In other words, you can be a “carrier” for schizophrenia. This is some of the strongest evidence yet that people are genetically vulnerable to schizophrenia. Remember, however, there is only a 17% chance of inheritance if your parent has schizophrenia, meaning that other factors help determine who will have this disorder.
• Linkage and Association Studies
• Endophenotypes Genetic research on schizophrenia is evolving, and the information on the findings from these sophisticated studies is now being combined with advances in our understanding of specific deficits found in people with this disorder. Remember, in complex disorders such as this, researchers are not looking for a “schizophrenia gene” or genes. Instead, researchers try to find basic processes that contribute to the behaviors or symptoms of the disorder and then find the gene or genes that cause these difficulties—a strategy called endophenotyping (Braff et al., 2007).
• Several potential candidates for endophenotypes for schizophrenia have been studied over the years. One of the more highly researched is called smooth-pursuit eye movement, or eye- tracking. Keeping their head still, typical people are able to track a moving pendulum, back and forth, with their eyes. The ability to track objects smoothly across the visual field is deficient in many people who have schizophrenia (Clementz & Sweeney, 1990; Holzman & Levy, 1977; Iacono, Bassett, & Jones, 1988); it does not appear to be the result of drug treatment or institutionalization (Lieberman et al., 1993). It also seems to be a problem for relatives of those with schizophrenia (Lenzenweger, McLachlan, & Rubin, 2007).

NEUROBIOLOGICAL INFLUENCES:

• Current thinking— based on growing evidence from highly sophisticated research techniques—points to at least three specific neurochemical abnormalities simultaneously at play in the brains of people with schizophrenia.
• Strong evidence now leads us to believe that schizophrenia is partially the result of excessive stimulation of striatal dopamine D2 receptors (Javitt & Laruelle, 2006). Recall that the striatum is part of the basal ganglia found deep within the brain. These cells control movement, balance, and walking, and they rely on dopamine to function. Current work on Huntington’s disease (which involves a deterioration of motor function) is pointing to deterioration in this area of the brain.
• How do we know that excessive stimulation of D2 receptors is involved in schizophrenia? One clue is that the most effective antipsychotic drugs all share dopamine D2 receptor antagonism—meaning they help block the stimulation of the D2 receptors (Ginovart & Kapur, 2010).
• A second area of interest to scientists investigating the cause of schizophrenia is the observation of a deficiency in the stimulation of prefrontal dopamine D1 receptors (Howes & Kapur, 2009). Therefore, while some dopamine sites may be overactive (for example, striatal D2), a second type of dopamine site in the part of the brain that we use for thinking and reasoning (prefrontal D1 receptors) appears to be less active and may account for other symptoms common in schizophrenia.
• Finally, a third area of neurochemical interest involves research on alterations in prefrontal activity involving glutamate transmission (Javitt & Laruelle, 2006). Glutamate is an excitatory neurotransmitter that is found in all areas of the brain and is only now being studied in earnest. Just as we saw with dopamine (for example, D1 and D2 receptors), glutamate has different types of receptors, and the ones being studied for their role in schizophrenia are the N-methyl-d-aspartate (NMDA) receptors. And, just as researchers were led to the study of dopamine by observations from the effects of dopamine-specific drugs on behavior, the effects of certain drugs that affect NMDA receptors point to clues to schizophrenia.
• Two recreational drugs described in Chapter 11—phencyclidine (PCP) and ketamine—can result in psychotic- like behavior in people without schizophrenia and can exacerbate psychotic symptoms in those with schizophrenia. Both PCP and ketamine are also NMDA antagonists, suggesting that a deficit in glutamate or blocking of NMDA sites may be involved in some symptoms of schizophrenia (Goff & Coyle, 2001).

BRAIN STRUCTURES:

• Evidence for neurological damage in people with schizophrenia comes from a number of observations. Many children with a parent who has the disorder, and who are therefore at risk, tend to how subtle but observable neurological problems, such as abnormal reflexes and inattentiveness (Wan, Abel, & Green, 2008). These difficulties are persistent: Adults who have schizophrenia show deficits in their ability to perform certain tasks and to attend during reaction time exercises (Cleghorn & Albert, 1990). Such findings suggest that brain damage or dysfunction may cause or accompany schizophrenia, although no one site is probably responsible for the whole range of symptoms (Belger & Dichter, 2006).
• One of the most reliable observations about the brain in people with schizophrenia involves the size of the ventricles. Ventricle size may not be a problem, but the dilation (enlargement) of the ventricles indicates that adjacent parts of the brain either have not developed fully or have atrophied, thus allowing the ventricles to become larger. Ventricle enlargement is not seen in everyone who has schizophrenia. Several factors seem to be associated with this finding.
• For example, enlarged ventricles are observed more often in men than in women (Goldstein & Lewine, 2000). Also, ventricles seem to enlarge in proportion to age and to the duration of the schizophrenia. One study found that individuals with schizophrenia who were exposed to influenza prenatally may be more likely to have enlarged ventricles (Takei, Lewis, Jones, Harvey, & Murray, 1996).
• In a study of ventricle size, researchers investigated the possible role of genetics (Staal et al., 2000). Both the people with schizophrenia and their other- wise unaffected siblings had enlargement of the third ventricle compared to the volunteers. This suggests that the enlargement of ventricles may be related to susceptibility to schizophrenia.
• The frontal lobes of the brain have also interested researchers looking for structural problems associated with schizophrenia (Shenton & Kubicki, 2009). As we described in the section on neurotransmitters, this area may be less active in people with schizophrenia than in people without the disorder, a phenomenon sometimes known as hypofrontality (hypo means “less active,” or “deficient”).
• Research by Weinberger and other scientists at the National Institute of Mental Health further refined this observation, suggesting that deficient activity in a particular area of the frontal lobes, the dorsolateral prefrontal cortex (DLPFC), may be implicated in schizophrenia (Berman & Weinberger, 1990; Weinberger, Berman, & Chase, 1988). When people with and without schizophrenia are given tasks that involve the DLPFC, less activity (measured by cerebral blood flow) is recorded in the brains of those with schizophrenia. Follow-up studies show that some individuals with schizophrenia show hyperfrontality (that is, too much activity), indicating that the dysfunction is reliable, but hyperfrontality displays itself differently in different people (Callicott et al., 2003; Garrity et al., 2007).
• It appears that several brain sites are implicated in the cognitive dysfunction observed among people with schizophrenia, especially the prefrontal cortex, various related cortical regions, and subcortical circuits, including the thalamus and the stratum (Shenton & Kubicki, 2009). Remember that this dysfunction seems to occur before the onset of schizophrenia. In other words, brain damage may develop progressively, beginning before the symptoms of the disorder are apparent, perhaps prenatally.

Maurits schreef:Er zijn hoogleraren psychiatrie die om duistere redenen vasthouden aan het idee dat schizofrenie een chronische en progressieve hersenziekte is.

Causes of schizophrenia: Research has not identified one single factor. It is thought that an interaction between genes and a range of environmental factors may cause schizophrenia.

Psychosocial factors may also contribute to schizophrenia.

Maurits schreef:De meta-studie van Menezes, maar ook die van de World Health Organisation laten zien dat een relatief flink percentage (volledig) herstelt van schizofrenie of aanverwante psychotische stoornis.

Maurits schreef:Ook is het herstel van schizofrenie in derde wereld landen veelal hoger dan in de westerse landen. Aantasting van de hersenen door anti-psychotica zouden hierin wel eens een grote rol kunnen spelen

• However, the course and outcome of schizophrenia vary from culture to culture. For example, the stressors associated with significant political, social, and economic problems that are prevalent in many areas of Africa, Latin America, and Asia may contribute to poorer outcomes for people with schizophrenia in these countries (Burns, 2009). These differences also may be the result of cultural variations or prevalent biological influences such as immunization, but we cannot yet explain these differences in outcomes.
• The differing rates of schizophrenia, therefore, may be partially the result of misdiagnosis rather than to any real cultural distinctions. However, an additional factor contributing to this imbalance may be the levels of stress associated with factors such as stigma and isolation (Pinto, Ashworth, & Jones, 2008). There also may be genetic variants unique to certain racial groups that contribute to the development of schizophrenia (Glatt, Tampilic, Christie, DeYoung, & Freimer, 2004).