Lecture 8 Flashcards
Schizophrenia
who is affected by schizophrenia
Affects almost 1% of the population worldwide, the ratio of men to women who are diagnosed is 1.4:1 (more men than women).
- More men have it than women, unlike bipolar which is about even
what is schizophrenia
A brain disorder that affects thought and perception, making it difficult for people to determine what is real. Hallucinations and delusions are frequent symptoms, but changes in social interactions, motivation, mood, and impaired cognitive functions are the most disabling and difficult to treat.
- Perception of reality is altered
- Mood is affected
- There are hallucinations
When is Schizophrenia’s onset
Onset in early adulthood, earlier for men than women. There is a “prodomal period” of 2-5 years before diagnosis, with subclinical behavioral changes noted by friends and family
where is schizophrenia found
- Globally one of the top ten causes of disability. Urbanicity is a risk factor.
- Potentially a developmental disorder that manifests in adulthood
why is schizophrenia caused
The precise cause of schizophrenia for each individual is unknown. Both genes and environment play an important role, with genetic risk factors contributing to 80% of the overall risk. Many of the environmental risk factors for schizophrenia are associated with prenatal development and early childhood
what are positive symptoms for schizophrenia
psychosis
- presentation of behaviors that are not normally seen in healthy people
list positive symptoms for schizophrenia
- hallucinations
- delusions
- disturbances of the flow, order, and content of thought
- neologism (creation of new words or expressions)
- nonsensical rhymes
how can positive symptoms for schizophrenia be addressed
with anti-psychotic medication
what are negative symptoms for schizophrenia
lack of behaviors that are normally present in healthy people
list negative symptoms of schizophrenia
- avolition (decreased motivation)
- Anhedonia – decreased ability to experience pleasure or identify activities as being pleasurable.
- Flattened affect – lack of emotion or expression of emotion.
- Poverty of speech – small vocabulary
- Social withdrawal
how can negative symptoms of schizophrenia be addressed
they are harder to address than positive symptoms
features of schizophrenia
- Postadolescent onset with sex differences – males earlier than females and perhaps more severe symptoms
- Subtle neurological changes: enlarged lateral ventricles, reductions in white matter tracts, and reduced cerebral grey matter (reduced synapses, not cell number)
How can we tell whether a disease is genetic or is caused by environmental exposure to causal risk factors
- Twin studies are very informative.
- Monozygotic twins = identical twins – they have the same genetic code * and experience the same prenatal environment.
○ Started off as one person and split in the womb
- Monozygotic twins = identical twins – they have the same genetic code * and experience the same prenatal environment.
- Dizygotic twins – fraternal twins – genetically they have the same similarity as siblings that are born at different times. However – they experience the same prenatal environment.
what is concordance
likelihood that two people will have the same diagnosis
environmental risk factors of schizophrenia
- Maternal infection in 2nd trimester
- Maternal starvation
- Infection with Plasmodium gondii (cat feces)
- Obstetric complications
- Physical or psychological abuse/trauma in childhood
- Low socioeconomic status
- Urbanicity
- Drug exposure (amphetamine, cannabis, phencyclidine)
how was schizophrenia treated before antipsychotics
- Lifetime institutionalization
- Induce fever
- Induce hypoglycemic shock
- Induce seizures with electrical stimulation
- Frontal lobotomy
○ Then substituted to Chloral hydrate and other barbiturates - Freudian psychotherapy
the discovery of chlorpromazine
- French surgeon Henri Laborit used a compound developed by Rhone-Poulenc – he was looking for a new anesthetic drug.
○ His patients became very calm when he gave it to them
○ He mentioned it to a psychiatrist friend, who started giving it to patients instead of lobotomies - Chlorpromazine was developed in 1950 and given to schizophrenia patients in 1952 after it was reported to generate a “chemical lobotomy” in patients.
- Other antipsychotics developed based on the chemical structure of chlorpromazine and screened with behavioral tests in rodents.
- Screens look for drugs that reduce motor activity elicited by amphetamine. Almost 20 antipsychotics were developed without knowing their mechanism of action (what receptors they were binding).
chlorpromazine and other antipsychotics are all
D2 dopamine receptor antagonists
too much dopamine leads to
paranoia, delusions
The first antipsychotics all worked by
blocking dopamine receptors (D2 dopamine receptor antagonists)
what were the first generation antipsychotics
chlorpromazine, haloperidol
how were these first gen APS meds discovered
Identified based on their ability to antagonize dopamine-mediated behaviors in rodents (locomotor activity)
effects of these first generation APS
- Induce serious motor impairments at or near therapeutic dose (due to D2R antagonism) – similar to Parkinson’s disease symptoms (muscle rigidity, slow movement, dystonia).
- Cause anhedonia (due to D2R antagonism) – non-compliance leading to relapse.
- Cause sedation and somnolence (due to antagonism at H1 histamine receptors) especially chlorpromazine.
- Have anti-emetic properties (used to treat vomiting).
- Cause weight gain.
- Do not cause withdrawal symptoms – relapse after discontinuation (hospitalization) 6 months.
___ marked the shift from first gen to second gen APS meds
Cloazapine
what did Clozapine do to change the assumptions for APS
- Pharmacologists originally believed that a drug must elicit parkinsonian adverse effects in order to be an effective antipsychotic.
- However, discovery of clozapine (1960’s) challenged that assumption. This drug was effective without inducing catalepsy (below)
what were the second gen APS meds
clozapine, olanzapine, risperidone
what did the clozapine work on
- Clozapine discovered to be effective and antagonizes serotonin receptors (5HT2A) as well as dopamine D2 receptors (also acts on other receptors – muscarinic, histamine).
- Many drugs developed to have dual actions on serotonin and dopamine receptors (olanzapine, risperidone, many others).
effects of second generation drugs
- Do not cause Parkinsonian motor impairments (EPS) and tardive dyskinesia.
- Cause extreme weight gain (olanzapine can cause 20-40 pound gains in one month) – increase in appetite.
- Cause metabolic syndrome - weight gain, unhealthy plasma lipid levels, type 2 diabetes. Increases risk of CVD.
adverse drug effects of first gen
Extrapyramidal side effects (Parkinsonian effects)
- Tardive dyskinesia
- Hyperprolactinemia – elevated prolactin hormone causes breast development in men & women, lactation in women, impotence in men, disruptions in menstrual cycle in women
adverse drug effects of second gen
○ Cardiovascular disorders: Blood disease – clozapine - agranulocytosis
○ All:
○ Anhedonia, flattened affect (worsening of negative symptoms)
○ Sedation/Somnolence
○ Weight gain
○ Extrapyramidal side effects (EPS)
- Typical or first generation APS can cause immobility and muscle rigidity similar to Parkinson’s disease at or near their therapeutic dose. They can also cause dystonia or akathisia (restlessness). This is thought to be a result of D2 antagonism.
- Tardive dyskinesia
Tardive Dyskinesia for Second Gen occasionally occurs
after long-term treatment with typical APS
- symptoms persist even after APS is discontinued
- patients have involuntary twitches of facial muscles predominantly, but also hands and legs
unmet needs in schizophrenia
- Antipsychotics take several weeks for full effect.
- They are effective at treating “positive symptoms” – hallucinations, delusions, agitation, thought disorder – however, there is a substantial percentage of patients who do not benefit from any antipsychotic.
- “Treatment-resistant” schizophrenia is best treated with clozapine (not chosen first because of risk for WBC loss).
- None of the current medications improve the negative and cognitive symptoms of schizophrenia – these are disabling and affect many aspects of daily living (mood, relationships, employment
third gen anti psychotics
Aripiprazole (Abilify) developed to have a similar structure to clozapine
how is Aripiprazole different than clozapine
- Instead of being a D2 dopamine receptor antagonist, it is a “weak” or “partial” agonist of D2 dopamine receptors.
- In brain regions where dopamine is too low, it activates the receptors (but not as well as dopamine does).
- In brain regions where dopamine is too high, it competes with the dopamine binding to its receptor and the receptor is only partially activated instead of fully activated.
- You can think of aripiprazole as a drug that normalizes dopamine receptor activity
new ideas about the causes of schizophrenia
- The genetics of schizophrenia tell us that there is no one gene or neurotransmitter system that is changed in all patients with the diagnosis.
- It is likely that this is an umbrella diagnosis that is applied to many different disorders.
current thinking is that schizophrenia is caused by
1) a rare de novo mutation in one of hundreds of genes that can lead to schizophrenia,
- OR 2) a combination of several risk genes plus environmental stressors.
- Recent GWAS studies identified 145 genetic areas where variants in DNA sequence increase risk for schizophrenia. Alone any one of these variants has very minor effect and is not likely to cause schizophrenia.
clues from genetic studies about schizophrenia
- Not surprisingly, genes for glutamate receptors, dopamine receptors, proteins for synaptic signaling and neuron excitability are all represented in genetic studies.
- Interestingly, genes for immune function are some of the risk genes. Is there a role for inflammation in schizophrenia?
- Overlap with risk genes for neurodevelopmental disorders, autism and bipolar disorder.
finding new treatments for schizophrenia
- mouse models
- induced pluripotent stem cells from patients
- clinical trials (double blind, placebo controlled)
