Psychopathology Flashcards
1
Q
what are positive and negative symptoms in schizophrenia?
A
Positive symptoms: abnormal behaviours that have been gained
* Hallucinations (typically auditory), delusions (paranoia), thought disorder, all three = PSYCHOSIS
Negative symptoms: normal functions that have been lost
* Blunted emotional responses, poverty of speech, social withdrawal, anhedonia, lack of insight, COGNITIVE DEFICITS
2
Q
what is the criteria for a DSM-5 diagnosis of schizophrenia?
A
- At least 1 of 3 core symptoms is required for diagnosis (DSM-5) although presentations varies greatly
○ Hallucinations, delusions, or disorganized speech
○ These symptoms also present in other conditions that need to be ruled out before schizophrenia is diagnosed
3
Q
how prevalent is schizophrenia? when is it’s onset?
A
- 1% of the population suffer from schizophrenia at any given time
- Onset is typically after puberty (18%)
- Typically does not onset after 30 in men, small number of women develop symptoms after menopause (+45 years)
4
Q
what are cognitive deficits in schizophrenia predictive of? where are the impairments located in the brain?
A
- Cognitive functioning is the #1 predictor of long term outcome (better function = better prognosis)
- Severity of psychotic symptoms not related to severity of cognitive deficits
- Many of the functions impaired in schizophrenia are mediated by the prefrontal cortex and/or hippocampus
5
Q
what did brain activation studies of schizophrenia patients during the wisconsin card sorting task tell us?
A
Schizophrenia patients and identical twin controls performed Wisconsin Card Sort
* Schizophrenia patients showed minimal increase in PFC activity when performing task, unlike controls (who had way more)
* Other brain regions were activated similarly in both groups
* Schizophrenia is associated with disruption in PFC function, but not as much as much for other cortical regions
6
Q
to what extent is schizophrenia hereditary?
A
- Odds of developing disorder increases if one has a relative diagnosed with schizophrenia, closer the relative, the more likely
- Highest concordance in identical twins, or if both parents have schizophrenia (~50%)
Findings indicated…
1. There is a strong genetic component to schizophrenia
2. Altered genes are NOT the only cause of the disease (only 50% with identical twins)
○ Genetic component not linked to just one gene, there are likely dozens that may be altered
7
Q
what developmental events/factors can influence the likelihood of having schizophrenia?
A
- In utero influences: poor nutrition during pregnancy, premature birth/low birth weight, physical/immune stressors during pregnancy
- Early developmental insults lead to brain abnormalities in adulthood, stressors later in life (after puberty) can trigger onset
- Genetics increase sensitivity to stressors by mother or child, either in utero or later in life
- Some people may have genetic susceptibility to acquiring the disease, but certain types of stressors needed to trigger it
8
Q
how is the hippocampus of people with schizophrenia different from controls?
A
- some individuals with schizophrenia have enlarged lateral ventricles, due to smaller hippocampus and other temporal lobe regions
- closer inspection reveals altered organization of hippocampal neurons in brains of those with schizophrenia
- not brain damage necessarily, changes in neural organization (occurring during development) can disrupt how brain regions process information
9
Q
how is the PFC of someone with schizophrenia different from controls?
A
- pyramidal neurons have reduced number of dendrites, which reduced processing power of these cells
- Hypofrontality (reduced PFC function) is a characteristic negative symptom of schizophrenia
10
Q
how are the GABAergic interneurons of someone with schizophrenia different from controls?
A
- GABAergic interneurons are connected to pyramidal cells, serve as a major information filter for PFC (and other regions like hippocampus)
- People with schizophrenia have reduced GABAergic interneurons in these regions
- This may lead to a noisy cortex, reducing information filtering and impaired functioning of these regions
11
Q
how was the dopamine hypothesis of schizophrenia developed?
A
- 1950s: chlorpromazine found to be antipsychotic; causes Parkinson’s symptoms in healthy individuals
○ Brains of Parkinson’s patients found to be depleted of dopamine (schizophrenia = too much dopamine) - 1960s: drugs that increase dopamine release (amphetamine) could induce psychotic symptoms
- Chlorpromazine, other antipsychotics found to block dopamine receptors
- 1970s: dopamine receptor subtypes discovered; antipsychotic potency of a drug correlated with binding to D2 receptors (not D1)
12
Q
what is the dopamine hypothesis of schizophrenia?
A
Schizophrenia is caused by an abnormal increase in dopamine transmission, leading to overstimulation of D2 receptors
13
Q
what is the support for the dopamine hypothesis of schizophrenia?
A
- All drugs that are effective in treating psychosis block D2 receptors to some degree
- There is greater dopamine release in striatum in those with schizophrenia
- More dopamine release correlated with more positive symptoms induced by amphetamine
- Dopamine release may be hypersensitive in schizophrenia
14
Q
is the problem in schizophrenia that there are more D2 receptors, or that there is more dopamine being released?
A
- It’s unclear if there are more D2 receptors in people with schizophrenia
- some post-mortem studies report more D2 receptors, but others do not
- may be because chronic antipsychotic medication leads to more dopamine receptors
- in a study where they give amphetamine to controls or people with schizophrenia, people with schizophrenia have more dopamine release in their striatum
- dopamine system is hypersensitive in schizophrenia
15
Q
how might a hypersensitive dopamine system contribute to delusions?
A
- Dopamine neurons show increased activity to highly salient/novel stimuli,
- Increase in activity (and dopamine release in striatum) may serve as a signal the brain uses to determine what’s important/relevant
- A hyperactive dopamine system may highlight normally irrelevant stimuli as important, and impair filtering out of irrelevant stimuli
- This leads to “aberrant salience attribution”, attribution of significance to stimuli that would normally be considered irrelevant that may contribute to delusions
16
Q
how does antipsychotic medication affect the aberrant salience attribution?
A
- Antipsychotic medications are thought to reduce aberrant salience by reducing dopamine activity
- Often, people with schizophrenia still report hearing voices when on medication, but they are no longer bothered by them
17
Q
what are some treatment issues in schizophrenia?
A
- Dopamine is involved in motor functions and long term treatment with antipsychotics (dopamine blockers) can cause movement side effects (extrapyramidal)
- Tardive dyskinesia occurs in about 1/3 of patients treated with classical antipsychotics
○ Grimacing, tongue protrusion, lip smacking, rapid limb/trunk movements, symptoms sometimes continue after discontinuing medication - Drugs that are more selective for dopamine vs. other receptors usually cause worst side effects
- Antipsychotic drugs treat psychosis (delusions, hallucinations), negative symptoms rarely improve with antipsychotics
18
Q
what are some limitations of the dopamine hypothesis of schizophrenia?
A
- antipsychotics block dopamine receptors right away, but drug treatment takes about 2 weeks to reach full effect
- not all with schizophrenia respond to drugs that block dopamine receptors
- dopamine blockers can alleviate psychosis but not negative symptoms
- some drugs that reduce symptoms do not block D2 receptors that well (clozapine, an atypical antipsychotic)
- drugs that increase dopamine release can improve negative symptoms
19
Q
what is an example of a drug that reduces symptoms but does not block D2 receptors that well? what does this tell us about the dopamine hypothesis?
A
- Clozapine and atypical antipsychotics are not as effective at blocking D2 receptors as classical antipsychotics, BUT LESS MOTOR SIDE EFFECTS
- much higher affinity to other receptors, like serotonin (5 HT)
- can sometimes improve negative symptoms, possibly through blocking serotonin
- if positive/negative symptoms are due to overstimulation of D2 receptors, atypical antipsychotics shouldn’t work as well
- treatment issue - some patients have an adverse blood reaction to clozapine, not all patients can take it safely
20
Q
what is an example of how drugs that increase dopamine release can improve negative symptoms? what does this tell us about the dopamine hypothesis?
A
- schizophrenia patients and healthy controls tested on working memory task
- give low dose of amphetamine (that increases dopamine release, but not psychotic symptoms) vs. placebo
- higher doses of amphetamine DO exacerbate psychotic symptoms
- amphetamine improved performance on working memory task for those with schizophrenia
- if schizophrenia is just an increase in dopamine, why should drugs that increase dopamine release improve cognition?
suggests dopamine is not increased in all brain regions in schizophrenia*
21
Q
what is the glutamate hypothesis of schizophrenia? what is it based on?
A
- abuse of phencyclidine (PCP, angeldust) or ketamine can cause psychotic symptoms and cognitive deficits resembling schizophrenia
- these drugs block NMDA glutamate receptors
- they don’t block where glutamate binds, blocks the ion channel and prevents APs, glutamate then cannot activate the receptor
- Glutamate hypothesis - schizophrenia is caused by decreased glutamate transmission
- PFC/hippocampal neurons use glutamate as transmitter
- degeneration of these neurons in schizophrenia disrupts their function, less glutamate released in these areas
22
Q
what did animal models tell us about the causes of symptoms in schizophrenia?
A
Rat/primate studies show that repeated PCP (which blocks NMDA glutamate receptors)…
a. Causes cognitive deficits on PFC dependent tasks
b. Decreases PFC dopamine levels
* Schizophrenia is also associated with reduced PFC dopamine activity
* Different symptoms may be driven by imbalance of dopamine transmission in PFC (too little) and striatum (too much)
* May explain why drugs that increase dopamine improve cognition in the disorder
* This model can encompass some of both the positive and negative symptoms of the disorder
23
Q
how can the salience attribution in schizophrenia be due to a PFC-GABA connection?
A
- People with schizophrenia display abnormal fear learning
- Inappropriate discriminative fear conditioning, decreased fear to CS that was paired with the shock (CS +) and increased fear to CS that was presented alone (CS -)
- Increased PFC activity when responding to CS- in patients with schizophrenia
- when we reduce PFC GABA in rats, they show the same pattern
- dysfunctional PFC GABA may also contribute to positive symptoms
24
Q
what are the integrative hypotheses for negative/positive symptoms and cognitive impairments in schizophrenia?
A
- Negative symptoms - decreased PFC dopamine/glutamate reduces activity overall
- Cognitive dysfunction - noisy PFC due to reduced GABA inhibition
- Positive symptoms - Increased subcortical dopamine transmission (striatum), dysfunctional GABA
25
what is major unipolar depression?
* one of the most common mood disorders, characterized by:
○ Unhappy mood (more an absence of happiness than increased sadness)
○ Worthlessness, guilt, desperation
○ Loss of interest, motivation (anergia), and appetite, blunted ability to experience pleasure (anhedonia)- or at least pursue it
○ Difficulty in concentration, restless agitation
26
what are the costs of major unipolar depression to the individual and society?
* Dramatically increased risk of suicide (7-15% vs ~1% general population)
* Impact on relatives/friends of the individual with depression
* Lost productivity costs
27
what is the DSM-5 diagnostic criteria for major depressive disorder?
* more than 5 symptoms during the same two week period that are a change from previous functioning
* depressed mood and/or loss of interest/pleasure must be present
* symptom clusters vary with individuals; there are depression subtypes (over 200 combinations)
28
how often and when do episodes of depression usually occur?
* unipolar depression alternates with normal emotional states, with an episode lasting up to 6-9 months
* an episode of depression may occur with no apparent cause (endogenous) or can be triggered by external events (reactive)
* episodes can recur through life, often increasing in frequency and intensity
29
what is the prevalence of unipolar depression? sex differences and trends in incidence.
* in North America, > 10% of population may be afflicted at any one time
* women more likely to be diagnosed (due to physiology and stress hormones)
* in women, incidence often coincides with major hormonal changes (post partum, menopause)
* incidence of depression has increased over the last 50 years, and age of onset has decreased (currently ~ 27 years old)
30
how is depression related to stress levels?
* depression is viewed as a stress-related disorder, can emerge during stressful life periods
* at least some forms of depression may be linked to alterations in HPA-axis and higher cortisol levels
* circulating CORT levels tend to be higher in depressed subjects vs. other disorders or controls
* usually the system shuts down CORT production through negative feedback methods when there is too much CORT, but people with depression have an inability to regulate CORT levels
31
what is cushing's syndrome and how is it related to depression?
Cushing's syndrome is an endocrine disorder where people have high levels of glucocorticoids (CORT) and are prone to depression
32
what is the diathesis-stress model?
idea that the individual has some sort of predisposition for depression, and stress can trigger the syndrome
33
what does the dexamethasone suppression test tell us about CORT release in people with depression?
* dexamethasone, a synthetic glucocorticoid, stimulates CORT receptors in order to suppress CORT release through negative feedback
* through negative feedback, levels drop in healthy controls
* in many depressed patients, negative feedback mechanisms are disrupted and CORT levels do not drop
34
what is the monoamine hypothesis of depression and how did it originate?
Depression is the result of abnormal reductions in brain monoamine levels (mostly 5-HT and noradrenaline, but also dopamine)
* 1950-60s: Reserpine: drug that reduces monoamine levels by preventing neurotransmitters from going into vesicles --> depression
* First monoamine oxidase inhibitors (which block metabolism of monoamines and increase brain levels) alleviated depression
* First tricyclic antidepressant (Imipramine, which blocks monoamine reuptake) also found effective
* 1980s: Fluoxetine (aka-Prozac™) a -selective serotonin reuptake inhibitor (SSRI) found to be effective at treating depression
35
what are some treatment issues and limitations of the monoamine hypothesis?
1. Antidepressants increase monoamine levels quickly, yet there is a lag in the reduction of symptoms (chronic treatment required)
2. Not all depressed patients respond to drugs that increase monoamine levels
○ There is a large placebo effect but antidepressants tend to improve symptoms vs. placebo in most severely depressed patients
○ SSRIs are not more effective than classic tricyclics that effect noradrenaline release as well (have fewer side effects)
3. SSRIs associated with increased risk of suicide in children and adolescents (but causal relationship unclear)
4. In animal models, depletion of 5-HT does not cause a depressive phenotype (there is more to the disorder than just a decrease in serotonin)
36
what have functional imaging studies of patients with depression shown us?
* increased blood flow to amygdala and ventral parts of medial prefrontal cortex
* aspects of depression may be caused by disrupted regulation of amygdala emotional processing by certain parts of PFC
* alterations in brain activation can be normalized with antidepressant treatment
* reduced hippocampal volumes also observed
* dysfunction of PFC may be one of the underlying mechanisms that leads to negative appraisals of life events
37
what are some other treatments for depression?
* electroconvulsive shock therapy (ECT)
* transcranial magnetic stimulation (TMS)
* deep brain stimulation (DBS)
* ketamine
* cognitive behavioural therapy
38
what is electroconvulsive shock therapy and how does it treat depression?
* sedate the patient then induce small seizure in the brain
* method of action is poorly understood but shock might cause intense release of NT which can reset the brain
* works relatively quickly
* one of the original treatments for depression and is still used today in extreme casesw
39
what is transcranial magnetic stimulation and how does it treat depression?
* also alters cortical electrical activity like ECT
* less intense than ECT
40
what is deep brain stimulation and how does it treat depression?
* electrode surgically implanted in the brain and high frequency stimulation given continuously
* thought to inactivate the targeted brain region
* DBS in ventromedial PFC or other subcortical areas has been effective in treating depression in treatment-resistant patients
* no controlled experiments have been done
41
what is ketamine and how does it treat depression?
* ketamine is a non-competitive NMDA antagonist
* sub-anethetic doses induce rapid reduction in symptoms for 70% of treatment-resistant patients (after psychosis)
* effects last about 1-3 weeks
* nasal formulation recently approved for use
* method of action not fully understood, but may be linked to increased cortical activity because NMDA receptors are on inhibitory neurons as well
42
how effective is cognitive behavioural therapy in treating depression?
* takes longer than antidepressant drugs but is just as effective
* is even more effective when used in combination with other treatments
43
how do certain experimental manipulations cause a depressed condition in lab animals?
* learned helplessness animal is exposed to a repetitive, inescapable stressful stimulus
* after repeated exposure, some more sensitive animals will not escape when given opportunity
* those that do not escape tend to have cellular/neurochemical alterations in the brain, (eg: decrease in 5-HT function)
* acute antidepressant treatment can reduce behavioral despair
44
what is bipolar disorder?
* bipolar disorder is characterized by periods of depression alternating with expansive mood, or mania
* the rate of cycling varies; rapid cycling consists of four or more cycles in one year, some may cycle several times in one day
45
what is the neural basis of bipolar disorder?
* neural basis not fully understood but appears to involve abnormalities in the hippocampus, amygdala
* lithium is a mood-stabilizing drug used to treat bipolar disorder that has widespread actions in the brain
* modulates 5-HT AND dopamine transmission
* lithium may enhance Brain Derived Neurotrophic Factor (BDNF) activity that may reduce cell death associated with BPD
