2. Learning objectives
Differential diagnosis for schizophrenia
Identify typical and atypical symptoms
Describe Pathology and Pathogenesis of schizophrenia
Determine risk factors
Determine specific disease state management
Based on the discussed treatment modalities you should be able to:
Outline pharmacological and non pharmacological management of Schizophrenia in a given case
Use your clinical judgment and analysis of given information to determine the DOC in any given
case and justify your selection
Use your clinical judgment and analysis to determine the best alternative treatment option based
on patients response to therapy
Monitor the efficacy and toxicity of different treatment modalities and use such details to identify
the DOC
Differentiate antipsychotic agents based on their efficacy and SE
Identify causes of SE and recommend their proper management
3. Definition
Schizophrenia is a neurodevelopmental disorder with complex genetics
and incompletely understood pathophysiology
It’s a challenging psychiatric disorder that involves chronic & recurrent
psychosis
Commonly associated with impairments in social and occupational
functions
It has multiple signs and symptoms involving thought, behavior, emotion
and perception
4. Epidemiology
Lifetime prevalence ~1%
It’s worldwide prevalence is approximately 0.85%
Ranked by WHO as 1 of the top 10 illnesses contributing to global disease burden
Onset is most common in late adolescence or early adulthood
Female ≈ male
Mortality is 1.5 times higher than general population
5. Risk factors:
Genetic factors
First-degree relatives
If both parents are affected, the risk for offspring is 40%
Schizophrenia-prone families are also at risk for other psychiatric disorders
Environmental factors:
Second trimester maternal viral infections
Obstetric and perinatal complications
Increasing parental age
Lower socioeconomic class
Being born during winter
7. Pathophysiology
Cont’d
1. Dopamine (DA) hypothesis:
Overactive DA receptors in the limbic system Positive symptoms
This hypothesis was reinforced by the high risk for drug-induced psychosis
among substances that directly increased synaptic DA availability
DA underactive in mesocortical neurons negative, cognitive & affective
symptoms
For more than 30 years, the dopamine hypothesis has dominated theories of
schizophrenia, based initially upon observations that drugs that increase
dopamine, can cause psychosis, whereas antipsychotic drugs that decrease
dopamine by blocking dopamine D2 receptors can treat psychosis
8. Pathophysiology
2. Serotonin (5-HT2) hypothesis
Overeactivity of 5-HT2 receptors Negative symptoms
Newer antipsychotics potently antagonize 5HT and also block D2 receptors
but less potently than older typical antipsychotics limited EPSE
Cont’d
9. 3. N-methyl-D-aspartate (NMDA) glutamate receptor antagonists
Glutamate, another neurotransmitter in abundance in the brain
NMDA receptors regulate DA neurons, the hypofunction of NMDA receptors
may be responsible for the abnormal DA activity associated with the
schizophrenia symptoms
Drugs which act to block the NMDA receptor for glutamate such as
ketamine, and phencyclidine produce effects which are very similar to the
positive symptoms of schizophrenia
Pathophysiology
Cont’d
10. Classification
Subtypes
1. Catatonic:
Changes in motor activity, negativism, echolalia, echopraxia
2. Paranoid
Delusions, hallucinations
3. Disorganized
Speech and behavior, flat or inappropriate affect
4. Residual
Symptoms no longer as severe as they were during acute illness but indicators of the
disorder are still evident, patient lacks interest in day-to-day living
5. Undifferentiated
Displays active-phase symptoms that do not meet the criteria for the catatonic,
disorganized, or paranoid subtypes.
11. Classification
Phases
1. Prodromal:
Gradual development of symptoms that may go unnoticed until a major
symptom occurs (isolation, loss of interest in school/work, bad hygiene)
2. Acute:
Psychotic behavior
3. Stabilization:
Acute symptoms start to decrease, may last several months
4. Stable:
Marked decrease in symptoms. Nonpsychotic symptoms might appear
Cont’d
13. Clinical Manifestations
Positive symptoms
Delusions: false beliefs strongly held in spite of invalid evidence
Hallucinations:
Visual
Auditory
Tactile
Olfactory
Gustatory experiences
Disorganized speech: "word salads". Ongoing monologues in which a person seems to
talking to himself or imagined people or voices.
Disorganized or catatonic behavior: stupor, inactivity, and either rigidity or extreme
flexibility of the limbs.
Cont’d
14. Clinical Manifestations
Negative symptoms
Negative symptom Definition
Alogia Less talking and less fluent speech
Affective flattening Reduction in the range and intensity of emotional
expression, such as less eye contact and muted vocal tone
Avolition, apathy Difficulty or inability to carry out goal-oriented behavior
Anhedonia Inability to experience emotions
Cont’d
15. Diagnosis
Most psychiatric disorders are heterogeneous, therefore, diagnosis is
made solely from clinical observations using the Diagnostic and
Statistical Manual of Mental Disorders criteria (DSM-IV)
DSM-IV criteria requires at least 2/5 types of symptoms to be present:
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly disorganized or catatonic behavior
5. Negative symptoms
16. Duration of symptoms:
Continuous signs of the disturbance persisting for at least 6 months and:
Must include 1 month or more of active-phase symptoms (or less if
successfully treated)
May include prodromal or residual symptoms that may present as:
2 or more active-phase symptoms in an attenuated form
Negative symptoms alone
Some patients with chronic schizophrenia, before the onset of flagrant
psychosis or when in remission, show none of the usual symptoms &
during brief testing of mental status might show being normal
Diagnosis:
Cont’d
17. Patient case 1
G.R. is a 14 year old female who presented to the doctor clinic with her
mom. Her mother is complaining that her daughter has been failing in class
and she is very isolated recently, doesn’t like to sit with her family anymore,
doesn’t reply to her friend’s phone calls and seems aggressive and moody
The mother noticed that G.R. is talking to herself a lot lately and seems like
leading a one way conversation.
G.R.’s mom is also complaining that she doesn’t play tennis anymore and
she used to play at least three times a week as it was her favorite hobby
18. Differential diagnosis
The diagnosis require the absence of significant mood symptoms, substance
abuse, and any concomitant relevant medical condition
Drug reactions that cause bizarre behavior, hallucinations, confusion or
paranoia may be dose-related
Most common drugs that are associated with Schizophrenia symptoms are:
Anti-parkinson medications
Clonidine
Quinacrine
Procaine derivatives
19. Bipolar disorder
Mood disorders with psychotic features
Schizophreniform disorder
Schizoaffective disorder
Substance induced
Other
Differential diagnosis
Cont’d
20. Prognosis:
Prognosis depends not on symptom severity but on response to
antipsychotics
There’s limited effect of treatment on negative & cognitive symptoms
resulting in only 15% of chronic schizophrenia patients being employed
& 11% being married
Poor adherence to treatment increases relapse risk. It is often related to
side effect of treatment, cognitive dysfunction, substance use, and other
factors
21. Suicide • People with schizophrenia have a 10x higher risk of suicide
• Risk for suicidal behavior is 20-40%
• Between 4-10% die by suicide
Remission • 70% of first-episode patients achieve remission of psychotic
symptoms within 3-4 months
• 83% achieve stable remission at the end of 1year
Relapse • Without maintenance treatment 60-70% relapse within 1 year
• Antipsychotics reduce the risk of relapse to <30% /year
• Indefinite maintenance treatment is recommended if multiple
prior episodes or 2 episodes within 5 years
Prognosis:
Cont’d
23. Management goals
Decreasing the severity of positive symptoms
Control of disturbed behavior
Prevention of harm to patient or others
Improving negative symptoms
Address factors that lead to acute presentation (eg, stress, drug use)
Decreasing social withdrawal
Prevent relapse
24. Antipsychotic drugs are first-line treatment for schizophrenia
The dose, route of administration, and choice of antipsychotic depend
on the underlying disease state, clinical acuity, drug-drug interactions
with other concomitant medications, etc.
Antipsychotic medications have significant side effects; assessment
and management of these adverse effects are an important part of
treatment
Drug selection
25. Mesolimbic pathway: is involved in reward and pleasure or
motivation, and also the positive symptoms of schizophrenia
Mesocortical pathway: involved in motivation and emotional
response, and also believed to be responsible for the negative
symptoms of schizophrenia
Reduced dopamine in the nigrostriatal pathway is believed to be
responsible for unwanted side effects, particularly movement
problems
The fourth dopamine pathway: the tuberoinfundibular pathway
can produce some unwanted hormonal effects. Dopamine
released in this pathway leads to the increase of prolactin levels
Antipsychotics:
Mode of action
27. Introduced more than 50 years ago
Known as neurleptics, conventinal, typical antipsychotics
Effective in treating acute psychosis & chronic psychotic disorders
MOA: strongly antagonize D2 receptors
They have comparable efficacy in the treatment of psychosis
Most available as po, some exist as IV and IM
They have marked cost advantages over second-generation drugs
Antipsychotics:
First generation-TYPICAL
28. 1st neuroleptic discovered by mistake was Chlorpromazine
Haloperidol is 100 times more potent as antipsychotic => more
parkinsonian side effects
Despite their higher potency, newer drugs in first generation
antipsychotics that block D2 are not more effective than
chlorpromazine when used in equipotent doses
Each drug in this class has distinct effects on other receptors like 5-
HT2a, alpha-1, histaminic and muscarinic, which generally correspond
with their different side-effects profiles
Antipsychotics:
First generation
Cont’d
29. Typical antipsychotics cause higher side effects because of the
nonspecific localization of their DA binding
Most have prolonged half-life
Subject to extensive metabolism via CYP 450
Have different chemical structures: phenothiazines, butyrophenones,
thioxanthenes, etc. or as phenothiazines and non-phenothiazines
Prefer high and low potency classification
Antipsychotics:
First generation
Cont’d
30. Antipsychotics:
First generation
Efficacy:
Therapeutic effects are mainly seen 6-8 weeks
after treatment initiation
About 20% of patient achieve complete
remission of symptoms
Most patient show improvement but still
experience few symptoms
30% of patients experience relapse during 1st
generation antipsychotic treatment
Cont’d
Generic Brand
Low potency
Chlorpromazine Thorazine
Thioridazine Mellaril
Mesoridazine Serentil
High potency
Trifluoperazine Stelazine
Perphenazine Trilafon
Loxapine Loxitane
Molindone Moban
Haloperidol Haldol
Fluphenazine Prolixin
Thiothixene Navane
31.
32. ExtraPyramidal Side Effects (EPSE)
Rigidity
Bradykinesia
Tremor
Akathisia (restlessness)
Tardive dyskinesia (TD): hyperkinetic, involuntary movements most
readily observed in the face and extremities
Antipsychotics:
First generation
Cont’d
33. Hyperprolactinemia
Neuroleptic malignant syndrome
Increased risk of mortality when used to treat psychiatric symptoms
associated with dementia in elderly patients
QT prolongation
Sudden death
Antipsychotics:
First generation
Cont’d
• Low-potency agents
• IV administration of high potency agents
• In the presence of other drugs that prolong QT
interval
34. Low potency first generation antipsychotics:
Dosed in 100s of milligrams
Highly sedating
Have strong anticholinergic properties
Cause significant weight gain
Induce hypotension
Have a lower risk of EPS
Antipsychotics:
First generation
Cont’d
35. High-potency first-generation antipsychotics:
Dosed in the one to tens milligram
Minimally sedating
Low anticholinergic
Have a higher risk of EPS
High rates of QT prolongation and cardiac arrhythmia are seen with
IV haloperidol and oral pimozide
Antipsychotics:
First generation
Cont’d
36. Haloperidol:
Available in tablets, liquid, short-acting injectable formulations for IM & IV
use, and a long-acting IM form for depot injection
Cleared by CYP3A4 and CYP2D6 and glucuronidation
Half life around 20 hours
Continuous EKG monitoring is recommended during acute IV administration
and for 2-3hours thereafter
IV dosing should be avoided in patients with pre-existing QT prolongation,
other cardiac abnormalities, electrolyte imbalance, or who are taking other
drugs known to increase QT interval
Antipsychotics:
First generation
Cont’d
37. Haloperidol Sedation, hypotension and prolongation of QTc interval more
pronounced with injection. ↑ EPS risk.
Droperidol Rapid onset of 3-10 minutes advantageous in severely
agitated violent patients. Dose related QTc prolongation and
risk of cardiac arrhythmias. ↑ EPS risk.
Chlorpromazine Hypotension, sedation and injection site pain are limiting side
effects. Not a first-line agent.
Antipsychotics:
First generation
Cont’d
39. Antipsychotics:
Second generation-ATYPICAL
Known as atypical antipsychotics
Lower risks of EPSE and TD and better overall tolerability
Generally cause higher rates of weight gain and metabolic side effects
Their 5HT2 receptor binding can exceed their affinity for D2 receptors
Enhanced efficacy on negative symptoms and cognition
Agents of choice nowadays in treating schizophrenia (except clozapine)
41. Antipsychotics:
Second generation
Aripiprazole has DA2 partial agonist action
Ziprasidone may cause QT prolongation
Largely metabolized by CYP except ziprasidone
Have long half life (approx 20-40hrs)
Bind tightly to DA2 receptors and turn over after several hours (=> more
EPSE), except for clozapine and quetiapine
Clozapine causes agranulocytosis, seizure, and myocarditis. Patients require
weekly to monthly monitoring of white blood cell counts
Cont’d
42. Antipsychotics:
Second generation
Cont’d
Risperidone:
Extensive clinical experience
Availability in multiple forms
Lower cost generic versions
Has a somewhat greater risk of EPSE, weight gain, and prolactin elevation
Risperidone dose > 6mg: SE profile is similar to typical antipsychotics
Decreased clearance in renal and/or hepatic impairment
Olanzapine:
Weight gain, hyperglycemia, and hyperlipidemia are greater
Costs more than other medications
Decreased clearance in non-smoking patients
43. Antipsychotics:
Second generation
Cont’d
Quetiapine:
Low incidence of EPSE even at higher doses
Causes sedation and hypotension, moderate risk of weight gain
Bid dosing
Ziprasidone:
Lower risks of weight gain, diabetes, and hyperlipidemia than other 2nd gen.
Bid dosing
Prolonged QT interval
Should be taken in conjunction with a meal of at least 500 calories
44. Antipsychotics:
Second generation
Cont’d
Aripiprazole:
Lower risk of weight gain, increased lipid or prolactin levels, EPS & sedation
Minimal prolongation of QTc interval or orthostatic hypotension
Long elimination time
Avoid co-administration with other antipsychotic drugs
Paliperidone:
Can be used to treat psychosis in patients with hepatic impairment
Can prolong the QT interval and should not be used with other drugs that
have similar effects
46. Main goal is to decrease the severity of psychotic behavior and thoughts in
order to prevent harm to the patient and others
Baseline assessment before therapy:
Physical exam
Neurologic exam
BP
HR
HbA1c
Serum lipids
BMI
Waist circumference
Any movement disorders (EPSE, TD)
EKG in some cases
Acute phase treatment
47. Start with an antipsychotic based on patient’s individualized case:
There is no convincing evidence that any of the antipsychotics are more effective
than the other when treating acute schizophrenia (except for clozapine)
Atypical agents not preferred??? acute episodes are usually positive in nature,
not all atypical are available in parenteral form => use typical antipsychotics???
Choice of antipsychotic depends on SE profile, available formulation, other
medical conditions, cost, etc.
Gradually titrate the dose of antipsychotic to reach lowest effective dose
Don’t use clozapine or olanzapine as first choice for 1st episode acute treatment
Acute phase treatment
Cont’d
48. Despite considerable debate, newer atypical
antipsychotic agents are not more effective in the
treatment of positive symptoms than typical agents
(Rosenheck et al., 2006; Sikich et al., 2008)
Although there may be small but measurable
differences in effects on negative symptoms and
cognition (Leucht et al., 2009).
Acute phase treatment
Cont’d
49. The route of administration influences time to onset
Oral: Risperidone 1-2 mg or aripiprazole 10mg
Available in rapidly dissolving oral dosage in case patient cannot swallow
Risperidone, aripiprazole, olanzapine
Liquid concentrate: aripiprazole, haloperidol, risperidone
IM: olanzapine 5-10mg, IM haloperidol + antihistamine
Reach plasma concentration sooner than oral formulations
Can be easily given to agitated patients
Effective within 10-30 minutes instead of 30-60min
Acute phase treatment
Cont’d
50. Although antipsychotic medications can take days to weeks before having
a solid effect, they generally have a calming effect within minutes for
agitated patients
Benzodiazepines (BDZ):
Add a BDZ in order to use lesser antipsychotic doses and decrease SE
Lorazepam 1-2mg po or 0.5-1mg IM
Rule out other causes of agitation
Oral or IM depend on patient level of agitation
Co-administration of parenteral olanzapine and BDZ is not recommended; if
considered, monitoring for excessive sedation, HON & cardiorespiratory depression
Acute phase treatment
Cont’d
51. Sudden discontinuation may result in withdrawal symptoms
Insomnia
Nightmares
Headaches
GI symptoms
Restlessness
Increased sweating and salivation
Acute phase treatment
Cont’d
52. Intramuscular formulations
Indicated when:
Oral dose is not convenient
Noncompliance
How to convert from oral:
Start with stabilizing an oral form from the same drug
Convert after few days-1 week in order to make sure
that patient is tolerating
Similar depot and oral doses result in a similar
incidence of side effects
Drug Frequency
Flupehenazine 1-2 weeks
Haloperidol 2-4 weeks
Paliperidone 4 weeks
Risperidone 2 weeks
Olanzapine 2-4 weeks
55. Resolution of psychotic symptoms generally occurs over several days
and may take as much as 6 weeks
Patients should be observed on a stable dose of an antipsychotic for
2-6 weeks before concluding the drug is ineffective
If antipsychotic is deemed ineffective, you may:
Increase the dose
Switch to another antipsychotic
Add a second antipsychotic
Clozapine
Refractory phase treatment
56. Clozapine
Indicated:
Patient has persistent and clinically significant positive symptoms after 2
years consistent with treatment
2 failures with other antipsychotics
Inadequate response for 5 years
Some trials show that it may reduce suicidal attempts
Common SE include: sedation, orthostatic hypotension, and weight gain
Serious SE include: agranulocytosis, seizures and myocarditis
Monitor WBC and ANC count weekly for the first 6 months, biweekly for the
next 6 months, and subsequently every month
Refractory phase treatment
Cont’d
58. If tolerated, patients should receive maintenance therapy for at least
one year in order to prevent relapse
Ongoing maintenance is recommended if multiple prior episodes or 2
episodes within 5 years
Use lowest effective dose
Less side effects, better tolerated, better compliance
Better QOL
Not too low in order not to increase relapse
Decrease dose by 20% q3-6 months
Maintenance phase treatment
59. When to monitor?
Poor response to therapy
Serious side effects at moderate doses of medication
Deterioration in a previously stable patient
Using high doses
Extreme age patients
Medically compromised patients
How to monitor?
Collect sample 5-7 days after fixed dose and 10-12 hours after last oral dose
Depot: samples should be collected after 2-3 months
Monitoring – serum concentration
63. Akathisia
Most common form of EPSE
Patient always wants to move and is unable to sit still
Occurs in 20-40% of patients treated with high-potency
traditional antipsychotics
Use the lowest possible traditional antipsychotic dose
Akathisia may occasionally occur with atypical antipsychotics
=> use atypical antipsychotics
64. Decrease the dose of antipsychotic if possible
Benzodiazepine:
Lorazepam 0.5mg po bid
Diazepam
Ineffective: use beta blockers
Propranolol 10mg po bid and may increase up to 20mg po tid
Monitor HR
Contraindications
Akathisia
Treatment
65. Pseudo-parkinsonism
Aka secondary parkinsonism
Manifested as:
1. Akinesia or bradykinesia
2. Resting tremor (decrease with movement)
3. Increased muscular resistance to passive
range of motion (cogwheel rigidity)
4. Postural instability
5. Mask-like faces
66. Atypical agents have significantly lower risk of EPSE
If dose reduction is not possible, add an anti-parkinson drug
Anticholinergic antiparkinsonian
Benztropine 1-2mg/day in divided doses
Diphenhydramine
Side effects of anticholinergics
Amantadine (symmetrel) 100mg po 2-3 times per day
Hypotension, mild agitation
Pseudo-parkinsonism
Treatment
67. Taper and discontinue agents used to treat EPSE symptoms 6 weeks
to 3 months after symptoms resolution
If symptoms reappear, then switching to an atypical antipsychotic
should be considered
Consider prophylaxis if:
Patient has a history of EPSE
He has high risk factors for EPSE
Patients at high risk for noncompliance if EPSE symptoms develop
Pseudo-parkinsonism
Treatment
Cont’d
68. Has the earliest onset of all EPSE symptoms
Occurs within 1-5 days of dose initiating or dose increase of first
generation antipsychotics
Dystonia is less frequent than parkinsonism or akathisia
Occurring in 2-5% of patients generally
However, in young men receiving high potency antipsychotics
parenterally, the frequency approaches 90%
Dystonia
69. Characterized by sustained, uncoordinated, or simultaneous agonist &
antagonist muscle contractions resulting in repetitive twisting
movements or abnormal postures:
Tongue protrusion
Lips distortion
Oculogyric crisis
Trismus
Torticollis
Opisthotonos
Laryngospasm
Dystonia
Cont’d
70. Risk factors include:
Mood disorders
Hypocalcemia
Thyroid disorders
Dehydration
Young patients
Males
Use of cocaine
History of dystonia
Dystonia
Cont’d
71. Treatment is symptomatic
IM or IV anticholinergic drugs
IM or IV diphenhydramine 50mg or benztropine 1-2mg
Can use oral in case it is mild
Benzodiazepines
Diazepam slow IV push or Lorazepam IM
If no response within 15 min of IV injection or 30 min of IM injection, repeat
the dose
Dystonia
Treatment
72. Prophylaxis not recommended routinely with all typical antipsychotics
Use in high risk patients who are taking high potency typical antipsychotics
Use of atypical antipsychotics to minimize the risk of dystonia is appropriate
High risk patients include:
Young age
Males
Patients using cocaine
Those who have a history of dystonia
Dystonia
Prophylaxis
73. Hyperkinetic movement disorder that occur in patients taking long-
term offending drugs
It is persistent and involuntary and has a delayed onset
In patients treated with first-generation antipsychotics, the annual
incidence is 3-8% overall, and 10-20% in patients >55 years
Resolves slowly after withdrawal of drug
May be irreversible if not detected early
It is much less common in children
Tardive dyskinesia (TD)
74. Clinical manifestations:
Face, tongue, lips, neck and trunk, and limbs are commonly involved
Frequent blinking, brow arching, grimacing, bulging of the cheeks, upward
deviation of the eyes, blepharospasm, and lip smacking
Twisting movements of the tongue, chewing & lateral jaw movements. It
can interfere with patient’s ability to chew, speak or swallow
Tapping foot movements, dystonic extensor posture of toes
Shoulder shrugging
TD
Cont’d
75. Risk factors:
Older patients
Previous history of EPSE
Female, DM, brain damage, etc.
African-Americans
Duration of antipsychotic therapy
Dose of antipsychotic (mainly in elderly)
Lower risk of TD with atypical antipsychotics
The risk of TD is probably lower with most 2nd-generation antipsychotic drugs than
with high-potency 1st generation antipsychotics
Clozapine and quetiapine
TD
Cont’d
76. Use of antipsychotic drugs for longer than 3-6 months, requires careful
evaluation & re-examination of the need for administration
Metoclopramide should not be used continuously for >12 weeks
Maintain patients on the lowest effective dose of antipsychotic
Chronic use of prophylactic anticholinergics should be discouraged
since they do not prevent TD and can aggravate existing involuntary
movements
TD
Prevention
Cont’d
77. No FDA approved agents for treating TD
Symptoms are often mild and not sufficiently bothersome to require
treatment
Discontinue the offending drug when symptoms start appearing
Dose reduction ???
Continued drug exposure doesn’t worsen the severity once its established or
chronic
TD
Treatment
Cont’d
78. Switch from 1st to 2nd generation antipsychotic drugs
In those developing signs of TD if treatment for psychosis remains
critical
In contrast to possible benefit in early TD, there’s no convincing
evidence that changing drugs is effective for ameliorating the course of
TD once symptoms are fully developed
Clozapine has been effective in some cases of severe tardive dystonia
Quetiapine appears to have a low or nonexistent TD & may alleviate TD
TD
Treatment
Cont’d
79. Benzodiazepines
Evidence of benefit in patients with TD is limited and inconclusive
Clonazepam: to reduce both dyskinesia and associated anxiety in patients with mild TD
No effect on severe TD
Botulinum toxin injections
Cervical dystonia, retrocollis, or blepharospasm
Tetrabenazine
Deplete DA storage in presynaptic vesicles
May be the most effective therapy for TD, particularly for debilitating tardive dystonia
Limited evidence
Anticholinergics
Vitamin E
TD
Treatment
Cont’d
80. Neuroleptic malignant
syndrome(NMS)
Rare: incidence is ~0.02-3%
Maybe life threatening: mortality rate 10-20%
Mental status change, rigidity, fever & autonomic dysfunction
Diagnosis is suspected when any 2/4 clinical features are present
Associated with medications that block dopamine transmission
Most cases are with the typical agents, high potency
Can occur hours to months after initiating therapy but usually seen in
the first two weeks
81. Risk factors:
Rapid dose escalation
Switch from one agent to another
Parenteral administration
Drug abuse
Concomitant use of contributing psychotropic agents (lithium,
anticholinergic therapy, serotonergic agents)
NMS
Cont’d
82. NMS
Treatment
1. Stop causative agent
2. If typical antipsychotic is required, the following minimizes risk of
NMS recurrence:
Wait at least 2 weeks before resuming therapy
Use lower rather than higher potency agents
Start with low doses and titrate upward slowly
Avoid concomitant lithium
Avoid dehydration
Carefully monitor for symptoms of NMS
3. Supportive care: BP, electrolyte imbalance, dehydration, DVT, fever, etc.
83. Treatment options are based upon case reports and not on clinical
trials. Their efficacy is unclear and disputed
Needed in patients with CK elevations or hyperthermia or who do not
respond to withdrawal of drug and supportive care within the 1-2 days
Dantrolene (dantrium) 0.25-5mg/kg IV q6-12hrs for malignant hyperthermia
Hepatotoxicity
DA agonists: Bromocriptine 2.5mg q6-8hrs (max 40mg/day)
Amantadine 100mg po: DA agonist + anticholinergic
Use for 10 days followed by slow tapering down
BDZ appear to have a little effect in most patients
Cont’d
NMS
Treatment
84. Dry mouth, exacerbation of glaucoma, confusion, decreased memory,
agitation, visual hallucinations, and constipation
Worse in elderly patients
Low potency first generation antipsychotics
Clozapine and olanzapine
Risperidone, aripiprazole, and ziprasidone have very low
anticholinergic side effects
Anticholinergic
85. Sedation
Can be seen with all antipsychotic but some are more severe than
others
More common in low potency 1st generation antipsychotic
Clorpromazine, clozapine, olanzapine, and quetiapine are most
frequently implicated
Occurs early in the treatment and may decrease with time
Administer drug at bedtime
86. Seizures
Many antipsychotics can lower the seizure threshold
When drugs are added to an existing antiepileptic regimen, increased
drug level monitoring
Antipsychotics should not be assumed to be the primary cause of a new
onset of seizure, because they rarely cause seizures in a patient not
prone to epilepsy
Higher incidence:
Using higher doses
Rapid dosage increase
Upon initiation of treatment
87. Risk increase if:
Pre-existing seizure disorder
History of drug-induced seizure
Abnormal EEG
Pre-existing CNS pathology or head trauma
Low potency antipsychotics
When patient experiences seizure, decrease antipsychotic dose first
Seizures
Cont’d
88. Hyperprolactenemia
Seen more with 1st generation antipsychotics as well as risperidone
and paliperidone
Leads to:
Galactorrhea
Menstrual irregularities and amenorrhea
Gynecomastia
Sexual dysfunction
Switch to an antipsychotic with low hyperprolactenemia incidence
Bromocriptine or amantadine
89. Weight gain
Frequently reported with antipsychotics
Mainly with: clozapine, olanzapine, quetiapine, risperidone
Lower incidence with ziprasidone and aripiprazole
Treatment:
Switching to an antipsychotic that doesn’t cause weight gain
Diet and exercise
Metformin: Evidence from randomized trials has shown metformin 1-2g/day well-
tolerated and effective in helping persons with schizophrenia lose weight
Metformin given for 12-16 weeks may lead to loss of ~50% of the weight gain
induced by antipsychotic treatment
Not for patients with impaired renal function
91. Greater caution in
1. Elderly
2. Preexisting cardiac disease
3. Patients on diuretics or medications that may prolong the QTc
interval
In patients older than 50 years of age, a pretreatment ECG is
recommended, as are baseline serum K+ and Mg++ levels
Cardiovascular SE
Cont’d
92. Orthostatic hypotension seen in patients taking antipsychotics with α-
adrenergic blocking effects
Clozapine, risperidone, paliperidone, iloperidone
Higher risk with:
Elderly patients
Initiation of therapy
With dose increases
Prevented by starting with a low dose and increase gradually in order
to develop tolerance
Cont’d
Cardiovascular SE