The document outlines learning objectives and provides information about schizophrenia, including: - Risk factors include genetic and environmental factors such as family history and obstetric complications. - Pathophysiology may involve dopamine, serotonin, and NMDA receptor abnormalities and structural brain changes. - Symptoms include positive symptoms like delusions and hallucinations, and negative symptoms such as reduced speech. - Treatment involves antipsychotic drugs to reduce positive symptoms as well as managing side effects and preventing relapse.

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

6. Pathophysiology
PATHOPHYSIOLOGY
NEUROTRANSMITTERS
DA
5HT2
NMDA
ANATOMIC
ABNORMALITIES
STRUCTURAL
CEREBRAL
ATROPHY
VENTRICULAR
ENLARGMENT
DECREASE
BRAIN SIZE
FUNCTIONAL

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

12. Clinical Manifestations
 Positive symptoms
 Negative symptoms
 Cognitive impairment, includes:
 Disorganized and slow thinking
 Difficulty understanding
 Poor concentration
 Poor memory
 Difficulty expressing thoughts, feelings and behavior

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

22. TREATMENT

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

26. ANTIPSYCHOTICS
TYPICAL ATYPICAL

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

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

38. Side effects

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)

40. Antipsychotics:
Second generation
Cont’d
Generic Brand
Risperidone Risperdal
Olanzapine Zyprexa
Quetiapine Seroquel
Ziprasidone Geodon
Aripiprazole Abilify
Paliperidone Invega
Iloperidone Fanapt
Asenapine Saphris
Lurasidone Latuda
Clozapine Clozaril

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

45. ACUTE PHASE
Management

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

53. Intramuscular formulations
 Short-acting parenteral antipsychotics include:
 Chlorpromazine
 Haloperidol
 Fluphenazine
 Aripiprazole
 Olanzapine
 Ziprasidone
 Long-acting injectable agents include:
 Haloperidol
 Fluphenazine
 Olanzapine
 Paliperidone
 Risperidone

54. REFRACTORY
SCHIZOPHRENIA
Management

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

57. MAINTENANCE PHASE
Management

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

60. SIDE EFFECTS
Management

61. Side effects
 EPSE
 Tardive dyskinesia
 Neuroleptic malignant syndrome
 Endocrine
 Sedation
 Anticholinergic
 Seizure
 Cardiovascular
 Hepatic
 Hematologic
 Sexual dysfunction

62. EPSE
AKATHESIA
PARKINSONISM
DYSTONIA

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

90. Cardiovascular SE
 ECG changes, QTc prolongation, & ventricular arrythmias
 Low-potency typical agents, clozapine and ziprasidone
 Antiemetics
 Other medications:
 Amiodarone
 Clarithromycin
 Erythromycin
 Methadone

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

93. Questions