Module: Pharmacotherapy III Module Coordinator: Dr. Arwa M. Amin Mostafa Academic Level: Postgraduate, Master of Pharmacy in Clinical Pharmacy School: Dubai Pharmacy College Year of first presented in Class: 2018 This presentation is for Educational Purpose. It has no commercial value associated with it.

1. ARWA M. AMIN MOSTAFA
PHD, M.PHARM CLINICAL PHARMACY, DIP. MANAGEMENT, BSC. PHARMACY.
SCHIZOPHRENIA

2. ARWA M. AMIN
What we are going to Discuss TODAY?
 What is Schizophrenia?
 What is the etiology of Schizophrenia?
 What are the Risk Factors of developing Schizophrenia?
 What is the Pathophysiology of Schizophrenia?
 How to Diagnose Schizophrenia?
 What are the Goals of Schizophrenia Therapy?
 What are the Non-Pharmacological Treatment of
Schizophrenia?
 What are the Pharmacological Treatment of Schizophrenia?
 How to evaluate Schizophrenia Therapy?

3. ARWA M. AMIN
Schizophrenia
 Schizophrenia is a severe
heterogenous syndrome and
chronic mental disorder
characterized by disturbed
thoughts, perception and
behavior.
 Person affected by
Schizophrenia may experience
delusions, auditory
hallucinations, cognitive deficit
and psychosis.

4. ARWA M. AMIN
Etiology of Schizophrenia
 Schizophrenia etiology is unknown. However, evidence
suggests that it is most likely multifactorial.
Multiple pathophysiologic abnormalities can play role in
producing schizophrenia.
Environmental Factors
Gut Microbiota, Trauma
Schizophrenia
Genetics & Epigenetics
Abnormalities in Brain
structure or Chemistry

5. ARWA M. AMIN
Risk Factors of Schizophrenia
 Age:
Appears in late adolescence or early adulthood.
 Genetics & Epigenetics
 Sex:
Slightly higher in Men than Women.
Men develop schizophrenia mostly earlier than
women (Men: 16 and 25 years old).
Women develop symptoms years later than men
(women > 30 years old).
 Family History
 Drug Intoxication
 Alcohol Intoxication
16 – 25 y
> 30 y

6. ARWA M. AMIN
Risk Factors of Schizophrenia
 Low Birth weight
 Prenatal Infections
 Maternal Stress
 e.g. Maternal Malnutrition
 Neonatal Hypoxia
 Trauma
 Abuse, Negligence
 War Experiences Trauma; Soldiers
 Gut microbiota Disturbances
 Celiac Disease
 Unhealthy Diet:
 Overconsumption of gluten-containing grains.
 Processed food, refined sugars may cause gut microbiota
disturbances.

7. ARWA M. AMIN
Pathophysiology of Schizophrenia
Pathophysiological Hypothesis:
 Hyperdopaminergic or Hypodopaminergic
activity of dopaminergic pathways in the CNS
 Deficiency of Glutamatergic Activity
 Anatomic Abnormalities
 Inflammation and Immune Function

8. ARWA M. AMIN
Pathophysiology of Schizophrenia: Dopaminergic activity
Dopamine Pathways in CNS
• Mesolimbic pathway
• Mesocortical pathway
• Nigrostriatal pathway
• Tuberohypophyseal pathway
Ac, nucleus accumbens; Am, amygdaloid nucleus; C, cerebellum; Hip, hippocampus;
Hyp, hypothalamus; LC, locus coeruleus; P, pituitary gland; SN, substantia nigra;
Sep, septum; Str, corpus striatum; VTA, ventral tegmental area.
Figure Source: Rang et al (2015); Rang &
Dale’s Pharmacology 8th Edition, Fig.
39.3

9. ARWA M. AMIN
Pathophysiology of Schizophrenia: Dopaminergic Activity
Dysfunction in the
Dopaminergic activity in the
Mesocorticolimbic pathways
Schizophrenia
• ↑↑ Dopaminergic activity in the
Mesolimbic pathway → Positive
symptoms of Schizophrenia.
• Therapeutic Goal: Slow-down
Dopamine Neurotransmission.
• ↓↓ Dopaminergic activity in the Miso-
cortical pathways → Negative &
Cognitive symptoms of Schizophrenia.
• Therapeutic Goal: Increase Dopamine
neurotransmission.
Ac, nucleus accumbens; Am, amygdaloid nucleus; C, cerebellum; Hip, hippocampus;
Hyp, hypothalamus; LC, locus coeruleus; P, pituitary gland; SN, substantia nigra;
Sep, septum; Str, corpus striatum; VTA, ventral tegmental area.
Figure Source: Rang et al (2015); Rang & Dale’s
Pharmacology 8th Edition, Fig. 39.3

10. ARWA M. AMIN
Pathophysiology of Schizophrenia: Glutamatergic Dysfunction
• NMDA Receptor Hypofunction
→ Enhanced activity in the
Mesolimbic dopaminergic
pathway (↑↑ Dopaminergic
activity) → Positive symptoms
of Schizophrenia.
• NMDA Receptor Hypofunction
→ Reduced activity in the
Mesocortical Dopaminergic
pathway (↓↓ Dopaminergic
activity) → Negative &
Cognitive symptoms of
Schizophrenia.NMDA Receptors: N-methyl-D-aspartate receptors
Glutamatergic Dysfunction (NMDA
Hypofunction Hypothesis)
Schizophrenia may result from
Glutamatergic Dysfunction
(Schizophrenia is largely considered
Hypoglutamatergic disorder)
Figure Source: Glutamate neurocircuitry: theoretical underpinnings in schizophreni, Thomas L.
Schwartz et al (2012), https://www.frontiersin.org/articles/10.3389/fphar.2012.00195/full

11. ARWA M. AMIN
Pathophysiology of Schizophrenia: Anatomic Abnormalities
Studies showed that
Schizophrenic patients
may have:
 ↑↑ Lateral Ventricular
volume.
 ↓↓ Whole brain
volume.
 Both Gray & White
matters.
Figure Source: https://commons.wikimedia.org/wiki/File:Schizophrenia_(Illustration).png

12. ARWA M. AMIN
Pathophysiology of Schizophrenia: Inflammation &
Immune Function
Overactivation of immune system →
overexpression of inflammatory
cytokines and subsequent alteration of
brain structure and function.
Insulin resistance & Metabolic
disturbances are common in
schizophrenic patients and are linked
to inflammation.

13. ARWA M. AMIN
Mood Symptoms
• Cheerful or sad
• In a Difficult way to
understand
• Depression
• Anxiety
• Social withdrawal
• Suspiciousness
• Poor selfcare skills
Clinical Presentations of Schizophrenia
Positive Symptoms
• Auditory Hallucination
• Delusions
• Illusions
• Disorganized speech &
Behavior
Negative Symptoms
• ↓↓ Emotional range
• Poverty of speech
• Loss of Interests & Drive
• ↑↑ Inertia
Cognitive Dysfunction
• Neurocognitive Deficits
• Deficit in working memory
• Deficit Executive function
• Impaired attention
Delusion: False Believes

14. ARWA M. AMIN
Clinical Presentations of Schizophrenia

15. ARWA M. AMIN
Phases of Schizophrenia
Acute / ActiveProdromal Residual / Chronic
►Psychotic Symptoms
(Positive Symptoms)
Begins:
►Hallucination
►Delusion
►Impaired self-care
►Disturbed
Thoughts.
►Aggression.
►Functional Decline
precedes 1st
psychotic episode
►Socially withdrawn
►Deterioration of
Hygiene
►Physical complaints.
►Occurs between
episodes of
Psychosis
►Some Positive
Symptoms and
Negative Symptoms
Persists. However,
the phase is
markedly Negative
symptoms.

16. ARWA M. AMIN
Phases of Schizophrenia
Figure Source: http://www.schizophrenia.com/images/earlygraph.gif

17. ARWA M. AMIN
Phases of Schizophrenia
Figure Source: Rajiv Tandon et al (2009): Schizophrenia, “just the facts” 4. Clinical features and conceptualization

18. ARWA M. AMIN
Schizophrenia Diagnosis
 Schizophrenia diagnosis is clinical and largely based on:
 Physical examination
to identify signs and symptoms of Schizophrenia.
 Psychiatric Diagnostic Interview
 Patient’s history (Medical history, traveling, family & social history)
 Mental status Examination
 Physical and Neurological Examination
 Gathered information will help to rule out other causes of the
psychotic symptoms.
 e.g. Antipsychotic Medications, Drug abuse
 Medical conditions: HIV, SLE, Lyme
SLE: Systemic Lupus Erythematosus

19. ARWA M. AMIN
Schizophrenia Diagnosis
Other Diagnostics to rule-out medical conditions:
► Brain imaging (MRI, CT, PET) to rule out:
► Subdural Hematomas
► Vasculitis
► Cerebral abscess
► Tumors
► Electroencephalography
► Electrocardiogram
► Chest Radiology to rule out occult Malignancy
MRI: Magnetic Resonance Imaging, CT: Computed Tomography, PET: Positron Emission Tomography
Figures sources:
Subdural Hematoma: Harvard Health Publishing https://www.health.harvard.edu/diseases-and-conditions/subdural-hematoma-
Cerebral abscess: https://www.drthindhomeopathy.com/disease/cerebral-abscess/
Cerebral Tumors: https://www.hopkinsmedicine.org/health/articles-and-answers/wellbeing/the-most-common-brain-tumor-5-things-you-should-know

20. ARWA M. AMIN
Schizophrenia DIAGNOSIS – Other Laboratory Tests
 Complete Blood cell (CBC)
counts
 Urine Drug Screening
 Opioids, Cannabis, Alcohol,
Cocaine
 Serum vitamin B12,
Methylmalonic acid, Folate
 Thyroid panel
 Fasting Serum Glucose
 Serum Lipids
 Serum electrolytes
The following laboratory tests should be performed to rule out other
disease conditions:
 Liver function tests
 Renal Function Tests
 UTIs
 HIV antibodies
 Lyme antibodies
 ANA for SLE
 CSF analysis
 To rule out Infectious CNS
diseases
UTIs: Urinary Tract Infections, ANA: Antinuclear antibody, SLE: Systemic Lupus Erythematosus, CSF: Cerebrospinal fluids

21. ARWA M. AMIN
Schizophrenia Diagnosis: DSM-5 Criteria
Schizophrenia is defined by the criteria of the Statistical Manual of
Mental Disorders (DSM-5) set by the American Psychiatric
Association as the following:
At least 2 of the following symptoms:
Delusion1
Hallucination2
Disorganized speech3
Grossly disorganized or Catatonic behavior4
Negative symptoms5
Should be one of the symptoms
Continuous signs of disturbance must persist for at least 6 months
During the persistence of signs, patient must experience at least 1
month of active symptoms (or less if successfully treated)
DSM-5: Diagnostic and Statistical Manual of Mental Disorders

22. ARWA M. AMIN
Schizophrenia Diagnosis: DSM-5 Criteria Cont..
DSM-5 Criteria cont.…
 Social and Occupational
deterioration problems occurring
over a significant amount of time.
Deterioration in one of the major
areas of functioning such as work,
interpersonal relations, or self-care.
 Problems must NOT be attributed to
other conditions.
Note: Schizophrenia subtypes were removed from DSM-5
because they didn’t appear to be helpful for targeted
therapy.
DSM-5: Diagnostic and Statistical Manual of Mental Disorders

23. ARWA M. AMIN
Complications of Untreated Schizophrenia
• Most schizophrenic patients have ongoing disability with relapses.
• Self injury and suicide attempts.
• Social Isolation.
• Alcohol abuse
• Excessive smoking
• Life Expectancy of Schizophrenic patients is reduced by 12 – 15
years; mostly due to:
• Obesity
• Little Exercise
• Smoking
• Suicide

24. ARWA M. AMIN
Case Discussion
Mr. JM is a 65-year-old war veteran with a
40-year history of schizophrenia. He showed
to have poor personal hygiene, blunted
affect, and delusions, accompanied by
auditory and visual hallucinations. His
delusions are related to his wartime
experiences.
His visual hallucinations involve enemy soldiers from the war
who he believes are stalking him. His auditory hallucinations
include the sounds of war, accompanied by enemy soldiers
threatening to end his life if he does not keep his guard up. He
has been unable to maintain a job or adequate housing for
many years. Case source: This case was adapted with modifications from case study by Lauren S. Schlesselman, PharmD at
https://www.pharmacytimes.com/publications/issue/2007/2007-05/2007-05-6515

25. ARWA M. AMIN
Case Discussion
He currently lives under a bridge "in case he
needs to make a getaway down the river."
When workers from the psychiatric clinic are
able to locate him, they attempt to provide
medical care and evaluate his schizophrenia.
According to their records, JM was given Haloperidol 15 mg 3
times daily and Benztropine 1 mg 3 Times daily when they last
evaluated him. He was given enough medication for a few
weeks so that they can evaluate the effectiveness and any
adverse effects. During previous trials with other neuroleptic
agents, extrapyramidal side effects have limited the dose JM
could tolerate. Case source: This case was adapted with modifications from case study by Lauren S. Schlesselman, PharmD at
https://www.pharmacytimes.com/publications/issue/2007/2007-05/2007-05-6515

26. ARWA M. AMIN
Case Discussion
Family History
 Father suffered Schizophrenia.
 Brother committed a suicide.
 Mother had MDD*.
 Medications:
Haloperidol 15 mg TDS
Benztropine 1 mg TDS
Acetaminophen 1000 – 1500 mg PRN
Assessment:
Schizophrenia *MDD: Major Depressive Disorder

27. ARWA M. AMIN
Case Discussion
PMH
 Schizophrenia since 40 years.
 Heavy smoker.
Social History
 Homeless & Divorced.
 He has no kids.
VS
 BP 135/85, P 75, RR 22, T 36.9°C;
Wt 190 lbs, Ht 6‘5''

28. ARWA M. AMIN
Case Discussion
What are the risk factors that may have lead to
Schizophrenia in Mr. JM?
• Family History of mental illnesses
• Schizophrenia, MDD and suicide.
• Previous Trauma
• Wartime experiences.
• Alcohol abuse.
*MDD: Major Depressive Disorder

29. ARWA M. AMIN
Case Discussion
What are the schizophrenic Signs & Symptoms that were clinically
manifested in Mr. JM?
• Hallucination
• Auditory and visual Hallucinations.
• Delusion
• Reduced interest and Drive
• Reduced Self-care: Poor personal hygiene
• Un-employed
• Homeless
• Divorced
• Blunted affect.

30. ARWA M. AMIN
Case Discussion
Indicate Schizophrenia Diagnosis in Mr. JM using DSM-5 Criteria?
• Mr. JM has
• Hallucination: Auditory and visual Hallucinations.
• Delusion
• Negative Symptoms (Blunted affect)
• Symptoms are continuous and persistent for more than 6
months.
• He is experiencing active symptoms for more than 1 month
(Hallucination).
• Deterioration in one of the major areas of functioning such as
work, interpersonal relations, or self-care.
• Problems NOT attributed to other conditions.

31. ARWA M. AMIN
Schizophrenia Therapeutic Goals
What are the therapeutic goals of Schizophrenia treatment?
• To alleviate symptoms.
• To avoid Antipsychotic Drugs’ side effects.
• To prevent relapse.
• To improve psychosocial functioning and productivity.
• To integrate the patient back into the community.
• To involve the patient in treatment planning.
• To ensure patient’s compliance to the prescribed
regimen.

32. ARWA M. AMIN
Case Discussion
What are the Non-pharmacological treatment options of
Schizophrenia that you can suggest for Mr. JM Therapy?

33. ARWA M. AMIN
Non-Pharmacological Therapy for Schizophrenia
• Psychosocial rehabilitation programs.
• Cognitive Behavioral Therapy (CBT).
• Ensure Family and Community Support.
• Diet
•Healthy Diet rich in Folate, Omega 3, Nuts
and vegetables.
•Ketogenic Diet (LCHF), why?
• Possible reasons*:
• Metabolic consequences from the elimination of gluten from
the diet.
• Modulation of the disease pathophysiology at the cellular level.
*Bryan D Kraft and Eric C Westman, Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature, Nutrition
& Metabolism 2009, 6:10 . LCHF: Low carbohydrate Healthy Fat.

34. ARWA M. AMIN
Case Discussion
 Discuss the pharmacological treatment options of
Schizophrenia?
 What are the main adverse effects of Antipsychotic Drugs?
 Was Haloperidol the best Pharmacological option to treat
Schizophrenia in Mr. JM? Explain your opinion on his
treatment?

35. ARWA M. AMIN
Pharmacological Therapy of Schizophrenia: General Approach
1st Generation Antipsychotics
(Traditional/Typical Antipsychotic)
Chlorpromazine
Fluphenazine
Haloperidol
Loxapine
Molindone
Perphenazine
Thioridazine
Thiothixene
Trifluoperazine
2nd Generation Antipsychotics
(Atypical Antipsychotics)
 Aripiprazole
 Asenapine
 Brexpiprazole
 Clozapine
 Iloperidone
 Olanzapine
 Paliperidone
 Quetiapine
 Risperidone
 ziprasidone

36. ARWA M. AMIN
Pharmacological Therapy of Schizophrenia: General Approach
 2nd generation (Atypical) antipsychotic are the First-line
treatment for Schizophrenia.
 1st generation (Typical/traditional) antipsychotics have
potent D2-receptors-blocking activity compared to
Atypical antipsychotic.
Therefore, they have the drawback of acute and long-term
difficulties associated with extrapyramidal symptoms (EPS)
side-effects (SE).
 Monotherapy or Combination Schizophrenic Treatment?
Antipsychotics treatment of Schizophrenia should be
Monotherapy
Optimize Efficacy-to-side Effect Ratios before progressing to
medications with greater side effect risks.
Combination regimens should only be used in the most treatment-
resistant patients.

37. ARWA M. AMIN
Pharmacological Therapy of Schizophrenia: General Approach
 Antipsychotics are largely metabolized by cytochrome
P450 (CYP) pathways
Genetic polymorphism of CYP450 enzyme should be
considered while choosing suitable drug treatment.
Drug-Drug interactions with drugs interfering with CYP450
pathways should be considered.
 Clozapine (2nd generation antipsychotic) is the most
effective antipsychotic but it is not recommended as First-
line Therapy.
It should be reserved for the management of Resistant
Schizophrenia.
Clozapine Dose should be titrated slowly to avoid Orthostatic
hypotension side-effect.
Clozapine use is limited by the agranulocytosis side-effect.
Increasing Age and Female gender increase risk

38. ARWA M. AMIN
Case Discussion
What are the main adverse effects of Antipsychotic Drugs?

39. ARWA M. AMIN
Pharmacological Therapy of Schizophrenia: General Approach
Antipsychotics Drugs Side-effects:
 EPS & Serum Prolactin SE in most of 2nd generation Antipsychotics is few or
NO compared to1st generation Antipsychotics drugs,
 2nd generation antipsychotic with increased Prolactin SE are Paliperidone and
Risperidone.
 Common EPS side-effects of antipsychotics are:
 Akathisia
 Pseudo-parkinsonism
 Tardive Dyskinesia
 Agents used to treat EPS side-effect associated with some antipsychotic
Drugs:
 Antimuscarinics: e.g. Benztropine
 Antihistaminic: e.g. Diphenhydramine
 Dopamine agonist: e.g. Amantadine
 Benzodiazepines: e.g. Diazepam, Lorazepam
 β-Blockers: e.g. Propranolol EPS: Extrapyramidal System, SE: Side-effects

40. ARWA M. AMIN
Pharmacological Therapy of Schizophrenia: General Approach
Antipsychotics Drugs Side-effects:
 Metabolic SE in 2nd Generation Antipsychotics is more than 1st
Generation Antipsychotics.
 Weight Gain
 Hyperlipidemia
 DM
 Sedation, Anticholinergic and Orthostatic Hypotension SE are ↑ ↑ in
Chlorpromazine & Thioridazine (1st generation) and Clozapine (2nd
generation).
 Neutropenia risk is ↑ ↑ in Chlorpromazine (1st generation), Clozapine
and Olanzapine (2nd generation).
 Seizures risk is high in Chlorpromazine (1st generation) and Clozapine
(2nd generation).
 Seizures are more likely with initiation of treatment, higher doses, and
rapid dose increases.
EPS: Extrapyramidal System, SE: Side-effects, DM: Diabetes Mellitus

41. ARWA M. AMIN
Source Reference: Schizophrenia, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017. Available at:
https://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146064659 Accessed: May 23, 2018
Copyright © 2018 McGraw-Hill Education. All rights reserved
Suggested
Schizophrenia
Pharmacotherapy
Algorithm

42. ARWA M. AMIN
Pharmacological Therapy of Schizophrenia: Dose Ranges for
Selected Antipsychotic Drugs
Usual dose
Range (mg/day)
Starting Dose (mg/day)Antipsychotic Agent
First Generation
300 - 100050 -150Chlorpromazine
16 - 644 - 24Perphenazine
2 - 202 - 5Haloperidol
Second Generation
15 - 305 - 15Aripiprazole
100 - 80025Clozapine
10 - 205 - 10Olanzapine
3 - 123- 6Paliperidone
2 - 81 - 2Risperidone

43. ARWA M. AMIN
Case Discussion
Was Haloperidol the best Pharmacological option to treat
Schizophrenia in Mr. JM? Explain your opinion on his treatment?

44. ARWA M. AMIN
Case Discussion
Was Haloperidol the best Pharmacological option to treat
Schizophrenia in Mr. JM? Explain your opinion on his treatment?
Haloperidol was not the best pharmacological option to treat
Schizophrenia in Mr. JM because it is a 1st generation
antipsychotic and it has high risk of developing EPS side-effects
which necessitated that Mr. JM was prescribed Benztropine.

45. ARWA M. AMIN
Case Discussion
► The physician would like to discontinue the haloperidol and
initiate an agent with fewer EPS side effects.
► He searches the medication supply and finds that he has
samples of Fluphenazine, Chlorpromazine, Thiothixene,
Risperidone and Aripiprazole. Which agent is least likely to
cause EPS and Prolactin SE for Mr. JM?

46. ARWA M. AMIN
Case Discussion
► The physician would like to discontinue the haloperidol and
initiate an agent with fewer EPS side effects.
► He searches the medication supply and finds that he has
samples of Fluphenazine, Chlorpromazine, Thiothixene,
Risperidone and Aripiprazole. Which agent is least likely to
cause EPS and Prolactin SE for Mr. JM?
► Risperidone is 2nd generation antipsychotic and it is less likely to
cause EPS SE. However, it has high chances to cause increased
Prolactin SE.
► Aripiprazole is less likely to cause EPS, Prolactin and Sedation SE.
Hence, it is more suitable treatment for Mr. JM.
► Starting Dose range: 5 – 15 mg daily
► Usual dose range:15 – 30 mg daily

47. ARWA M. AMIN
Evaluation of Schizophrenia Therapy
 Using Standardized Psychiatric rating scales to rate
response
Positive Symptom Rating Scale
Brief Negative Symptom Assessment
 Patient’s self assessment and engaging patient in
treatment.
 Monitor for Medication side-effects.
 Monitor after 3 months then annually BP, BMI, Waist
Circumference, CBC, FPG & FLP.
BP: Blood pressure, BMI: Body Mass Index, CBC: Complete Blood Cell counts, FPG: Fasting Plasma Glucose, FLP: Fasting Lipid profile

48. ARWA M. AMIN