Schizophrenia

Nota:

• Affects 1% of the population worldwide symptoms arise in early adulthood Evidence of genetic suseptibility contribution of environmental factors

1. Symptoms
   1. Positive
      1. Delusions

         Nota:

         • delusional thought processes (false beliefs)
      2. Hallucinations

         Nota:

         • false perception- mostly auditory>> develop their own reality
      3. Disturbances in speech/ appearance and behaviour
   2. Negative
      1. Apathy

         Nota:

         • is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion
      2. Lack of emotion
      3. Catatonic posture

         Nota:

         • freezing in a bizzare position for an extended period of time >> rare now because of mediation
2. Diagnosis

   Nota:

   •    Both define symptoms and characteristic impairments of schizophrenia in a similar way, and have improved the reliability of diagnosis    DSM-IV requirements of social or occupational dysfunction and a 6-month duration of illness  ICD-10 – 1month duration, 
   1. ICD-10

      Nota:

      • Tenth Revision of the International Classification of Diseases 1 month duration 
   2. DSM-IV

      Nota:

      • Diagnostic and Statistical Manual, Fourth Edition  6 month duration
3. Definition
   1. Kraeplin

      Nota:

      • long-term deterioration of the illness
   2. Bleuler

      Nota:

      • emphasised that the core symptoms of the disorder as difficulties in thinking straight, incongruous or flattened affect, loss of goal-directed behaviour and retreat into inner world (autism)
4. Phases

   Nota:

   • these stages cycle in days
   1. Prodromal

      Nota:

      • preceds the first episode- headaches, pain and emergence of disordered thoughts
   2. Psychotic stage

      Nota:

      • symptoms appear
   3. Residual stage

      Nota:

      • may show more negative symptoms- more in touch with reality

1. DA hypothesis
   1. Version I- DA receptor

      Nota:

      • came from the dicovery of antipsychotic drugs
      1. Carlsson and Lindqvit (1963)

         Nota:

         • It emerged from the discovery of antipsychotic drugs and the seminal work of Carlsson and Lindqvit who identified that these drugs increased the metabolism of dopamine when administered to animals
         1. increased metabolism DA
      2. Carlsson et al (1957)

         Nota:

         • Further evidence came from observations that reserpine, which is effective for treating psychosis, was found to block the reuptake of dopamine and other monoamines, leading to their dissipation
         1. Reserpine- block DA reuptake
      3. amphetamine

         Nota:

         • Studies showing that amphetamine, which increases synaptic monoamine levels, can induce psychotic symptoms (reviewed in Lieberman et al., 1987)
      4. clinical evidence

         Nota:

         • clinical effectiveness of antipsychotic drugs was directly related to their affinity for dopamine receptors
         1. Seeman et al (1976)
      5. excess transmission

         Nota:

         • The focus at the time was on excess transmission at dopamine receptors and blockade of these receptors to treat the psychosis 
         1. Limitaitons

            Nota:

            • without a clear articulation of its relationship to any particular dimension (eg, positive vs negative symptoms) and no link was made to genetics and neurodevelopmental deficits (understandably as little was then known about them), and there was little clear indication of where the abnormality was in the living brain—this would require the later application of in vivo imaging techniques. Additionally, dopamine was thought of in isolation, with little consideration of how it might relate to known risk factors for schizophrenia, and finally there was no framework for linking the dopaminergic abnormality to the expression of symptoms.
            1. Positive/negative symptoms
            2. genetics
            3. neurodevelopmental deficits
            4. location of abnormality
            5. DA in isolation of other factors
   2. Version II- regional specificity
      1. D2/3 receptors
      2. location of D-receptors

         Nota:

         • dopamine receptors show different brain distributions—characterized as D1 predominantly cortical and D2 predominantly subcortical—to provide a basis for suggesting that the effects of abnormalities in dopamine function could vary by brain region
         1. Davis et al (1991)

            Nota:

            • first outlining the theory
      3. Hypofrontality

         Nota:

         • schizophrenia is characterized by frontal hypodopaminergia resulting in striatal hyperdopaminergia
         1. PET studies

            Nota:

            • showing reduced cerebral blood flow in frontal cortex that provided the best evidence of regional brain dysfunction in schizophrenia
            • “Hypofrontality” in these studies was directly correlated with low CSF dopamine metabolite levels. >>Because CSF dopamine metabolite levels reflect cortical dopamine metabolism, they argued that the relationship between hypofrontality and low CSF dopamine metabolite levels indicates low frontal dopamine levels 
         2. Lesions of DA neurons in prefrontal

            Nota:

            • Lesions of dopamine neurons in the prefrontal cortex result in increased levels of dopamine and its metabolites and D2 receptor density in the striatum
            1. Pycock et al (1980)
         3. DA agonists

            Nota:

            • while the application of dopamine agonists to prefrontal areas reduced dopamine metabolite levels in the striatum
            1. Scatton et al (1982)
         4. Negative symptoms

            Nota:

            • negative symptoms of schizophrenia resulted from frontal hypodopaminergia, based on the similarities between the behavior exhibited by animals and humans with frontal lobe lesions and the negative symptoms of schizophrenia
         5. Positive symptoms

            Nota:

            • Positive symptoms were hypothesized to result from striatal hyperdopaminergia, based on the findings that higher dopamine metabolite levels are related to greater positive symptoms and response to antipsychotic drug treatment
      4. Limitations
         1. No direct evidence

            Nota:

            • Most evidence came from animal studies, or other disorders no direct evidence for low dopamine levels in the frontal cortex and limited direct evidence for elevated striatal dopaminergic function >>It was unclear how the dopaminergic abnormalities were linked to the clinical phenomena—there was no framework describing how striatal hyperdopaminergia translates into delusions or how frontal hypodopaminergia results into blunted affect
         2. oversimplified

            Nota:

            • cortical abnormalities are more complicated that just the hypofrontality proposed at that time- little clear evidence of frontal hypodopaminergia in schizophrenia has emerged
         3. How is DA transmission abnormal?

            Nota:

            • beyond specifying “hyperdopaminergia” or “hypodopaminergia,” did not pinpoint which element of dopaminergic transmission was abnormal
   3. Version III
      1. DA receptors
         1. Antipsychotics
            1. block striatal D2
               1. Early onset of antipsychotic action

                  Nota:

                  • onset of antipsychotic action is early Furthermore, other studies showed this response is related to striatal D2 receptor occupancy, and D2 occupancy at as early as hours predicts the nature of response that follows over the next 2 weeks
                  1. Kapur et al (2005)
               2. consistent with version I
         2. Elevated D2/3- striatal
            1. Meta-analysis of SPECT/ PET
               1. Laruelle (1998)

                  Nota:

                  • modest (10%–20%) elevation in striatal D2/3 receptor density in schizophrenia independent of the effects of antipsychotic drugs >>This appears to be specific to D2/3 receptors—striatal D1 receptor densities are unaltered
         3. Reduced D2/3 -extrastriatal
            1. Takahashi et al (2006)

               Nota:

               • thalamus and anterior cingulate
         4. D1 -prefrontal

            Nota:

            • Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors, and D1 dysfunction has been linked to cognitive impairment and negative symptom in schizophrenia
            1. cognitive impairment and negative symptoms

               Nota:

               • D1 receptor levels in drug-free patients with schizophrenia and found associations with cognitive impairment and negative symptoms
            2. inconsistencies in D1 receptor levels

               Nota:

               • This variation may be explained by different properties of the radiotracers: the effect of dopamine depletion on binding by the tracer used in the first 2 studies may obscure D1 receptor density elevation that is detectable by the tracer used in the last study
               1. Abi-Dargham et al (2002)

                  Nota:

                  • increase in D1 receptors was correlated with cognitive impairment  >>is thus consistent with chronic low levels of dopamine in the prefrontal cortex underlying cognitive dysfunction in schizophrenia, assuming that there has been a compensatory D1 receptor density upregulation
                  1. Reduced D1 receptors in schizo
      2. Presynaptic/ synaptic DA function
         1. elevated DA synthesis
            1. PET

               Nota:

               • patients who were acutely psychotic at the time of PET scanning found elevated presynaptic striatal dopamine availability
               1. e.g. Hietala et al (1995)
            2. Radiolabelling

               Nota:

               • Presynaptic striatal dopaminergic function can be measured using radiolabelled L-dopa, which is converted to dopamine and trapped in striatal dopamine nerve terminals ready for release >>7/9 studies in patients with schizophrenia using this technique have reported elevated presynaptic striatal dopamine synthesis capacity in schizophrenia
               1. e.g. Reith et al (1994)
            3. Moderate-large effect size

               Nota:

               • most widely replicated brain dopaminergic abnormality in schizophrenia, and the evidence indicates the effect size is moderate to large
         2. increased DA release
            1. PET
            2. SPECT

               Nota:

               • single photon emission computerized tomography-  The released dopamine competes with the radioligand and leads to a reduction in radiotracer binding and is considered to be an indirect index of released dopamine
               • studies found doubled radiotracer displacement in patients with schizophrenia compared with controls
               1. e.g. Abi-Dargham et al (2000)
         3. increased synaptic DA
            1. SPECT- Abi-Dargham et al (2000)

               Nota:

               • SPECT study using a dopamine depletion technique that found that baseline occupancy of D2 receptors by dopamine is also increased in schizophrenia
      3. Genetic Etiology
         1. Not one gene encodes Schizo
         2. Number of genes, small effect

            Nota:

            • However, the functional relevance of most of them to dopamine function is not known.68 This view of schizophrenia genetics then reemphasizes a critical role for other interacting factors—particularly the environmental risk factors for schizophrenia.
            1. 4/10 top genes associated with DA pathways

               Nota:

               • The strongest association is with a gene variant affecting the vesicular monoamine transporter protein >>This protein acts to accumulate dopamine and other monoamines into vesicles, which fits with the PET studies that show elevated radiolabeled dopamine accumulation into striatal vesicles in schizophrenia
               1. other indirect affect DA system
            2. genes for dysbindin

               Nota:

               • involved in brain development
            3. genes influencing transmitters

               Nota:

               • such as glutamate/ GABA
         3. GWAS
            1. (-) requires large no. of subjects and controls
            2. ZNF804A
               1. unknown function
               2. predisposes Schizo and bipolar
         4. Twin studies

            Nota:

            • 48% chance of schizo>> environmental influences
         5. many dimensions of schizo

            Nota:

            • because the symptoms of schizo varies so much it is unlikely that only one gene will produce schizo
      4. Environmental factors
         1. social adversity

            Nota:

            • migration, unemployment, urban upbringing, lack of close friends, and childhood abuse are all associated with a well-established increased risk for schizophrenia
            1. animal studies of social isolation

               Nota:

               • find that these factors lead to dopaminergic overactivity
         2. pregnancy
         3. pre- and perinatal factors

            Nota:

            • e.g. neonatal exposure to toxins, neonatal stress by maternal seperation etc
            1. animal models

               Nota:

               • evidence from animal models that pre- and perinatal factors can lead to long-term overactivity in mesostriatal dopaminergic function
            2. increased presynaptic DA function
         4. psychoactive substances
            1. PET

               Nota:

               •  few doses of a stimulant may sensitize the striatal dopamine system and can lead to enduring increases in dopamine release to amphetamine even after many months of abstinence
            2. Cannabis
               1. animals
                  1. increase striatal dopamine release
            3. indirect influence on DA

               Nota:

               • by potentiating dopamine release caused by other effects. This has been shown for the NMDA blocker ketamine, which has been found to increase amphetamine-induced dopamine release in healthy humans to the levels seen in schizophrenia
      5. Howes and Kapur (2009)
      6. GENES and ENVIRONMENT

         Nota:

         •  evidence indicates that many disparate, direct and indirect environmental and genetic, factors may lead to dopamine dysfunction and that some occur independently while others interact
         • Thus, as the dopamine hypothesis evolves, the scientific challenge will be not just to find predisposing genes but to articulate how genes and environment interact to lead to dopamine dysfunction.
         1. synergistic effects
            1. animal studies
               1. social isolation

                  Nota:

                  • at least some of these factors interact in their effects on the dopamine system: social isolation rearing potentiates the later effects of stimulants or of stress on the dopamine system
                  1. Jones (1992)
            2. Interactions between gene variants
               1. Caspi et al (2005)- cannabis

                  Nota:

                  • findings that variants of the catechol-O-methyltransferase gene (involved in dopamine catabolism) interact with early cannabis exposure to increase the subsequent risk of psychosis
            3. van Os et al (2004)

               Nota:

               • Family history of psychosis also interacts with environmental factors such as urbanicity to increase the risk of schizophrenia
      7. DA abnormalities and clinical expression of Schizo
         1. abnormal DA neuron firing

            Nota:

            • the abnormal firing of dopamine neurons and the abnormal release of dopamine leads to an aberrant assignment of salience to innocuous stimuli
         2. positive symptoms

            Nota:

            • especially delusions and hallucinations, emerge over time as the individual's own explanation of the experience of aberrant salience
            • Psychosis is, therefore, aberrant salience driven by dopamine and filtered through the individual's existing cognitive and sociocultural schemas—thus allowing the same chemical (dopamine) to have different clinical manifestations in different cultures and different individuals
         3. negative symptoms

            Nota:

            • dopamine dysregulation may increase the noise in the system, “drowning out” dopaminergic signals linked to stimuli indicating reward >>The net result would be reduced motivational drive that would lead over time to negative symptoms, such as social withdrawal, and neglect of interests
            1. (+)face validity
         4. (-) needs to be tested further

            Nota:

            • in in-vivo studies of neurochemical function in patients
      8. VERSION III

         Nota:

         • Firstly, we hypothesize that multiple “hits” interact to result in dopamine dysregulation—the final common pathway to psychosis in schizophrenia. This is illustrated schematically in figure 1. Second, the locus of dopamine dysregulation moves from being primarily at the D2 receptor level to being at the presynaptic dopaminergic control level. Third, dopamine dysregulation is linked to “psychosis” rather than schizophrenia, and perhaps in the fullness of time it will be about “psychosis proneness.” The exact diagnosis, however, reflects the nature of the hits coupled with sociocultural factors and not the dopamine dysfunction per se. And finally, the dopamine dysregulation is hypothesized to alter the appraisal of stimuli, perhaps through a process of aberrant salience.

         Adjunto:

         • Schizophrenia
         1. Implications
            1. Antipsychotics treating symptoms NOT cause

               Nota:

               • current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis
               1. increase presynaptic DA synthesis
                  1. Vernaleken et al (2006)
               2. elevated in patients

                  Nota:

                  • elevated in patients who have received antipsychotic treatment for many years
                  1. McGowan et al (2004)
               3. Explains relapse

                  Nota:

                  • This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects.
         2. Rejection
            1. PET studies

               Nota:

               • PET studies directly implicating presynaptic dopamine dysfunction are a major foundation of this new version of the hypothesis. 
               1. indirect measures

                  Nota:

                  • PET data require to be modeled to provide estimates of L-dopa uptake or synaptic dopamine levels—and the results are inferred rather than direct measurements
            2. New drugs not affecting DA pathway

               Nota:

               • a new drug is found that treats psychosis without a direct effect on the dopamine system. In other words, the dopamine abnormalities continue unimpeded, and psychosis improves despite them
               1. e.g. mGlu 2/3 agonist
                  1. Patil et al (2007)

                     Nota:

                     • phase II clinical trials
            3. Pathophysiology mechanism not affecting
         3. Other dimensions
            1. version II

               Nota:

               • a dysfunction in the dopamine system as a complete explanation for schizophrenia: a prefrontal hypodopaminergia leading to a subcortical hyperdopaminergia
               1. little evidence
            2. multiple factors

               Nota:

               • multiple routes (genetic, neurodevelopmental, environmental, social) that lead to the striatal hyperdopaminergia
               • Thus, in contrast to version II, which proposed a single pathway, we propose that changes in multiple transmitter/neural systems underlie the cognitive dysfunction and negative symptoms of schizophrenia, and in many cases these dysfunctions precede the onset of psychosis. It is when these pathways, in convergence with other biological or environmental influences, lead to striatal dopamine hyperfunction that psychosis becomes evident and the label of schizophrenia is assigned. 
               1. Correlation evidence
                  1. Howes et al (2008)

                     Nota:

                     • dopamine abnormalities are associated with poor performance on cognitive tasks
                  2. Howes et al labs (2008)

                     Nota:

                     • higher striatal dopamine synthesis capacity is linked to functional abnormalities in the cortical regions engaged by these tasks
2. Glutamate

   Nota:

   • see mind map

   Adjunto:

   • Schizo- glutamate

Nota:

• see lecture notes

1. Typical antipsychotics

   Nota:

   • don't treat negative symptoms 
   1. D2 receptor antagonists
      1. 1950s- Chlorpromazine
      2. haloperidol
      3. motor side affects- dyskinesia
         1. involuntary face movements
         2. twisting/ jerking of arms/ legs
2. Atypical

   Nota:

   • also treat negative symptoms
   1. 1961- clozapine

      Nota:

      • most efficacious drug to date- treats negative symptoms too
3. Future
   1. mGlu2/3 agonist- phase II clinical
      1. Patil et al (2007)

         Nota:

         • LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo
         1. LY404039- improved + and - symptoms

            Nota:

            • in Schizo patients compared to controls- placebo controlled, double-blind etc
   2. glycine transporter 1- clinical trials