Schizophrenia: Symptoms, Genetics, and Treatment

• Schizophrenia is defined by a broad range of disturbances in thinking, perception (hallucinations), speech, emotions, and behavior.
• Diagnosis requires two or more positive, negative, and/or disorganized symptoms present for at least 1 month.
• Complete recovery is rare.

Prevalence and Onset

• Affects 0.2% to 1.5% of the population with equal occurrence in men and women.
• Typically emerges in early adulthood (ages 16-25).
• Has a strong genetic component, evidenced by family, twin, adoption, and genetic marker studies.

Psychotic behavior

• Characterized by hallucinations, delusions, and a loss of contact with reality.

Positive Symptoms

• Involve an abnormal response, like hallucinations and delusions.
• Hallucinations are sensory experiences not caused by external stimuli.
• Delusions are idiosyncratic, rigidly held beliefs despite being erroneous.
• These symptoms tend to be less stable over time.

Hallucinations

• Most often auditory, like voices commenting on behavior or arguing.
• Most patients find hallucinations frightening, however they can sometimes be pleasing or comforting
• Persistent over time.

Delusions

• Include thoughts being inserted into the patient's head and other people reading the patient's thoughts.
• Can also include the belief of being controlled by external forces.
• Often have grandiose or paranoid content and are frequently fragmented.

Negative Symptoms

• Represent deficits in behavioral responses or functions.
• More subtle/difficult to identify initially, as compared to positive symptoms.
• More stable over time and are best seen as a continuum.
• Major types include affective and emotional disturbances, social withdrawal, avolition, and alogia.

Affective and Emotional Disturbances

• Blunted affect: failure to show signs of emotion/feeling; faces are expressionless, voices lack fluctuation in volume and pitch, poor eye contact, lack of concern.
• Anhedonia: inability to experience pleasure, including loss of interest in activities/relationships and lack of physical pleasure and may signal onset of prodomal phase.

Social Withdrawal

• Malfunction of interpersonal relationships.
• A seriously debilitating feature of schizophrenia.
• Can be a symptom and a strategy employed by patients and may develop before the onset of other symptoms.

Avolition

• Includes ambivalence, loss of willpower, and indecisiveness.
• Characterized by a lack of goal-directed or independent behavior.
• Person may lack personal hygiene habits.

Alogia

• Impoverished thinking translates to "speechlessness".
• Includes poverty of speech, marked reduction in amount of speech, and thought blocking, in which speech is interrupted before an idea is completed.

Disorganization (Third Symptom Dimension)

• Some schizophrenic symptoms fit neither positive nor negative categories.
• Includes disorganization (Grube, Bilder, & Goldman, 1998; Peralta & Cuesta, 1999).
• Two major symptoms consist of thinking disturbances and bizarre behavior.

Thinking Disturbances

• Disorganized speech: the tendency in speech to not make sense.
• Includes loose associations, tangentiality, perseveration, and incoherence/ "word salad."

Bizarre Behavior

• Unusual motor behavior: includes catatonia (immobility and marked muscular rigidity) and stuporous state (generally reduced responsiveness).
• Inappropriate affect: affective responses obviously inconsistent with the current situation, incongruity, and lack of adaptability in emotional expression.

Schizophrenia Subtypes

• Paranoid type: Includes delusions/hallucinations but with relatively intact cognitive skills and affect, a better prognosis.
• Disorganized type: includes disrupted speech/behavior, delusions, hallucinations, flat/silly affect, and person is self-absorbed.
• Catatonic type: motor disturbances predominate and include major symptoms of schizophrenia with no particular type.
• Residual type: person has experienced at least one episode of schizophrenia but no longer has active major symptoms.

Traditional Types of Genetic Research: Family Studies

• These studies investigate whether schizophrenia '"runs" in families.

Twin Studies

• Comparing identical twins (100% genetics) to fraternal twins (50% genetics).

Adoption Studies

• Used to rule out environmental factors.

Gottesman & Shields (1976) Hereditability Study

• Based on 5 twin studies.
• Monozygotic twins had a percentage of 35-58% and dizygotic twins had a percentage of 9-26%.
• Severe forms had a percentage of 75-91% and milder forms had a percentage of 17-33%.
• The heredity estimate is approximately 85%.
• Twin studies assume equal environmental effects for both MZ and DZ twins.

Adoption Studies

• Children of schizophrenia parents have the same risk of becoming affected, regardless of whether raised by those biological parents or not.
• 13% of biological relatives of adoptees with schizophrenia have schizophrenia.
• Adopted children with an adoptive parent who have schizophrenia are not at an increased risk of developing schizophrenia.

Tienari et al (1991) Adoption Study

• 144 offspring of SZ biological mothers: 13/144 (9.1%) had psychotic offspring.
• 178 offspring of control biological mothers: 2/178 (1.1%) had psychotic offspring.
• Among the 144 offspring of SZ biological mothers: 7 exhibited SZ, 2 schizophreniform disorder, 2 delusional disorder, and 2 psychotic bipolar illness.

SZ as a Spectrum Disorder

• Concordance rates range from 48% - 86% when schizophrenia-related disorders are included.

Genome Wide Association Studies (GWAS)

• Involves multitude of small-moderate effect genes. Considerable within-group heterogeneity and different disease courses/outcomes

Identifying Susceptibility Genes

• Candidate genes have a role in neurotransmitter functions, nervous system development, and synaptic plasticity.
• Expressed in prefrontal cortex.
• Implicated in "endophenotypes," e.g. working memory impairment, sensorimotor integration, or eye-tracking or event-related potential.

Most Compelling Evidence Comes From

• Neuregulin-1: Chromosome 8, CNS development and function.
• PRODH: Chromosome 22, sensorimotor gating (Gogos, 1999), reduce availability of glutamate.
• Dysbindin: Chromosome 6p, function uncertain, perhaps has role in presynaptic glutamate function.
• COMT: Chromosome 22, encodes key dopamine catabolic enzyme, cannabis use (Caspi, 2005), and Changes in expression/activity in PFC (Turnbridge, 2007)

DISC-1 Gene

• Identified in large Scottish family whose members suffered from schizophrenia, bipolar disorder, and major depression.
• Highly expressed during brain development.
• Plays a role in neurogenesis and neuronal migration.
• Regulates function, structure, and expression of postsynaptic density of excitatory synapses.

Dysbindin-1 Gene

• Present in Schizophrenia and bipolar disorder cases.
• Decreased levels in post-mortem schizophrenia hippocampus and PFC.
• Involved in membrane-protein trafficking.
• Mutations involved in impaired function of dopamine D2 and NMDA receptors.
• Null mutation in mice results in endophenotypes, i.e., Long-term and working memory deficits.

Neuregulin-1 Gene

• Plays role in the expression of NMDA, GABA, and acetylcholine receptor.
• Essential in the development of the nervous system.
• Regulates the development of glial cells and myelination.

Chromosomal Abnormalities

• Interstitial deletion of region 22q11 is called VCFS.
• In addition to physical defects and heart problems, also associated with psychosis.
• In 50 adults with VCFS (Murphy et al., 1999), 30% had a psychotic disorder and 25% DSM 1V schizophrenia.

Linkage Analysis

• Most replicated analysis concerns chromosomes 8, 13, 22, and 2.
• Support also obtained for chromosomes 5,3,11,6 and 20.
• Most often implicated in meta-analysis concerns chromosomes 8 & 22 (Badner & Gershon, 2007).

Summary of Genetic Findings

• There are inconsistent findings involving the number of putative schizophrenia susceptibility loci and weak replication evidence across studies.

Limitations of Genetic Studies

• Genes may also be found in other psychiatric disorders.
• Heterogeneous presentation in different patients results in a diagnostic uncertainty of clinical phenotype.
• Tendency to genotype single genetic marker of the hundreds that might be available in a gene.
• There is complex interaction between genetic and environmental etiological influences.

Conclusions of Genetic Studies

• Strong/consistent genetic evidence from family, twin, and adoption studies.
• Multitude of genes w/small effects.
• A few susceptibility genes seem promising (3, 13, 6, 8, 22).
• Data is confusing.
• Most complex of human disorders: Multifactorial or polygenetic inheritance.
• There is unclear mode of inheritance.
• Etiological heterogeneity may need more complicated genetic models than other biomedical disorders.
• Insufficient evidence to declare a clear-cut cause of schizophrenia.

Changes Brain Morphology

• Lateral Ventricular Enlargement worsens over time and has some correlation with clinical outcome and antipsychotic treatment (Barondes, 1993).
• Frontal Lobe: Some studies show reduced volume, e.g., Premkumar et al (2006), Molina et al (2004); Prefrontal cortical grey matter.

Temporal Lobe Changes

• Reduced temporal volume in FE's, but no further reductions in chronic patients.
• Large scale study looking specifically at the hippocampus (Velakoulis et al, 2006): Reduced left hippocampal (HC) volume in FE patients and bilateral HC volume in chronic patients.
• Normal HC volume in high-risk subjects, including those who later developed schizophrenia.

Conclusions about Brain Morphology

• Frontal/temporal lobe changes follow different timelines indicate different processes at work.
• MRI studies show brain morphology with conflicting results.
• Local vs. global measures of brain: heterogeneous patient populations and small sample sizes.

Diffusion Tensor Imaging (DTI)

• Used an MR scanner to measure the diffusion of water in the brain.
• Diffuses perpendicular to white matter tracts (anisotropy), in all directions in CSF (isotropy), and somewhere in between in grey matter.
• White matter anisotropy depends on myelination, fiber tract density, thickness and other properties.
• Indicates degree and quality of connectivity between brain regions.
• Studies show abnormal anisotropy
• Most common abnormalities found: Reduced anisotropy in corpus callosum (hallucinations) and reduced anterior cingulate cortex (attentional deficits in SZ)

Differences in Brain Function: Hypofrontality

• Reduced activation of prefrontal cortex during cognitive tasks.
• Reproduced fairly consistently in PET and fMRI studies.

Antisaccade task

• Assesses an abrupt and rapid movement of the eyes.
• Subjects are asked to suppress normal saccadic movement towards a target and to move instead in the opposite direction.
• Schizophrenics make more errors and the antisaccadic movements they do correctly make are done at a slower pace compared to healthy controls.

Differences in Brain Physiology

• Show decreased [certain amino acids] in temporal lobe and prefrontal cortex lead to neuronal cell loss and decreased volume in area.
• Decoupling of ↓ [amino acid] & ↓ volume in grey and white matter: Grey includes no ↓ [amino acid] but ↓ volume and White indicates ↓ [amino acid] but no↓ volume.

Neurodevelopmental or Neurodegenerative?

• Neurodevelopmental: Begins prenatally, alters neurons and circuits, culminates in a first episode triggered by environmental factor.
• Neurodegenerative: Neuronal structure/function loss that gets worse over time.

Competing Process Conclusions

• Current techniques for detecting brain changes may not be sophisticated enough.
• Evidence exists for multiple processes working concurrently in different brain areas

Dopamine: Role and Function

• Motor control and emotion (reward).
• Stored in nerve terminals, released in response to action potential.
• Binds to receptors in the postsynaptic cell.
• Action terminated by metabolism and reuptake into the cell.

Dopamine Receptors

• D1-Like: Includes D1 and D5 and increases CAMP with exhibitory function.
• D2-Like: Includes D2, D3, and D4 and decreases CAMP with inhibitory function.
• D1 and D2 most common in Nucleus accumbens and striatum.

Dopamine Pathways

• Nigrostriatal: Substantia nigra to striatum.
• Mesolimbic: Ventral tegmental area to nucleus accumbens, amygdala, hippocampus.
• Mesocortical: Ventral tegmental area to prefrontal cortex.
• Tuberoinfundibular: Hypothalamus to pituitary gland.

Formulating a Dopamine Hypothesis of Schizophrenia

• 1960s: DA hyperactivity → positive symptoms of schizophrenia
• 1970s: Antipsychotics block D2 receptors. Stimulants affecting DA system → psychotic effects.
• 1990s: Negative symptoms not respondent to classical antipsychotics and reduced DA transmission to the prefrontal cortex via D1 receptors.

Too Much Dopamine (Mesolimbic)

• Increases from DA/VTA to Limbic area, resulting in positive symptoms.

Dopamine Imbalance

• Increased Mesolimbic, leading to DA from the DA / VTA area to the Limbic area, resulting in more positive symptoms.
• Decreased Mesocortical, leading to DA from the DA/VTA area to the Prefrontal Cortex, resulting in fewer negative symptoms.

Higher Baseline Levels of DA

• Higher at D2 receptors (Abi-Dargham et al., 2000).
• Amphetamine-induced increase in DA release (Laruelle et al.,, 1996). Increases psychotic symptoms, but does not create new symptoms.

Current Dopamine Evidence

• Decrease in DA innervation to DLPC via Postmortem study (Akil et al., 1999).
• Deficit in prefrontal DA activity at D1 receptors which causes evidence mixed.

Beyond Dopamine

• Patients vary in the extent to which they demonstrate increased DA levels.
• Symptoms due to dopaminergic and non-dopaminergic imbalances.

Dopamine Conclusions

• It is not simply too much dopamine, but a dysregulation of the dopaminergic system.
• Complex interactions with other neurotransmitters, such as glutamate.

General Conclusions

• Dopamine hypothesis does not explain cause of schizophrenia. Possible genetic differences that may cause disturbances in the dopamine and glutamate systems.
• The dopamine hypothesis does suggest targets for treatment such as typical and atypical antipsychotics that target DA receptors.

Other Psychotic Disorders

• Schizophreniform disorder has symptoms of schizophrenia for a few months only (up to 6 months
• Schizoaffective disorder has symptoms of schizophrenia as well as a major mood disorder.
• Delusional disorder includes persistent belief contrary to reality (delusion) without other symptoms of schizophrenia and onset that generally occurs between 40 and 49.
• Brief psychotic disorder involves delusions, hallucinations, disorganized speech or behavior that lasts less than 1 month and is often in reaction to a stressor.

Explore schizophrenia, covering neurological changes, genetic factors, and symptom presentation. Understand dopamine's role and medication side effects, including Parkinsonian symptoms. Investigate the interplay of genetic predisposition and environmental influences in schizophrenia.