1. Schizophrenia overview part II Ewa Pilaczyńska-Jodkiewicz

2. Positive Symptoms
Positive symptoms are those that have a positive reaction from some treatment.
In other words, positive symptoms respond to treatment.

3. Negative Symptoms
Those that appear to reflect a diminution or loss of normal functions.
May be difficult to evaluate because they are not as grossly abnormal as positive symptoms.

4. Summary of Negative Symptoms
Lack of emotion
Low energy
Lack of interest in life
Affective flattening
Alogia
Inappropriate social skills
Inability to make friends
Social isolation

5. Difficulties in concentration and memory:
Cognitive Symptoms
Difficulties in concentration and memory:
Disorganized thinking
Slow thinking
Difficulty understanding
Poor concentration
Poor memory
Difficulty expressing thoughts
Difficulty integrating thoughts, feelings, behaviors

6. DRUG TARGETS
Dopamine receptors: D1, D2, D3, D4, D5
Serotonin receptors: 5-HT-1A, 2A, 3, 6, 7
Norepinephrine: -1 & -2
Muscarinic acetylcholine: mACh-1 & 4
Histamine: H-1 & 2
Dopamine, norepinephrine & serotonin transporters
NMDA-glutamate receptor

7. Dopamine Receptors Occupancy—therapeutic vs. side effects
At therapeutic doses the “classical” antipsychotics occupy >75% of dopamine D-2 receptors.
85% occupancy needed to get extrapyramidal side effects.
Clozapine, the “atypical”, blocks only 35% D-2 receptors at therapeutic doses.

8. DRUG CLASSES Phenothiazines: eg. chlorpromazine
Thioxanthenes:chlorprothixen, flupentixol, clopixol
Butyrophenones: eg. haloperidol
Diphenylbutylpiperidine
Dihydroindolone: sertindol
Dibenzoxazepines: eg. Clozapine, olanzapina, quetiapina
Benzisoxazol: eg. Risperidon, ziprazidone
Benzamide: amisulprid

9. Schizophrenia Treatment Psychopharmacology - Antipsychotic medications
Atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole)
First-line drugs of choice - 70% of patients respond
Clozapine is effective in 35-50% of patients who do not respond to other antipsychotics (80-85% of all patients)
Conventional antipsychotics (neuroleptics)
70% of patients respond

10. PHARMACOLOGICAL PROPERTIES
Neuroleptic syndrome:
suppression of spontaneous behavior
loss of initiative and interest (anhedonia)
loss of affect and emotional content
slowness of movement
Parkinson-like extrapyramidal effects
Unpleasant when given to non-psychotic individual

12. SIDE EFFECTS
Autonomics--related to blockade of alpha- adrenergic and muscarinic receptors
Endocrine effects, primarily prolactin increases
Disruption of thermoregulatory control
Hypersensitivity reactions; eg. agranulocytosis with clozapine; browning of vision with thioridizine

13. SIDE EFFECTS, cont’d.
Parkinsonian syndrome
neuroleptic malignant syndrome
akathisia
acute dystonic reactions
tardivie dyskinesia

14. Shift in Risk Perception of Antipsychotics
Past Areas of Concern
Current Medical Realities
Diabetes TD
Weight Gain
Tardive Dyskinesia
Prolactin
Hyperlipidemia
Insulin
Resistance
Sedation
Weight Gain
Insulin
Resistance
Hyper-
lipidemia
Coronary Heart
Disease
Sedation
CHD
Prolactin

15. What We Should Be Doing Inquiry Measure Lab
Personal or family history:
Diabetes
Hypertension
CHD (MI or Stroke)
Cigarette smoking
Diet
Physical Activity
Measure
Height
Weight
Waist circumference
Blood Pressure
Lab
Fasting Glucose
Fasting Lipids
And - trying to use medications which have fewer metabolic side effects!

16. Clinical Issues
Lack of access to medical care for patients with severe mental illnesses
Switching to more metabolically neutral medications may reverse many problems, but requires careful attention by the psychiatrist and motivation by the client

26. Indications for Antipsychotic Drugs
Schizophrenia
Schizoaffective disorders
Acute control of mania
Tourette’s syndrome
Huntington’s chorea and ballism
Intractable hiccups

27. Antipsychotics: Typicals
Are D2 dopamine receptor antagonists
High potency typical antipsychotics bind to the D2 receptor with high affinity. As a result they have higher risk of extrapyramidal side effects. Examples include Fluphenazine, Haloperidol, Pimozide.

28. Antipsychotics
Low potency typical antipsychotics have less affinity for the D2 receptors but tend to interact with nondopaminergic receptors resulting in more cardiotoxic and anticholinergic adverse effects including sedation, hypotension. Examples include chlorpromazine and Thioridazine.

29. Antipsychotics: Atypicals
The Atypical Antipsychotics - atypical agents are serotonin-dopamine 2 antagonists (SDAs)
They are considered atypical in the way they affect dopamine and serotonin neurotransmission in the four key dopamine pathways in the brain.

30. The newest medication is Invega.
Medications
In general it may take up to 6 months for medications to show consistent effects.
The newest medication is Invega.
Meds include atypicals: Abilify, Geodon, Clozapine, Risperidone, Seroquel, Zyprexa.
[Remember: a giraffe can really see a zebra]

31. These medications may have such intolerable side effects that the patient will stop the drugs.
One study showed the average time the meds were taken regularly was 3 months.

32. Biomedical Therapies Drug Therapies Brain Stimulation Psychosurgery
Antipsychotic Drugs
Antianxiety Drugs
Antidepressant Drugs
Mood-Stabilizing Medications
Brain Stimulation
Electroconvulsive Therapy
Alternative Neurostimulation Therapy
Psychosurgery

33. Biomedical Therapies (1) Drug Therapies
1-Antipsychotic Drugs
2-Antidepressant Drugs
3-Tranquilizers
4-Mood-Stabilizing Medicines

34. Antipsychotic Drugs and Schizophrenia
Good for reducing:
Agitation
Delusions
Hallucinations
Can shorten schizophrenic episodes
Offers little relief from:
Jumbled thoughts
Difficulty concentrating
Inability to interact with others

35. After the Introduction of Anti- psychotic Drugs

36. Treatment of Schizophrenia
The acute psychotic schizophrenic patients will respond usually to antipsychotic medication.
According to current consensus we use in the first line therapy the newer atypical antipsychotics, because their use is not complicated by appearance of extrapyramidal side-effects, or these are much lower than with classical antipsychotics.
conventional antipsychotics
(classical neuroleptics)
chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine
droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine
atypical antipsychotics
amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride

37. Types of Drug Treatment
Typical Antipsychotics
Dopamine antagonists
Atypical Antipsychotics
5-hydroxytryptamine effect, also effect dopamine
Combination Drugs

38. Tend to produce Extrapyramidal side effects:
Typical
Tend to produce Extrapyramidal side effects:
Parkinsonism – tremors, rigidity, slowness of movement, temporary paralysis
Dystonia – involuntary muscle contractions
Akathisia – inability to resist urge to move
Tardive dyskinesia – involuntary movements of the mouth, lips, and tongue
Chewing, puckering, grimacing, etc.

39. Typical - Phenothiazines
Dopamine D2 receptor antagonists
Chlorpromazine first developed from promethazine, first tricyclic antihistamine
Promethazine
Chlorpromazine
Trifluoperazine

40. Haloperidol
Butyrophenone
Used in 1970s almost exclusively
No anticholinergic effects – therefore used in patients with delirium

41. Atypicals do not induce EPSE
Block D2 receptors and 5-HT seratonin receptors (decreases EPSE)
As opposed to typicals, these are more loosely bound to D2 receptors
Easier dissociation
Shown that higher occupation of D2 receptors by drug, higher incidence of EPSE

42. Most effective in reducing EPSE, also in reducing negative symptoms
Clozapine
First atypical (1990)
Most dangerous atypical: risk of agranulocytosis (severe decrease in WBC count)
Most effective in reducing EPSE, also in reducing negative symptoms
Increases Fos-positive neurons in the prefrontal cortex (shown to affect negative symptoms)

43. Clozapine (Clozaril) Available in 1 form- a regular tablet
Is reserved for treatment resistant patients because of side effect profile but this stuff works!
Associated with agranulocytosis (0.5-2%) and therefore requires weekly blood draws x 6 months, then Q- 2weeks x 6 months)
Increased risk of seizures (especially if lithium is also on board)
Associated with the most sedation, weight gain and transaminitis
Increased risk of hypertriglyceridemia, hypercholesterolemia, hyperglycemia, including nonketotic hyperosmolar coma and death with and/or without weight gain

46. Predominantly blocks D2, then 5-HT
Risperidone
Low doses needed
Predominantly blocks D2, then 5-HT
Does not exhibit multireceptor action
Lacks anticholinergic activity – makes it better for youth, elderly
Problem – increases prolactin levels (shouldn’t give to people with breast cancer)

47. Risperidone (Risperdal)
Available in regular tabs, IM depot forms and rapidly dissolving tablet
Functions more like a typical antipsychotic at doses greater than 6mg
Increased extrapyramidal side effects (dose dependent)
Most likely atypical to induce hyperprolactinemia
Weight gain and sedation (dosage dependent)

50. Olanzapine
Zyprexa is number one antipsychotic in sales (Eli Lilly)
Exhibits multireceptor action
Good for controlling mood symptoms
Available in a wafer
Problems: Sedation and
weight gain

51. Olanzapine (Zyprexa)
Available in regular tabs, immediate release IM, rapidly dissolving tab, depo form
Weight gain (can be as much as 30-50lbs with even short term use)
May cause hypertriglyceridemia, hypercholesterolemia, hyperglycemia (even without weight gain)
May cause hyperprolactinemia (< risperidone)
May cause transaminitis (2% of all patients)

57. Ziprasidone (Geodon)
Available regular tabs and IM immediate release form
Clinically significant QT prolongation in susceptible patients
May cause hyperprolactinemia (< risperidone)
No associated weight gain
Absorption is increased (up to 100%) with food

59. Quetiapine (Seroquel)
Available in a regular tablet form only
May cause transaminitis (6% of all patients)
May be associated with weight gain, though less than seen with olanzapine
May cause hypertriglyceridemia, hypercholesterolemia, hyperglycemia (even without weight gain), however less than olanzapine
Most likely to cause orthostatic hypotension

61. Aripiprazole (Abilify)
Available in regular tabs, immediate release IM formulation and depo form
Unique mechanism of action as a D2 partial agonist
Low EPS, no QT prolongation, low sedation
CYP2D6 (fluoxetine and paroxetine), 3A4 (carbamazepine and ketoconazole) interactions that the manufacturer recommends adjusted dosing. Could cause potential intolerability due to akathisia/activation.
Not associated with weight gain

62. Citrome L, Postgraduate Medicine 2011
Iloperidone (Fanapt)
Comes in regular tabs
Needs BID dosing
Titrate over 4 days to 12mg/day in order to minimize risk of orthostatic hypotension
Low EPS, akathisia, wt gain and metabolic disturbances
Inhibitors of 3A4 (ketoconazole) or 2D6 (fluoxetine, paroxetine)-Can increase blood levels two-fold!
QT Prolongation- mean increase of 19msec at 12mg BID
Not recommended for patients with hepatic impairment
Due to α-adrenergic blockade
Citrome L, Postgraduate Medicine 2011

64. Timeline of Major Antipsychotic Therapies
Paliperidone
ECT, etc.
Olanzapine
Quetiapine
Aripiprazole
Consta
Chlorpromazine
Fluphenazine
Risperidone
Thioridazine
Haloperidol
Clozapine
Ziprasidone
Consta = Long-acting injectable risperidone

66. Agents for EPS
Anticholinergics such as benztropine, trihexyphenidyl, diphenhydramine
Dopamine facilitators such as Amantadine
Beta-blockers such as propranolol
Need to watch for anticholinergic SE particularly if taken with other meds with anticholinergic activity ie TCAs

67. Objectives
To outline the cognitive understanding of symptoms of schizophrenia
To review the cognitive therapy approach to ameliorating these symptoms

68. Therapy Approaches Biomedical Therapy Psychotherapy
Alternative Therapies
The Power of Forgiveness

69. Introduction
Of patients with diagnosis of schizophrenia, 25% to 50% continue to experience persistent symptoms.
There is need to develop effective psychological interventions that target persistent symptoms and that also address frequently occurring co-morbid conditions, such as depression and anxiety
In a recent review of controlled trial studies testing the efficacy of cognitive therapy for schizophrenia:

70. Introduction (cont.)
Cognitive therapy reduces delusions, hallucinations, and negative symptoms and that these gains are sustained over time
Patients receiving cognitive therapy as well as routine care [that is, pharmacotherapy + case management] show significantly greater improvement than do patients receiving supportive therapy + routine care.

71. General Structure of Therapy
Cognitive therapy for psychosis is active, structured, time-limited (between 6 and 9 months)
Establish a strong therapeutic alliance through gentle questioning and guided discovery aiming to create a climate of openness and trust
Develop and prioritize problem list
Pursue psychoeducation and normalize symptoms of psychosis

72. General Structure of Therapy (cont.)
Develop cognitive conceptualization
Cognitive and behavioral techniques to treat positive and negative symptoms
Cognitive and behavioral strategies to treat co-morbid depression and anxiety
Relapse Prevention
Establish step-by-step action plan to deal with setbacks

73. Cognitive Focus in Negative Symptoms
Anhedonia, apathy, low motivation, and emotional withdrawal, are not specific to schizophrenia and found to be even more in depression
Affective flattening: the problem may lie in expressing emotions rather than in a deficit in the ability to feel
Alogia may reflect difficulty in finding the right words rather than representing a dearth of communication skills

74. Cognitive Focus in Negative Symptoms (cont.)
In summary, negative symptoms reflect cognitive, emotional, and behavioral dysfunction rather than stable deficits
These may be amenable to change through cognitive technique

75. Cognitive Therapy of Negative Symptoms
Thorough functional analysis of the patient's behavior
Identifying barriers of engagement including co-morbid depression and anxiety
20% to 50% have severe depression at the time of relapse

76. C.T. of Negative Symptoms (cont.)
More than two-thirds of schizophrenia patients will experience a depressive episode at some time
Withdrawal and apathy may be due to fears associated with anxiety conditions (unmanageable somatic experiences, feelings of helplessness, and negative evaluation)

77. C.T. of Negative Symptoms (cont.)
Anhedonia, apathy and withdrawal may be the result of avoidances to prevent the onset of distressing positive symptoms which will lead to readmission, overmedication or medication side effects

78. C.T. of Negative Symptoms (cont.)
The same strategies used for depression
Behavioral self-monitoring
Activity scheduling
Mastery and pleasure ratings
Graded task assignment

79. C.T. of Negative Symptoms (cont.)
Assertiveness training methods
Eliciting the patient's reasons for inactivity
Behavioral experiments for testing these beliefs
Stimulate new interests or reactivate previously held interests

80. Conclusions
Psychosis can benefit from cognitive strategies that identify, test, and correct distorted interpretations that underly the production of delusions and hallucinations
Cognitive Therapy can enhance motivation, reduce emotional withdrawal and improve engagement in social events
More attention to therapist training in this modality is needed
More studies testing its effectiveness in community clinical settings are wanted

81. Psychosocial interventions
Schizophrenia
Treatment
Psychosocial interventions
Social skills training
Vocational rehabilitation
Family psychoeducation – especially for families with high levels of “expressed emotion”
Supportive psychotherapy

82. Psychosocial Support System
Community-based Interdisciplinary Treatment Team
Provide basic necessities:
Finances
Housing
Personal support network
All other treatments require these to be in place

83. Treatments
Psychotherapy - an adjunct to meds and is very useful to keep the patient on the meds.
Group therapy
Family therapy
Community support groups

84. Family Therapy
The therapist helps family members understand how their ways of relating to one another create problems.
The treatment’s emphasis is not on changing the individuals, but on changing their relationships and interactions.

85. Anxiolytics
Used to treat many diagnoses including panic disorder, generalized Anxiety disorder, substance-related disorders and their withdrawal, insomnias and parasomnias. In anxiety disorders often use anxiolytics in combination with SSRIS or SNRIs for treatment.

86. Benzodiazapines
Used to treat insomnia, parasomnias and anxiety disorders.
Often used for CNS depressant withdrawal protocols ex. ETOH withdrawal.
Side effects/cons
Somnolence
Cognitive deficits
Amnesia
Disinhibition
Tolerance
Dependence

87. i. Electroconvulsive therapy - a history
Convulsions and electricity have been known to reduce symptoms in people with neurological disorders for many years
- hippocrates saw that insane patients
showed reduced symptoms after
suffering from convulsions brought on
by malaria.
There is an account in ad 47, of a
physician using an electric eel to cure
headaches of the roman emperor claudius.
- In the 1500s
a jesuit missionary wrote of ethiopians using electricity to “expel devils.”
paracelsus, a swiss physician, used camphor to produce seizures to cure insanity.

88. The mechanism of ect is not fully understood, but in order to understand some of the explanations it is important to know something about neurons and how they work.

95. Case
21 yo AA male with symptoms consistent with schizophrenia is admitted because of profound psychotic sx. He is treatment naïve. You plan to start an antipsychotic- what baseline blood work would you obtain?

96. Many atypical antipsychotics can cause dyslipidemia, transaminitis and elevated blood sugars and there is a class risk of diabetes unrelated to weight gain so you need the following:
Fasting lipid profile
Fasting blood sugar
Lfts
CBC

97. His labs come back as follows:
Total Cholesterol:215 HDL:30 LDL:145
Glucose 88
Others normal
What agent would you like to start?

98. Pt has mildly elevated total cholesterol and a low HDL for his age
Pt has mildly elevated total cholesterol and a low HDL for his age. Would not choose Olanzapine or Quetiapine given risk of dyslipidemia. Risperidone, Ziprasidone or Aripiprazole are good choices.
You start Risperidone and titrate to 3mg BID (high average dose). He starts to complain that he “feels uncomfortable in my skin like I can’t sit still”. What is likely going on and what are you going to do about it?

99. He is likely experiencing akathisia
He is likely experiencing akathisia. This is not uncommon with Risperidone. Given he was very ill reducing the dose may not be the best choice so likely treat with an anticholinergic agent or propranolol. You need to treat akathisia because it is associated with an increase risk for suicide!