pharm chapter 13 [4-20

pharm chapter 13
Biochemistry and Cell Biology of Dopaminergic Neurotransmission
 Dopamine (DA) – catecholamine family of neurotransmitters (w/epi and norepi (NE))
o Basic structure consists of catechol moiety connected to amine group by ethyl bridge
o Single source-divergent organization (arise from small clusters fo catecholamine neurons that give rise
to widely divergent projections
o Modulate function of point-to-point neurotransmission and affect complex processes such as mood,
attentiveness, and emotion
 Neutral amino acid tyrosine is precursor for all catecholamines; majority of tyrosine obtained from diet and
small proportion synthesized in liver from phenylalanine
o Tyrosine converted to L-DOPA by oxidation of 3 position on benzene ring (catalyzed by tyrosine
hydroxylase (TH), which requires Fe2+ and cofactor tetrahydrobiopterin); rate limiting step of all cats
o L-DOPA converted to DA by aromatic amino acid decarboxylase (AADC), which cleaves carboxyl group
from α-carbon of ethylamine side chain, liberating CO2
 Requires pyridoxal phosphate as cofactor
 Also involved in synthesis of non-catecholamine neurotransmitters (like serotonin)
 Expressied by dopaminergic neurons, but present in non-dopaminergic cells and glia in brain
 Expressed throughout body in almost all cell types
o Cells that secrete NE – DA converted to NE by dopamine β-hydroxylase
o NE can be converted to EPI by phenylethanolamine N-methyltransferase
Dopamine Storage, Release, Reuptake, and Inactivation
 DA synthesized from tyrosine in cytoplasm of neuron and then transported into secretory vesicles for storage
and release
o Transporting DA into synaptic vesicles requires proton ATPase (concentrates protons in vesicle, creating
electrochemical gradient characterized by low intravesicular pH and electropositive vesicle interior) and
vesicular monoamine transporter (VMAT; proton antiporter, which allows protons to move down
gradient out of vesicle and transports DA into vesicle against concentration gradient)
o Upon nerve cell stimulation, DA storage vesicles fuse w/PM in Ca2+-dependent manner, releasing DA
into synaptic cleft
 Most DA transported back into presynaptic cell by dopamine transporter (DAT)
o Involves transport of DA against concentration gradient; coupled w/Na+ down concentration gradient
into cell
 Na+ gradient maintained by Na+/K+-ATPase pump
o DA either recycled into vesicles for further use (by VMAT) or degraded by monoamine oxidase (MAO) or
catechol-O-methyltransferase (COMT)
 MAO key enzyme that functions to terminate action of catecholamines in brain and periphery
 MAO-A expressed in brain and periphery; can degrade dopamine; inhibition retards breakdown
of all central and peripheral catecholamines and may lead to life-threatening toxicity when
combined w/catecholamine releasers (such as indirect-acting sympathomimetic tyramine found
in aged wines and cheeses)
 MAO-B concentrated in CNS; under normal conditions, responsible for catabolizing most CNS
dopamine; selective inhibition used to augment function of CNS dopamine
o Synaptic DA that isn’t taken up into presynaptic cell can either diffuse out of synaptic cleft or be
degraded by action of COMT, which is expressed in brain, liver, kidney, and heart
 COMT inactivates catecholamines by adding methyl group to hydroxyl group at 3 position of
benzene ring
 Expressed primarily by neurons in CNS
o Sequential action of COMT and MAO degrades DA to stable metabolite homovanillic acid (HVA), which is
excreted in urine
Dopamine Receptors
 G protein-coupled family of receptor proteins
 Activation of D1 receptors leads to increased cAMP; class contains dopamine receptors D1 and D5
 Activation of D2 receptors inhibits cAMP generation; class contains D2, D3, and D4 receptors
2 forms of D2: D2S (short) and D2L (long), which represent alternate splice variants of same gene;
difference lies in 3rd cytoplasmic loop, which affects G protein interaction, not dopamine binding
 D1 and D2 receptors expressed at high levels in striatum (caudate and putamen), where they play role in motor
control by basal ganglia; also in nucleus accumbens and olfactory tubercle
 D2 receptors expressed at high levels on anterior pituitary lactotrophs (regulate prolactin secretion)
o Play role in schizophrenia because many antipsychotic medications have high affinity for these
 High levels of D3 receptors expressed in limbic system, including nucleus accumbens and olfactory tubercle
 D4 receptors localized to frontal cortex, diencephalon, and brainstem
 D5 receptors distributed sparsely and expressed at low levels, mainly in hippocampus, olfactory tubercle, and
 Most dopamine receptors expressed on surface of postsynaptic neurons at dopaminergic synapses; density of
receptors tightly controlled through regulated insertion and removal of dopamine receptor proteins from
postsynaptic membrane
 DA receptors expressed on presynaptic terminals of dopaminergic neurons
o Most of these D2 class
o Serve as autoreceptors (sense dopamine overflow from synapse and reduce dopaminergic tone by
decreasing DA synthesis in presynaptic neuron and reducing rate of neuronal firing and DA release
 Inhibition of DA synthesis occurs through cAMP-dependent down-regulation of TH activity
 Inhibitory effect on DA release and neuronal firing due in part to increased K+ channel opening
resulting in larger current that hyperpolarizes neuron
 Decreased Ca2+ channel opening results in decreased levels of intracellular Ca2+; because Ca2+
required for synaptic vesicle trafficking to and fusion w/presynaptic membrane, decreases in
intracellular Ca2+ results in decreased dopamine release
Central Dopamine Pathways
 Largest DA tract in brain is nigrostriatal system (contains 80% of brain’s DA)
o Tract projects rostrally from cell bodies in pars compacta and substantia nigra to terminals that richly
innervate caudate and putamen (collectively called striatum)
o Dopaminergic neurons of nigrostriatal system involved in stimulation of purposeful movement;
degeneration results in abnormalities of movements characteristic of Parkinson’s disease
 Ventral tegmental area (VTA) – medial to substantia nigra; dopaminergic cell bodies in midbrain
o Widely divergent projections that innervate many forebrain areas (cerebral cortex, nucleus accumbens,
and other limbic structures) that play role in motivation, goal-directed thinking, regulation of affect, and
positive reinforcement
 Derangement may be involved in development of schizophrenia
 Blocking of dopaminergic neurotransmission can lead to remission in psychotic symptoms
 Tubero-infundibular pathway – DA-containing cell bodies in arcuate and paraventricular nuclei of hypothalamus
projecting axons to median eminence of hypothalamus
o Dopamine released by neurons into portal circulation connecting median eminence w/anterior pituitary
and tonically inhibits release of prolactin by pituitary lactotrophs
 Area postrema – floor of 4th ventricle; contains modest number of intrinsic dopamine neurons but high density
of dopamine receptors (D2 class)
o One of circumventricular organs (fenestrated blood vessels outside BBB) that function as blood
o Stimulation of DA receptors here activates vomiting centers of brain and is one of causes of emesis
o Drugs that block dopamine D2 receptors used to treat nausea and vomiting
Physiology of Nigrostriatal Pathways
 Basal ganglia have crucial role in regulation of purposeful movement and are site of pathology in Parkinson’s
disease; don’t connect directly to spinal motor neurons, so no direct control of individual movements of muscles
o Function by assisting in learning coordinated patterns of movement and facilitating execution of learned
motor patterns
o Dopamine signals when desired movements executed successfully and drives learning process
 Basal ganglia form reentrant loop by receiving input from cerebral cortex, processing info in context of
dopaminergic input from substantia nigra, and sending info back to cortex by way of thalamus
Internal circuitry of basal ganglia consists of striatum (caudate and putamen; primary input nucleus of
system), globus pallidus pars interna, and substantia nigra pars reticulata (output nuclei)
 Pars interna and pars reticulata connected through subthalamic nucleus and globus pallidus pars
 Much of info processing performed by basal ganglia occurs in striatum; cortical inputs excitatory and use
glutamate as transmitter
o Target of dopaminergic nigrostriatal pathway
o Majority of neurons are medium spiny neurons (studded w/spines that receive input from corticostriatal
axons; release inhibitory GABA and send projections to 2 downstream targets, forming direct pathway
and indirect pathways)
o Contains interneurons that participate in intercommunication between direct and indirect pathways
o Balance of activity between direct and indirect pathways regulates movement
 Direct pathway – formed by striatal neurons expressing primarily D1 receptors; projects directly
to output of basal ganglia (internal segment of globus pallidus), which tonically inhibits
thalamus, which sends excitatory projections to cortex that initiate movement
 Activation of direct pathway stimulates movement by disinhibiting thalamus
 Indirect pathway – formed by striatal neurons expressing predominantly D2 receptors; projects
to external segment of globus pallidus, which inhibits neurons in subthalamic nucleus
 Neurons in subthalamic nucleus excitatory glutamatergic neurons that project to
internal segment of globus pallidus
 Activation of indirect pathway disinhibits neurons of subthalamic nucleus, which
stimulates neurons in internal segment of globus pallidus to inhibit thalamus
 Activation of indirect pathway inhibits movement
o Differential expression of D1 and D2 receptors in both pathways leads to differing effects of
dopaminergic stimulation
 Increased levels of dopamine activates D1-expressing neurons of direct pathway while inhibiting
D2-expressing neurons of indirect pathway; both effects promote movement
 Parkinson’s disease – state of dopamine deficiency; directly pathway shows reduced activity,
while indirect pathway overactive, leading to reduced movement
Parkinson’s Pathophysiology
 In Parkinson’s disease, there is selective loss of dopaminergic neurons in substantia nigra pars compacta
o 70% of neurons destroyed at time symptoms first appear; 95% missing by autopsy
o Destruction of neurons results in core motor features of disease: bradykinesia, rigidity, impaired
postural balance, and characteristic tremor when limbs at rest
 Contaminant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in batch of meperidine caused Parkinson’s in
young, otherwise healthy people
o MPTP forms as impurity in synthesis of meperidine when manufacture carried out for too long and at
too high a temperature
o MPTP oxidized in brain to MPP+, which is selectively toxic to neurons in substantia nigra
 May be environmental factors that have effect on development of Parkinson’s (exposure to certain pesticides)
 Genetic factors that contribute to Parkinson’s disease – mutations in or overexpression of protein α-synuclein,
which leads to autosomal dominant forms of Parkinson’s
o α-synuclein involved in formation of neurotransmitter vesicles and release of dopamine in brain
 Etiology of Parkinson’s likely multifactorial (genetic and environmental)
Parkinson’s Pharmacologic Classes and Agents
 All currently available treatments of Parkinson’s are symptomatic
 Most pharmacologic interventions currently used aimed at restoring DA levels in brain
 Levodopa – L-DOPA; DA itself not suitable because it can’t cross BBB, but L-DOPA readily transported across BBB
by neutral amino acid transporter; once in CNS, levodopa converted to dopamine by AADC
o Because it must compete w/other neutral amino acids, its availability in CNS may be compromised by
recent protein meals
o Orally administered levodopa readily converted into DA by AADC in GI tract, which diminishes amount of
L-DOPA that reaches BBB for transport into CNS and increases peripheral adverse effects that result
from generation of dopamine in peripheral circulation (nausea due to binding of dopamine to receptors
in area postrema)
o When administered alone, only 1-3% of L-DOPA reaches CNS unchanged
o Almost always administered in combo w/carbidopa (inhibitor of AADC), which effectively prevents
conversion of L-DOPA to DA in periphery
 Because carbidopa can’t cross BBB, it doesn’t interfere w/conversion of L-DOPA to DA in CNS
 Increases fraction of orally administered L-DOPA available in CNS to 10%, reducing incidence of
peripheral adverse effects
o Symptomatic improvement w/levodopa/carbidopa combo, especially during early phase of disease
 Improvement in symptoms following initiation of levodopa therapy diagnostic of Parkinson’s
o Over time, effectiveness of levodopa declines; continued use results in tolerance and sensitization to the
medicine, manifested as drastic narrowing of therapeutic window
 Develop fluctuations in motor function that include periods of freezing and increased rigidity
(off periods) w/periods of normal or dyskinetic movement (on periods)
 On periods occur shortly after administration of levodopa/carbidopa when large bolus of
dopamine delivered to striatum
 Overcome initially by taking smaller doses of medication (increases likelihood of off periods)
 Off periods occur as plasma levels of levodopa decline and can be compensated for by
increasing either dose or frequency of L-DOPA
 As disease progresses, symptoms increasingly difficult to manage
o Most profound adverse effect is dyskinesias (uncontrollable rhythmic movements of head, trunk, and
limbs); appear in at least half patients within 5 years of starting drug and worsen as disease progresses
 Usually linked to levodopa dosing, mostly occurring at times of max L-DOPA plasma levels
 Managed initially by using smaller doses of levodopa more frequently
o Continued destruction of dopaminergic neurons as disease progresses results in striatum’s increasing
inability to store dopamine effectively and reduces ability of dopamine terminals to buffer synaptic
concentrations of dopamine
o Chronic therapy w/levodopa causes adaptations in postsynaptic neurons in striatum
 Dopamine concentrations in striatal synapses normally tightly regulated; large fluctionations in
dopamine concentration produced by intermittent oral levodopa administration induce changes
in cell surface expression of dopamine receptors and in postreceptor signaling events
 Alters cell’s sensitivity to synaptic dopamine levels, further accentuating responses
associated w/high (on period, dyskineasia) and low (off period, akinesia) transmitter
o Remains most effective therapy for Parkinson’s disease and should be initiated soon as other therapies
unable to control Parkinsonian symptoms effectively
 Further delays in levodopa therapy associated w/reduced rates of symptom control and
increased mortality
Dopamine receptor agonists
o Ergot derivatives bromocriptine (D2 agonist) and pergolide (D1 & D2) used to be used, but cause fibrosis
of cardiac valves
o Nonergot agonists – pramipexole (D3>D2) and ropinirole (D3>D2)
o Nonpeptide molecules that don’t compete w/levodopa or other amino acids for transport across BBB
o Don’t require enzymatic conversion by AADC, so remain effective late in disease course
o Half-lives longer than levodopa, which allows for less frequent dosing and more uniform response
o Major limitation is tendency to induce nausea, peripheral edema, and hypotension
o All may produce variety of adverse cognitive effects (excessive sedation, vivid dreams, hallucinations),
particularly in elderly patients
o May trigger symptoms of dopamine dysregulation syndrome (patients exhibit impaired impulse control)
 Pathological gambling, overspending, compulsive eating, and hypersexuality
o Use of dopamine receptor agonists as initial treatment for Parkinson’s disease delays onset of off
periods and dyskinesias, but increased rate of adverse effects compared to initial treatment w/levodopa
Inhibitors of dopamine metabolism
Inhibitors of MAO-B (isoform that predominates in striatum) and COMT used as adjuvants to levodopa
in clinical practice
 Selegiline – MAOI that is selective for MAO-B in low doses; doesn’t interfere w/peripheral
metabolism of monoamines by MAO-A and avoids toxic effects of dietary tyramine and other
sympathomimetic amines associated w/nonselective MAO blockade
 Forms amphetamine as metabolite; causes sleeplessness and confusion, esp. in elderly
 Improves motor function in Parkinson’s disease when used alone; can augment
effectiveness of levodopa
 Rasagiline – MAO-B inhibitor; doesn’t form toxic metabolites; improves motor function in
Parkinson’s disease when used alone; can augment effectiveness of levodopa
o Tolcapone and entacapone inhibit COMT and thus degradation of levodopa as well as DA
 Tolcapone highly lipid-soluble agent that can cross BBB and inhibit central as well as peripheral
 Entacapone distributes only to periphery
 Both decrease peripheral metabolism of levodopa, making it more available for CNS; reduce off
periods associated w/decreasing levodopa levels
 Amantadine, trihexyphenidyl, and benztropine – nondopaminergic pharmacology
o Amantadine – developed and marketed primarily as antiviral that reduces length and severity of
influenza A infections
 Used to treat leavodopa-induced dyskinesias that develop late in course of disease
 Mechanism involves blockade of excitatory NMDA receptors
o Trihexyphenidyla dn benzotropine – muscarinic receptor antagonists that reduce cholinergic tone in CNS
 Reduce tremor more than bradykinesia; more effective in treating patinets for whom tremor is
major clinical manifestation of Parkinson’s disease
 Act by modifying actions of striatal cholinergic interneurons, which regulate interactions of
direct and indirect pathway neurons
 Cause range of anticholinergic adverse effects (dry mouth, urinary retention, and impairment of
memory and cognition)
Treatment of Patients with Parkinson’s Disease
 No lab tests that confirm diagnosis; based on history and physical w/lab studies that exclude other possibilities
 In early disease, emphasize nonpharmacologic approach to treatment that emphasizes exercise and lifestyle
 In patients w/mild symptoms, use MAO-B inhibitors, amantadine, or anticholinergic meds
 w/more advanced symptoms, dopaminergic therapy indicated
 Be vigilant for development of cognitive symptoms and adverse effects which may require modification of Tx
Pathophysiology of Schizophrenia
 Thought disorder characterized by one or more episodes of psychosis (impairment in reality testing)
 May manifest disorders of perception, thinking, speech, emotion, and/or physical activity
 Positive symptoms – development of abnormal functions (delusions, hallucinations, disorganized speech, and
catatonic behavior)
 Negative symptoms – reduction or loss of normal functions; includes affective flattening (decrease in range or
intensity of emotional expression), alogia (decrease in fluency of speech), and avolition (decrease in initiation of
goal-directed behavior)
 Multifactorial etiology (genetic and environmental components)
 Dopamine hypothesis – illness caused by increased and dysregulated levels of DA neurotransmission in brain
o Treatment w/DA receptor antagonists (D2 antagonists) relieve number of symptoms of schizophrenia in
many, but not all, patients w/disease
o Some patients taking drugs that increase DA levels or that activate DA receptors in CNS (amphetamines,
cocaine, and apomorphine) develop schizophrenia-like state that subsides when dose of drug lowered
o Hallucinations are known adverse effect of levodopa therapy for Parkinson’s disease
o Decreased DA metabolite levels seen w/clinical improvement in some schizophrenic systems
Mesolimbic system – DA tract that originates in ventral tegmental area and projects to nucleus accumbens in
ventral striatum, parts of amygdala and hippocampus, and other components of limbic system
o Involved in development of emotions and memory
o Hyperactivity could be responsible for positive symptoms of schizophrenia
 Imbalance in glutamatergic neurotransmission plays important role in schizophrenia
o PCP (antagonist at NMDA receptors) causes symptoms similar to those of schizophrenia; syndrome seen
in patients taking PCP chronically (psychotic symptoms, visual and auditory hallucinations, disorganized
throught, blunted affect, withdrawal, psychomotor retardation, and amotivational state) has
components of both positive and negative symptoms of schizophrenia
o DA neurons and excitatory glutamatergic neurons often form reciprocal synaptic connections (could
account for efficacy of DA receptor antagonists in schizophrenia)
o No useful therapies that act at glutamate receptors
o Glutamate is primary excitatory transmitter in brain
Pharmacologic Classes and Agents
 Medications can lead to remission of psychosis and allow patient to integrate into society; patients only rarely
return completely to premorbid state
 Neuroleptics – emphasizes drugs neurological actions commonly manifested as adverse effects of treatment
o Adverse effects are extrapyramidal effects; result from DA receptor blockade in basal ganglia and
include Parkinsonian symptoms of slowness, stiffness, and tremor
 Antipsychotics – drugs that abrogate psychosis and alleviate disordered thinking in schizophrenics
o Typical antipsychotics – older drugs w/prominent actions at D2 receptor; therapeutic efficacy and
extrapyramidal adverse effects correlate directly w/affinity for D2 receptors
 Block D2 receptors in all of CNS dopaminergic pathways; antagonizes mesolimbic (possibly
mesocortical) D2 receptors
 Less effective at controlling negative symptoms of schizophrenia
 Many adverse effects mediated by binding to D2 receptors in basal ganglia (nigrostriatal
pathway) and pituitary gland
 Phenothiazine and butyrophenone structures – both have similar clinical efficacy at standard
doses; aliphatic phenothiazines (such as chlorpromazine) less potent antagonists at D2 receptors
than are butyrophenones (such as haloperidol), thioxanthenes, or phenothiazines functionalized
w/piperazine derivative (such as fluphenazine)
 Adverse effects divided into 2 categories: those caused by antagonist action at D2 receptors
outside mesolimbic and mesocortical systems (on-target effects) and those caused by
nonspecific antagonist action at other receptor types (off-target effects)
 Antagonism of D2 receptors can disinhibit indirect pathway and induce Parkinsonian symptoms
 Can sometimes be treated w/non-dopaminergic therapies for Parkinson’s disease
 Dopaminergic drugs could cause relapse of schizophrenic symptoms
 Neuroleptic malignant syndrome (NMS) – rare syndrome characterized by catatonia, stupor,
fever, and autonomic instability; myoglobinemia and death occur in about 10% of cases
 Most commonly associated w/typical antipsychotic drugs that have high affinity for D2
receptors (such as haloperidol)
 Can be seen in patients w/Parkinson’s disease who abruptly discontinue dopaminergic
 Symptoms arise in part from actions of antipsychotics on dopaminergic systems in
hypothalamus (essential for body’s ability to control temperature)
 Tardive dyskinesia – abnormal movements observed most frequently after prolonged treatment
w/drugs that have high affinity for D2 receptor (such as haloperidol)
 Occasionally seen in patients after short-term treatment or single dose of D2 antagonist
 Characterized by repetitive, involuntary, stereotyped movements of facial musculature,
arms, and trunk
 Mechanism involves adaptive hypersensitivity of D2 receptors in striatum, resulting in
excessive dopaminergic activity
 Anti-parkinsonian drugs can exacerbate; discontinuation can ameliorate
Administration of high doses of high-potency typical antipsychotics can temporarily
suppress tardive dyskinesia by overcoming adaptive response in striatal neurons, but
may in long run lead to worsening of symptoms
 Cessation of all typical antipsychotic medications will lead to slow reversal of striatal
adaptations w/eventual improvement in symptoms of tardive dyskinesia
 Antagonist action at dopamine receptors in pituitary gland – dopamine tonically inhibits
prolactin secretion; leads to amenorrhea, galactorrhea, and false-positive pregnancy tests in
women, and gynecomastia and decreased libido in men
 Nonspecific antagonism of muscarinic receptors – anticholinergic effects including dry mouth,
constipation, difficulty urinating, and loss of accommodation
 Antagonism of α-adrenergic receptors causes orthostatic hypotension and failure to ejaculate
 Sedation can occur because of inhibition of central α-adrenergic pathways in reticular
activating system
 High-potency drugs have fewer sedative effects and cause less postural hypotension than drugs
w/lower potency
 Lower potency tend to cause fewer extrapyramidal adverse effects
 High-potency drugs have high affinity for D2 receptors and more selective in action;
more likely to cause adverse effects mediated by D2 receptors (extrapyramidal) and
fewer adverse effects mediated by muscarinic and α-adrenergic receptors
(anticholinergic effects, sedation, and postural hypotension)
 Highly lipophilic; tend to be metabolized in liver and exhibit high binding to plasma proteins and
high first-pass metabolism
 Generally oral or IM forms (IM for acute patients, oral for chronic therapy)
 Elimination half-lives erratic because kinetics of elimination typically follow multiphasic pattern
and aren’t strictly first-order; most half-lives about a day
 Haloperidol and fluphenzaine available as decanoate esters; highly lipophilic drugs injected IM,
where they are slowly hydrolyzed and released
 Decanoate ester dosage forms provide long-acting formulation that can be administered
every 3-4 weeks; useful for poorly compliant patients
 Inhibit action of levodopa and dopamine agonists; often leads to marked worsening of
Parkinsonian symptoms in Parkinson’s patients
 Potentiate sedative effects of benzodiazepines and centrally active antihistamines (results from
nonspecific binding of antipsychotics to cholinergic and adrenergic receptors)
Atypical antipsychotics – new generation of drugs w/less prominent D2 antagonism and fewer
extrapyramidal effects
 Risperidone, clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole
 More effective than typical antipsychotics at treating negative symptoms of schizophrenia
 Risperidone more effective than haloperidol at combating positive symptoms of schizophrenia
and preventing relapse of active phase of disease
 Cause significantly milder extrapyramidal symptoms than typical antipsychotics
 Relatively low affinity for D2 receptors; affinity doesn’t correlate w/clinically effective dose
 Antagonist action at serotonin 5-HT2 receptor as well as D2
 Many D4 receptor antagonists (except quetiapine)
 Bind to D2 receptors more transiently than typical antipsychotics; allows atypical antipsychotics
to inhibit low-level tonic dopamine release that may occur in mesolimbic system; drugs
displaced by surge of dopamine, as would occur in striatum during initiation of movement, so
extrapyramidal adverse effects minimized
 Administration of clozapine requires frequent monitoring of WBC counts and close follow-up
 Also used in management of psychosis associated w/Parkinson’s disease and dementia
 Use for managing patients w/dementia carries risk of stroke and cerebral vascular disease