Term
| positive symptoms of schizophrenia |
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Definition
positive symptoms are development or appearance of abnormal functions; symptoms that didn't exist before the disease; development of an abnormal characteristic
delusions (false beliefs)
hallucinations (especially auditory)
disorganized thinking (for example, loose thought associations)
agitation
result of over activity in the mesolimbic system (associated with feelings of reward and desire) |
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Term
| negative symptoms of schizophrenia |
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Definition
negative symptoms are loss or reduction of normal functions
apathy (decreased goal directed behavior and planning; state of indifference)
affective flattening (decreased emotional response)
alogia (unable to carry on a conversation; poverty of speech)
anhedonia (lack of pleasure)
negative symptoms are thought to arise from dysfunction is the mesocortical system (involved in motivation and emotional response) |
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Term
| underlying causes of schizophrenia: genetic component |
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Definition
strong genetic component
1% general population, 10% for first degree relative, 50% identical twins
genes involved in neurotransmission identifired
genetic causes do not explain 100% of the schizophrenia incidence (environmental factors involved)
etiology involved multiple factors consisting of genetic components, acute events, and persistent environmental conditions |
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Term
| underlying causes of schizophrenia: associated environmental factors |
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Definition
second trimester viral infections
neonatal hypoxia
some studies associate low birth weight
urban environment
poverty also linked to schizophrenia
etiology involved multiple factors consisting of genetic components, acute events, and persistent environmental conditions |
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Term
| proposed neurotransmitter hypotheses that explain schizophrenia |
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Definition
neurotransmitters involved: dopamine, glutamate, serotonin
dopamine:
excess dopaminergic transmission in certain parts of the brain that cause the POSITIVE symptoms of schizophrenia
abnormal dopamine neurotransmission in the mesolimbic and mesocortical systems
the hallucinations, delusion, and psychosis of schizophrenia is the result of too much dopamine being active in the brain
glutamate:
people with schizophrenia have a deficiency or a defect in the glutamate receptors and the receptor cannot be properly stimulated by glutamate
serotonin:
too much serotonin in the brain
combination of all these neurotransmitters are probably involved in the disease |
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Term
| dopamine theory of schizophrenia evidence |
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Definition
1) effects on D2 receptor agonists or levodopa mimic symptoms of schizophrenia (hallucinations and delusions)
2) close correlation between D2 receptor affinity and clinical potency; anti-psychotic drugs (especially 1st generation/typical class) are D2 dopamine receptor antagonists; the affinity of typical anti-psychotics for D2 receptors correlates very well with the clinical potency
3) brain imaging studies show greater dopamine receptors in patients with schizophrenia |
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Term
| correlation between D2 affinity and clinical potency |
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Definition
[image]
therapeutic potency of anti-psychotic drugs and their affinity for binding to D1 (top) or D2 (bottom)
clinical potency is on the horizontal axes, it decreases to the right
D1 receptor plot: there is no correlation; the y-axis is the binding rate of a D1 specific ligand in the presence of antipsychotic drug
D2 receptor plot: there is a very good correlation; drugs in the lower-left corner have high affinity and high clinical potency; drugs in the upper-right corner have low affinity and low clinical potency |
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Term
| dopamine pathways in the brain |
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Definition
SITE OF THERAPEUTIC ACTIONS:
mesolimbic - positive symptoms; this pathway is involved in memory, arousal, motivational behavior, stimulus processing; it is thought that over activity (excessive dopaminergic neurotransmission) of this pathway is responsible for the positive symptoms of schizophrenia
mesocortical - negative symptoms; thought to play a role in attention, planning, social interaction, and communication; this pathway is thought to have low dopaminergic activity in schizophrenia (negative symptoms)
cause of ADRs:
nigrostriatal - extrapyramidal side effects; regulates movement; blockage of dopamine receptors in this pathway mimic the symptoms of PD
tuberoinfundibular - prolactin release; neurons in the hypothalamus that release dopamine onto the pituitary gland are tonically active and inhibit prolactin secretion
area postrema - vomiting; contains a high density of dopamine receptors, stimulation of these receptors activates the vomiting centers of the brain |
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Term
| origin and axon projections of the dopamine pathways in the brain |
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Definition
[image]
mesolimbic: neurons originate in the ventral tegmental area and innervate the areas of the limbic system (involved in memory, arousal, motivational behavior, stimulus processing)
mesocortical: originates in the ventral tegmental area and projects axons to the prefrontal cortex; plays a role in attention, planning, social interactions, and communication
nigrostriatal: dopaminergic neurons originate in the substantia nigra and innervate the striatum
tuberoinfundibular: dopamine containing neurons originate in the hypothalamus and release DA which binds to receptors in the anterior pituitary gland
area postrema: chemoreceptor trigger zone is a sensor of noxious substances in the blood located on the floor of the fourth ventricle |
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Term
| glutamate hypothesis of schizophrenia evidence |
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Definition
this hypothesis states that schizophrenia is caused by deficiency of glutamate transmission in the brain
1) NMDA receptor antagonists (phencyclidine and ketamine) can produce psychotic symptoms such as hallucinations and disorganized thoughts
2) decreased glutamate and glutamate receptors reported in post-mortem brains
3) mice that are genetically engineered to have low glutamate receptors in the brain have signs similar to schizophrenia patients and these animals respond to anti-psychotic drugs |
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Term
| serotonin hypothesis of schizophrenia evidence |
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Definition
this hypothesis says that serotonin dysfunction may be an underlying factor in the cause of schizophrenia symptoms
1) serotonin receptor agonists (LSD) can cause symptoms that mimic schizophrenia
2) many effective anti-psychotics have 5HT-2A receptor antagonist activity |
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Term
| first generation (typical) anti-psychotics |
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Definition
chlorpromazine
fluphenazine
haloperidol
flupenthixol
clopenthixol |
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Term
| second generation (atypical) anti-psychotics |
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Definition
clozapine
quetiapine
zotepine
asenapine
risperidone
iloperidone
sertindole
amisulpride
aripiprazole |
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Term
| the classification of anti-psychotics as either a first generation (typical) or second generation (atypical) is based on differences in what 3 properties? |
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Definition
1) receptor binding profile:
anti-psychotic drugs are D2 and 5HT2 receptor antagonists
typical anti-psychotic drugs are more selective for D2 compared to 5HT2 receptors
atypical drugs are more selective for 5HT2 receptors compared to D2 receptors
2) incidence of extrapyramidal side effects (EPS):
incidence of EPS is less with the atypical drugs
3) efficacy against negative symptoms:
atypical class of drugs are more effective in treating negative symptoms of schizophrenia (attributed to greater 5HT-2A antagonism) |
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Term
| anti-psychotic drugs are antagonists of several receptors including: |
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Definition
dopamine
serotonin 5HT-2A
alpha-adrenergic
histamine
muscarinic |
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Term
| receptor antagonism of alpha1-adrenergic receptors causes what therapeutic and adverse effects of schizophrenia? |
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Definition
therapeutic effects:
none
adverse effects:
antagonism causes vasodilation and hypotension with reflex tachycardia
dizziness, orthostatic hypotension |
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Term
| receptor antagonism of dopamine D2 receptors causes what therapeutic and adverse effects of schizophrenia? |
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Definition
therapeutic effects:
alleviation of positive symptoms of schizophrenia
adverse effects:
extrapyramidal effects - akathisia (inner restlessness), dystonia, and pseudoparkinsonism)
the extrapyramidal side effects are result of D2 antagonism in the basal ganglia (D2 receptor antagonism causes activation of the indirect pathway)
elevated serum prolactin levels |
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Term
| receptor antagonism of dopamine D4 receptors causes what therapeutic and adverse effects of schizophrenia? |
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Definition
therapeutic effects:
alleviation of negative symptoms of schizophrenia and decrease in the incidence of extrapyramidal side effects |
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Term
| receptor antagonism of histamine H1 receptors causes what therapeutic and adverse effects of schizophrenia? |
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Definition
therapeutic effects:
none
adverse effects:
drowsiness (RAS), increased appetite and weight
diphenhydramine causes drowsiness (crosses BBB); drowsiness probably through receptor antagonism on the reticular activating system (RAS), the brain stem area controlling arousal and consciousness |
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Term
| receptor antagonism of muscarinic receptors cause what therapeutic and adverse effects of schizophrenia? |
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Definition
therapeutic effects:
none
adverse effects:
blurred vision, constipation, dry mouth, and urinary retention
adverse effects result from PARASYMPATHETIC NERVOUS SYSTEM INHIBITION (unbalanced sympathetic activity)
may alleviate pseudoparkinsonism symptoms |
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Term
| receptor antagonism of serotonin 5HT-2A receptors cause what therapeutic and adverse effects of schizophrenia? |
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Definition
therapeutic effects:
alleviation of negative symptoms of schizophrenia
2A receptors located in the cerebral cortex
adverse effects:
anxiety, insomnia, weight gain
could be related to the observation that SSRIs are effective treatment of social anxiety and panic disorder |
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Term
| therapeutic mechanisms of anti-psychotic drugs on the positive and negative symptoms of schizophrenia |
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Definition
mesocortical pathway: low dopamine activity causes negative symptoms
mesolimbic pathway: high dopamine activity causes positive symptoms
[image]
the negative symptoms of schizophrenia are postulated to arise from under activity of the MESOCORTICAL PATHWAY
inhibition of presynaptic 5HT2 receptors by atypical anti-psychotic drugs cause more dopamine release thus restoring the activity in the mesocortical path and alleviated the negative symptoms of schizophrenia
the typical antipsychotic drugs have insufficient affinity for 5HT2 receptors therefore are not as effective for treating the negative symptoms
the positive symptoms of schizophrenia are thought to be caused from excessive dopaminergic transmission in the MESOLIMBIC PATHWAY
blockage of postsynaptic D2 receptors (in nucleus accumbens and likely other areas in the limbic system) in this pathway alleviates the positive symptoms of schizophrenia (both typical and atypical drugs have sufficient D2 receptor antagonist activity) |
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Term
| amount of dopaminergic neurons in the nigrostriatal and mesolimbic pathways after weeks of treatment with haloperidol |
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Definition
[image]
receptor binding happens quickly, yet benefits and anti-psychotics require weeks
secondary, longer term effects likely to be important
D2 receptor antagonism occurs soon after drug administration, but the alleviation of schizophrenia symptoms requires weeks to occur
decreased number of mesolimbic dopaminergic neurons correlates with the alleviation of symptoms
there is also reduction of dopaminergic neurons in the nigrostriatal system resulting in extrapyramidal symptoms (pseudoparkinsonism) |
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Term
| ADRs of anti-psychotics: endocrine effects |
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Definition
inhibition in the tuberoinfundibular pathway (blockage of D2 receptors) causes increase in prolactin secretion
increased prolactin -> breast swelling, pain, lactation
in normal function of the tuberoinfundibular pathway, secretion of prolactin from the pituitary gland is inhibited by tonic (basal) release of dopamine from the hypothalamus
blockage of D2 receptors releases this inhibition and as a result, prolactin secretion is increased from the anterior pituitary
this ADR is very low or non-existent with the second generation antipsychotics (related to D2 affinity) |
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Term
| ADRs of anti-psychotics: extrapyramidal symptoms (EPS) |
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Definition
anti-psychotic drugs inhibit the nigrostriatal pathway (block D2)
resemble Parkinson's disease symptoms
acute dystonias (involuntary movements, muscle spasms, protruding tongue, fixed upward gaze, torticollis)
tardive dyskinesia (after months or years; involuntary movements of face, tongue, and sometimes trunk and limbs)
EPS LESS WITH SECOND GENERATION/ATYPICAL DRUGS is attributed to lower D2 receptor affinity
EPS may be counteracted by anti-cholinergic activity (Parkinson's disease treatment includes muscarinic receptor antagonists) |
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Term
| ADRs of anti-psychotics: muscarinic antagonism |
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Definition
blurring of vision, dry mouth, constipation, urinary retention
associated with exacerbation of certain forms of glaucoma
slows detrusor muscle of bladder
decreased peristalsis
lack of lens accommodation |
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Term
| anti-psychotics can inhibit both branches of the autonomic nervous system: |
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Definition
muscarinic antagonism and alpha-adrenergic antagonism
there is a balance between the parasympathetic nervous system and the sympathetic nervous system
some organ systems have more baseline input from one branch or the other (organs that have predominant parasympathetic tone will be more affected from the anti-muscarinic action) |
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Term
| ADRs of anti-psychotics: alpha-adrenergic antagonism |
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Definition
orthostatic hypotension - common; sudden drop in blood pressure when moving from sitting to standing position)
thought to be caused from alpha receptor antagonism (blocks blood vessel constriction)
tachycardia results from response to blood pressure drop |
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Term
| ADRs of anti-psychotic drugs: neuroleptic malignant syndrome |
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Definition
begins with muscle rigidity and progresses to hyperthermia and autonomic nervous system instability
autonomic nervous system instability (blood pressure instability, heart and respiratory rates may increase, urinary and fecal incontinence)
hyperthermia may result from dysfunction of thermoregulatory mechanism (in the hypothalamus) and muscle rigidity
increased serum creatine kinase, LDH, ALT and AST enzymes (the enzymes are released from muscle cells after muscle damage)
greater risk associated with first generation antipsychotics |
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Term
| ADRs of anti-psychotics: increased seizure risk |
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Definition
mechanism not known
occurs especially with seizure history, abnormal EEG, or head trauma history |
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Term
| ADRs of anti-psychotics: electrocardiogram changes |
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Definition
prolonged Q-T interval (thioridazine)
abnormal ECG reading is attributed to muscarinic receptor antagonism and Na channel blockage
prolongation of QT interval (beginning of ventricular depolarization to end of ventricular repolarization) is clinically important
slowed conduction through the heart |
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Term
| ADRs of anti-psychotics: protect against nausea and vomiting |
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Definition
| protective against vomiting as a result of D2 receptor antagonism in chemoreceptor trigger zone |
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Term
| ADRs of anti-psychotics: sedation |
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Definition
| sedation is common and is attributed to histamine (H1) receptor antagonism in reticular activating system (RAS) |
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Term
| ADRs of anti-psychotics: weight gain |
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Definition
mechanism uncertain
H1 and 5HT2 receptor antagonism? |
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Term
| ADRs of anti-psychotics: hypersensitivity/idiosyncratic reactions |
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Definition
rare but serious agranulocytosis
leucopenia common with clozapine (~1%)
jaundice with some phenothiazines
skin UV sensitvity |
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Term
| generalization of pharmacokinetic properties of anti-psychotics |
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Definition
variable oral absorption of phenothiazines
most very lipid soluble
high protein binding
most undergo significant first pass metabolism
many hepatic metabolites
plasma half life: terminal >>> steady state
terminal half life - no more drug coming into the body, it is only being eliminated
after these drugs are stopped, there is a reservoir in the CNS and fatty tissue (very lipophilic), the drugs is till being released from the tissue
individual variation in the relation between dose and plasma concentration; the unpredictable relationship between dose and plasma concentration is common among anti-psychotics especially with phenothiazines
[image] |
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Term
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Definition
used to stabilize mood in bipolar disorder
reduces both manic and depressive symptoms
LOW THERAPEUTIC INDEX
similar to Na and K metabolism
important EXCEPTION: Li is not a substrate for Na/K/ATPase, thus no concentration gradient across cell membrane is formed
no plasma protein binding
renal tubule reabsorption
eliminated in urine |
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Term
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Definition
therapeutic mechanism uncertain
proposed to involve inhibition of intracellular IP3 and DAG formation
action of lithium on phosphatidylinositol signaling:
[image]
PIP2 converted to IP3 and DAG
IP3 increases Ca
DAG activates PKC
lithium decreases IP3 and DAG production by inhibiting the recycling of inositol substrates causing depletion of the second-messenger source PIP2
uncertain how the above mechanism relates to therapeutic effect of lithium |
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Term
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Definition
POLYURIA FROM ADH INHIBITION - AD
H stimulates adenylyl cyclase causing rise in cAMP; lithium inhibits the rise in cAMP levels
tremor
nausea
vomiting
hypothyroidism
convulsions and death at plasma levels 3-5 mmol/L; low therapeutic index |
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