SCHIZOPHRENIA Flashcards
what characterizes anxiety disorders?
Characterised by the inappropriate expression of fear
e.g. Panic attacks (sudden, intense feeling of terror);
Generalised Anxiety Disorder (at least 6 months of persistent and excessive anxiety or worry); PTSD (re-experiencing of an extremely traumatic event; various phobias
what characterizes affective disorders?
Affect =mood. = Disordered emotions
e.g. Major depression (symptoms everyday for at least 2 weeks)
Bipolar Disorder (repeated episodes of mania and depression)
epidemiology of schizophrenia
________ risk in general population
Typically starts in ____________
Men (______) are at a slightly greater risk of developing SZ
Women (___________) are at a greater risk of bipolar disorder
Higher incidence associated with________ and ____________
In all cultures, similar incidence across continents
fill in the blanks
1/100 lifetime risk in general population
Typically starts in late adolescence or early adulthood
Men (15-25) are at a slightly greater risk of developing SZ
Women (20-30) are at a greater risk of bipolar disorder
Higher incidence associated with urbanicity and migration
In all cultures, similar incidence across continents
what are the positive symptoms of schizophrenia?
Delusions
Hallucinations
Disorganised speech
Grossly disorganized or catatonic behaviour
what are the Negative symptoms of schizophrenia?
Reduced expression of emotion
Poverty of speech
Difficulty in initiating goal-directed movements
Cognitive/Memory impairment
list the types of schizophrenia?
Paranoid schizophrenia
Disorganised schizophrenia
Catatonic schizophrenia
what characterizes Paranoid schizophrenia
delusions and hallucinations are present
thought disorder, disorganized behaviour, and mood flattening are absent
what characterizes disorganoized schizophrenia?
thought disorder and mood flattening are present
what characterizes Catatonic schizophrenia?
exhibits agitated, purposeless movement
what is the Aetiology (Causes) of schizophrenia?
Environmental factors
genetics
what are the Environmental factors that cause schizophrenia?
Social stress
Prenatal infection and famine
Obstetric and perinatal complications
Older paternal age
Cannabis use
how do genetics affect schizophrenia?
Pathophysiology of Schizophrenia
what are the core features of schizophrenia?
The core features of schizophrenia include deficits in cognitive processes mediated by the circuitry of the dorsolateral prefrontal cortex (DLPFC).
These deficits are associated with a range of molecular and morphological alterations in the DLPFC,
Could be a cause, consequence, or compensation in relation to other changes
what are the number of hypotheses based pathophysiology of schizophrenia?
Pharmacology
Genetics
Neurochemistry
which neurotransmitters are hypothetically involved in schizophrenia?
Dopamine hypothesis
Glutamate hypothesis
GABA hypothesis
in the dopamine hypothesis of schizophrenia
which brain structures are involved?
Substantia Nigra (SN)
Ventral tegmental area (VTA)
Tuberohypophyseal system
how is the substantia nigra involved in schizophrenia?
what does it do normally?
Projects to the striatum (Facilitates the initiation of voluntary movements (Parkinson’s Disease)
how is the Ventral tegmental area (VTA) involved in schizophrenia?
what does it do normally?
Innervates frontal cortex and limbic system
Called Mesocorticolimbic dopamine system
Involved in reward/motivation; psychiatric disorders
how is the Tuberohypophyseal system involved in schizophrenia?
what does it do normally?
Connects Arcuate & Paraventricular neurons to Hypothalamus and Pituitary
Dopamine release inhibits prolactin secretion
what is the Most widely considered neurochemical hypothesis of schizophrenia
The dopamine hypothesis of schizophrenia
The dopamine hypothesis of schizophrenia Postulates ___________________
Postulates that symptoms of schizophrenia may result from excess dopaminergic neurotransmission particularly in mesolimbic and striatal brain regions
list 5 evidence for The dopamine hypothesis of schizophrenia
Many antipsychotic drugs strongly block D2 receptors, especially in mesocorticolimbic system
Drugs that increase dopaminergic activity such as levodopa (precursor) ; amphetamine (releases dopamine); apomorphine (direct agonist) either aggravate schizophrenia or produce psychosis
D receptor number increased in post-mortem brains of schizophrenics
PET scans show increased D receptor density in schizophrenics
Successful treatment of schizophrenics changes the levels of homovanillic acid (a metabolite of dopamine)
list 3 evidence against The dopamine hypothesis of schizophrenia
Antipsychotic drugs only partially effective for most (ineffective for some) patients
NMDA receptor (glutamate receptor) antagonists (phencyclidine) more potent in inducing schizophrenic symptoms than dopamine agonists
Dopamine receptors. Which D receptors are involved?
what are the evidence for the The glutamatergic hypothesis of schizophrenia
NMDA receptor antagonists (phencyclidine; ketamine; MK-801)
potent activators of dopamine release
cause marked psychotic symptoms in healthy human volunteers and
exacerbation of symptoms in schizophrenic patients
Treatment of schizophrenia with D-Serine, glycine, and sarcosine:
modulate NMDA receptors
has therapeutic benefit, particularly with regard to negative symptoms
what is the evidence for the The glutamatergic hypothesis of schizophrenia
in reference to NMDA Receptor agonist
NMDA receptor antagonists (phencyclidine; ketamine; MK-801)
🡺 potent activators of dopamine release
🡺 cause marked psychotic symptoms in healthy human volunteers and
exacerbation of symptoms in schizophrenic patients
what is the evidence for the The glutamatergic hypothesis of schizophrenia
in reference to Treatment of schizophrenia with D-Serine, glycine, and sarcosine
Treatment of schizophrenia with D-Serine, glycine, and sarcosine:
🡺 modulate NMDA receptors 🡺 has therapeutic benefit, particularly with regard to negative symptoms
what is the glutamatergic hypothesis of schizophrenia?
Hypofunction of the NMDA receptor, possibly on critical GABAergic interneurons
Less inhibition onto Principal Glutamatergic cells 🡺 excessive activity of Glutamatergic cells
This activates Dopamine expressing cells
🡺 More Dopamine released
what is the evidence for The GABAergic hypothesis of schizophrenia
Inhibitory interneurons are essential for controlling the activity of the excitatory pyramidal cells
Deficiency in signalling through the TrkB neurotrophin receptor
leads to reduced GABA synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia
Death of a sub-population of these neurons
decreased GABA production
enhanced excitability of pyramidal neurons
Enhanced activation of DA neurons more DA release
R
how does “Deficiency in signalling through the TrkB neurotrophin receptor” provide evidence for The GABAergic hypothesis of schizophrenia
🡺 leads to reduced GABA synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia
how does “Death of a sub-population of these neurons” provide evidence for The GABAergic hypothesis of schizophrenia
🡺 decreased GABA production
🡺 enhanced excitability of pyramidal neurons
🡺 Enhanced activation of DA neurons 🡺 more DA release
what are the drug therapies used for schizophrenia?
Antipsychotic drugs
Dopamine
dopamine is one of the therapies for schizophrenia?
this principle takes advantage of major dopamine pathways in the CNS
Any drug affecting Dopamine activity has the potential to act in any/all of these pathways
🡺 Diverse adverse effects
describe the different dopamine pathways in the CNS?
Meso-cortical-limbic pathway: VTA to limbic and neocortex
Nigro-striatal pathway: Substantia Nigra to Striatum
Tuberoinfundibular system: Hypothalamus to Pituitary
Medullary-Periventricular pathways: Neurons in the motor nucleus of the vagus
Incertohypothalamic pathway: From Zona incerta to hypothalamus and amygdala.
all the dopamine pathways affect something in the brain
which pathway is mostly related to behaviour?
Meso-cortical-limbic pathway
all the dopamine pathways affect something in the brain
which pathway is involved in the cordination of voluntary movement?
Nigro-striatal pathway
all the dopamine pathways affect something in the brain
which pathway is involved in the inhibition of of prolactin release?
Tuberoinfundibular system
all the dopamine pathways affect something in the brain
which pathway might be involved in feeding behaviour but the real projections are unknown?
Medullary-Periventricular pathways
all the dopamine pathways affect something in the brain
which pathway is involved in fear conditioning?
Incertohypothalamic pathway
dopamine Generally exerts _____________
Generally exerts slow inhibitory action in CNS (depends on the specific D receptor)
The functions of dopaminergic pathways divide broadly into?
list 3
motor control (nigrostriatal system)
behavioural effects (mesolimbic and mesocortical systems)
endocrine control (tuberohypophyseal system).
state features of Dopamine Receptors
5 Dopamine receptors (D1 to 5)
Functionally 2 families: D1-like (D1 & D5) + D2-like (D2; D3;D4)
All are metabotropic (G-protein coupled
function of D1 receptor?
increases cAMP by Gs-coupled activation of adenylyl cyclase
expressed mainly in Putamen; Nucleus Accumbens; Olfactory tubercle
function of D1 receptor?
increases cAMP expressed in hippocampus and hypothamus
function of D5 receptor?
increases cAMP expressed in hippocampus and hypothamus
Therapeutic potency of Antipychotic drugs does not ________________
Therapeutic potency of Antipychotic drugs does not correlate with their affinity for binding the D1 receptor
function of D2 receptor?
decreases cAMP by Gi-coupled inhibition of adenylyl cyclase
inhibits calcium channels
opens potassium channels
expressed both pre- and post-synaptically on neurons caudate-putamen; nucleus accumbens; olfactory tubercle
Activation of D2 receptors 🡺 increased ___________ in rats. 🡺 Model for screening antipsychotic drugs
Activation of D2 receptors 🡺 increased motor activity and stereotypes behaviour in rats. 🡺 Model for screening antipsychotic drugs
Antipsychotic agents _________
Antipsychotic agents block D2
Binding affinity to dopamine receptor strongly correlated with ______ and _______effects
Binding affinity strongly correlated with antipsychotic potency and extrapyramidal effects
function of D3 receptor?
decreases cAMP frontal cortex; medulla; midbrain
function of D4 receptor?
decreases cAMP
Classification of antipsychotic drugs
what are they?
first-generation (‘typical’) antipsychotics
second-generation (‘atypical’) antipsychotics
list different examples of first-generation (‘typical’) antipsychotics
list 5
chlorpromazine, haloperidol, fluphenazine, flupenthixol, clopenthixol
list different examples of second-generation (‘atypical’) antipsychotics
clozapine, risperidone, sertindole, quetiapine, amisulpride, aripiprazole, zotepine
state differences between typical and atypical groups pf antipsychotics
receptor profile
incidence of extrapyramidal side effects (less in atypical group)
efficacy (specifically of clozapine) in ‘treatment-resistant’ group of patients
efficacy against negative symptoms
Antipsychotic drugs
First generation
what are the classes?
Phenothiazine class
Butyrophenone class
Phenothiazine class has 3 groups what are they?
group1: chlorpromazine; levomepromazine; promazine
group 2: pericyazine; pipotiazine
group 3: fluphenazine; prochlorperazine
what are the features of group 1 of phenothiazine class?
First to be developed#
Binding affinities for different receptors (D2;adrenergic > H1; mACh; 5-HT2)
🡺 Marketed under the name Largactil
Pronounced sedative effects which wear off with repeated administration
Moderate anti-muscarinic and extrapyramidal side effects
Also endocrine;hypotensive S/E
Relatively inexpensive
Low clinical potency (chlorpromazine)
what are the features of group 2 of phenothiazine class?
Moderate sedative effects
Severe anti-muscarinic but fewer extrapyramidal side effects
what are the features of group 2 of phenothiazine class?
Moderate sedative effects
Severe anti-muscarinic but fewer extrapyramidal side effects
what are the features of group 3 of phenothiazine class?
Fewer sedative and anti-muscarinic effects
Pronounced extrapyramidal side effects
what are the features of haloperidol in the Butyrophenone class
these are typically why it is worse than second generation antipsychotics?
Use is limited due to severe EPS
High D2 receptor affinity
Potent antipsychotic
More severe EPS though less anticholinergic; hypotensive S/E
which dopamine receptors are really important in dopamine drug therapy?
D2, D3, AND D4
which drug is under the butyrophenone class?
Haloperidol
what is the features of clozapine
this is a second generation
why is it better than first generation?
Greater affinity for 5HT2 receptors than D2
Potent antagonist at D4-receptors
Efficacy in treatment-resistant patients
Effective against negative and positive symptoms
No EPS
Risk of agranulocytosis (2%):regular blood counts required
Lowers seizure threshold 🡺
Weight gain
Clozapine licensed for use in treatment of Schiz only in patients unresponsive to or intolerant of conventional therapy 🡺 patient monitoring
Olanzapine is similar, without risk of agranulocytosis
what are the features of risperidone?
this is also a second generation
what advantage does it offer?
Greater affinity for 5HT2 receptors than D2
Broad efficacy and more potent than clozapine
Little or no EPS, ANS and Cardiac side effects at low dose
what are the features of Aripiprazole ?
this is also a second generation
what advantage does it offer?
Fairly new
Partial agonist at D2 receptor
Limited S/E effect profile (Maybe not known yet)
Long half life
what are the Advantages of 2nd generation agents over 1st
Little or no EPS
Treating positive and negative symptoms
Treatment resistant patients
what are 7 NICE guidelines on the use of atypical antipsychotics.
Considered when choosing “newly diagnosed” psychotic patients.
For management of an acute schizophrenic episode when discussion with the patient is not possible.
Considered for a patient experiencing unacceptable S/E of conventional antipsychotics
Considered for a patient in relapse whose symptoms were previously inadequately controlled.
No need to change to atypical antipsychotics if patient stabilised and no SE with 1st generation
Clozapine introduced if schizo inadequately controlled despite the sequential use of 2 or more antipsychotics (one of which should be 2nd generation) each for 6-8 weeks
If symptoms do not respond to optimised dose of clozapine, measure clozapine plasma levels before adding 2nd antipsychotic to augment clozapine.
what are the Non-psychiatric indications for antipsychotics
Anti-emetics
Sedatives
how do antipsychotics act like anti-emetics?
Act by blocking dopamine receptors centrally and peripherally in the stomach
E.g. Prochlorperazine used solely for this purpose
this happens mainly with older agents
how do antipsychotics act like sedatives?
Block Histamine 1 receptor e.g. Promethazine
what are the adverse effects of Antipsychotics
1 Extrapyramidal Reaction:
Acute dystonia (Parkinsonian movements)
Tardive dyskinesia
2 Seizures
what adverse effects of antipsycotics called extrapyramidal reaction?
(part of the Motor System involved in the co-ordination of movement)
what is the onset of Acute dystonia (Parkinsonian movements)?
is it reversible?
Early onset: (dopamine receptor blockade in Nigrostriatal pathway)
Often reversible.
what is the onset of Tardive dyskinesia ?
also what is it?
is it reversible?
(involuntary, repetitive movements)
Late onset: (dopamine receptor supersensitivity)
More serious. Very debilitating. Often irreversible. Most serious/debilitating S/E
what decreases the threshold for seizures as an adverse effects?
Mainly Chlorpromazine. Sometimes Clozepine
what are the Autonomic Nervous System Effects as Adverse Events of Antipsychotics
Anti-muscarinic effects:
Loss of accommodation; dry mouth; difficulty urinating; constipation
- Adreno-receptor blocking effects:
Othostatic hypotensions; impotence
what are the Metabolic and Endocrine Effects as Adverse Events of Antipsychotics
Weight gain (esp clozapine; olanzapine) (5HT2 blockade)
Hyperglycaemia secondary to insulin resistance
Hyperprolactinaemia (Dopamine normally blocks prolactin secretion)
what are the cardiac Effects as Adverse Events of Antipsychotics
Thioridazine (first generation): ventricular arrythmias; cardiac conduction block; sudden death
Ziprasidone (2nd generation): carries greatest risk of ECG effects (QT prolongation)
what are the toxic or allergic reactions as Adverse Events of Antipsychotics
Agranulocytosis: Clozapine; life threatening 🡺 regular blood tests
Jaundice; skin eruptions
what are the behavioural Effects as Adverse Events of Antipsychotics
Older agents are unpleasant to take
Pseudodepression
Toxic confusional state
