1. Psychopharmacology of Antipsychotics
Michael S. Adragna, MD
Assistant Professor of Psychiatry
Department of Psychiatry
University at Buffalo

2. Objectives Distinguish between typical and atypical antispychotics
Compare and contrast the action of typical and atypical antipsychotics in each dopamine pathway
List common side effects associated with the antipsychotics
Describe the clinical presentation of NMS and treatment options

3. Objectives
Distinguish between Clozaril and the other atypical antipyschotics
Outline the effects of antipsychotics on the cardiac system
Describe the relationship between antipsychotics and metabolic syndrome

4. Where do you see psychosis?
Schizophrenia/Schizoaffective Disorder
Bipolar Disorder
Major Depression
Dementia
Delirium
Secondary to General Medical Condition
Secondary to Substance Use or Withdrawal

5. Psychotic Symptoms POSITIVE Symptoms:
Hallucinations, Delusions, Disorganized Speech and Disorganized Behavior
NEGATIVE Symptoms:
Emotional Withdrawal, Blunted Affect,
Avolition, Anhedonia and Alogia
The majority of my talk will focus on how to treat schizophrenia and the associated psychotic symptoms. However, keep in mind that psychosis can be part of other illnesses than schizophrenia. We will touch on them briefly later. Antipsychotics are for both positive and negative symptoms. Let’s just review what we mean by positive and negative symptoms. You can think of positive symptoms as being an excess/exaggeration of normal functioning. Normal to be able to interpret sounds in our environment, in schizophrenia this is happening with no outside stimulus, the person is experiencing voices, hearing things other people cannot. Delusions can be a misinterpretation of experiences. May believe certain color cars have special meanings and that someone may be sending them special messages through their body language/mannerisms. May not be able to follow someones speech. Posturing/agitation
Negative: reduction in normal functions. Social withdrawal, less interest and pleasure in activities. Restricted range of expression. Less goal directed behavior. Alogia – speech may be slowed down, less spontaneity, brief responses, don’t offer much to questions.
May see as part of illness of schizophrenia, or depression, or side effect to some antipsychotics

6. Types of Antipsychotics
Typical Antipsychotics
(Conventional)
Atypical Antipsychotics
(Second Generation)

7. Typical Antipsychotics
Four Main Actions:
D2 receptor blockade (antagonists)
M1 muscarinic blockade(anticholinergic)
Alpha1 adrenergic blockade
H1 histaminic blockade
To undersatnd how the typicals work and what side effects they produce, you want to be aware that they bind to these four main receptor types. Binding to the doapmine recptors is the desired action, the recptor that gives us the improvement in psychotic symptoms. It is the binding to the other three receptor sites to varying degrees among the speicfic medications that produces much of the side effects profile.

8. Schizophrenia and Dopamine
Efficacy of antipsychotics correlates with dopamine blockade
Psychotic symptoms can be induced by dopamine agonists (amphetamines, cocaine, amantadine)
Although we do not have a full understanding of the biological basis of schizophrenia…we do know that dopamine plays a key role. How do we know that??? Medications that block dopamine receptors, improves psychotic symptoms. Furthermore, dopamine agonists can cause psychotic symptoms.
I had a patient at the college counseling center who was a young male, just the age where you would think about schizophrenia starting. He had a flat affect, was somewhat withdrawn, having difficulty making interpersonal connections. Describes have some suspiciousness that cameras were in rooms watching him, believed that he could hear God’s voice………………….and I later find out he had been abusing over the counter Coricidan tablets.

9. D2 Blockade Mesolimbic Mesocortical Nigrostriatal Tuberoinfundibular
Four Dopamine Pathways
Mesolimbic
Mesocortical
Nigrostriatal
Tuberoinfundibular
After oral ingestion, the medication seeks out every D2 receptor in the brain, located in these four main pathways. it doesn’t discriminate. We will look at each pathway individually to learn the impact of an antipsychotic binding to D2 receptors and this will help us understand some of the side effects produced.

11. Mesolimbic Pathway
Blockade of postsynaptic D2 receptors reduces the positive symptoms of schizophrenia
Approximately 70-90% of D2 receptors are blocked at therapeutic doses of typical neuroleptics
No difference in efficacy among typical antipsychotics
Individual responses do vary among agents
Axons extending from the brainstem area and terminating in the limbic system.
Pathway important role in emotional behavors

12. Mesocortical Pathway Dopamine blockade causes a dopamine deficiency
Results in negative symptoms and cognitive slowing (impaired attention, information processing, serial learning)
Dopamine deficiency may be primary (schizophrenia) or secondary (drug induced)
Arising in brainstem, projecting to the cerebral cortex, including limbic cortex. If there is not sufficient dopamine in this pathway, you see the negative psychotic symptoms we discussed and adverse effects on cognition. Dopamine may already be deficient in this pathway in schizophrenia but the blockade of dopamine receptors also creates a state of dopamine deficiency. So although we may improve hallucinations and delusions, the positive symptoms, these same medications may actually produce negative symptoms.

13. Nigrostriatal Pathway
Pathway extends from substantia nigra to the basal ganglia. This is part of the extrapyramidal nervous system.
Extrapyramidal nervous system controls motor movements
In the basal ganglia there is a reciprocal relationship between dopamine and acetylcholine.

14. Nigrostriatal Pathway
Dopamine blocks Ach release, suppressing Ach activity
Dopamine receptor blockade (typical antipsychotic) results in Ach release and over activity of Ach
Anti-cholinergic drugs will help treat these movement disorders
When dopamine is available in synapse it binds to cholinergic neuron and prevents release of Ach into synapse. If dopamine receptors are blocked and dopamine can not do its job, Ach will be released into synapse and results in Ach over activity

15. Nigrostriatal Pathway
Hypokinetic movement disorders result from dopamine deficiency (Parkinson’s Disease)
Hyperkinetic movement disorders result from increased dopamine activity (chorea, tics)

16. EPS (Extra Pyramidal Symptoms)
Drug-Induced Parkinsonism: shuffling gait, muscular rigidity, tremor, bradykinesia
Drugs with Anti-Cholinergic properties
Benztropine (Cogentin)
Trihexyphenidyl (Artane)
Diphenyhydramine (Benadryl)
Lets look at the abnormal motor movements.

18. EPS
Akathisia - movement disorder characterized by an urge to move, unpleasant sensations in the legs, and an inner restlessness.
Akathisia is primarily a psychological symptom and not just a movement disorder; patients experience the urge to move, and motor and behavioral symptoms result from this phenomenon.
Treatments: 1st with beta-blocker (Propranolol); benzodiazepines can also be helpful.

20. EPS
Dystonia – painful, involuntary muscle spasms, usually in head or neck muscles
50% occur within 48 hours and 90% occur within 5 days of treatment
Types: Oculogyric crisis, Torticolis, Trismus, Buccolingual Crisis
Diphenhydramine (Benadryl) or Benztropine (Cogentin) administered IM
Dystonia – potentially painful sustained muscle contraction most commonly occurring in the muscles of the head or neck. Although this is reversable…you can imagine this is frightening and can impact the patient’s ability to trust the doctor and willingness to continue with the needed medication.
Hyperactivity of dopamine in this pathway as you might expect results in hyperkinetic movement disorders – choreaform movements, tics

21. Nigrostriatal Pathway
Tardive Dyskinesia – continual blockade of dopamine receptors results in up-regulation and a hyperkinetic movement disorder
Abnormal, involuntary movements usually of face, neck, or extremities
Chewing movements, tongue protrusions, grimacing
Incidence is about 5% after one year
Example of hyperkinetic movement disorder. Subtle in some cases, much more disbaling in others. Use AIMS test to help monitor for development of this disorder, especially if on a typical/older agents
Irreversible, permanent once it emerges.

22. Tuberoinfundibular Pathway
Dopamine normally inhibits Prolactin secretion
Elevated Prolactin levels (hyperprolactinemia) causes galactorrhea, amenorrhea, sexual dysfunction and weight gain
Elevated Prolactin levels expected in the post- partum state
Projecting form hypothalamus to the anterior pituitary. Normally dopamine neurons are active and inhibiting prolactin release. For example, in post-partum state, levels are allowed to rise so that lactation occurs.

23. Four Dopamine Pathways
Mesolimbic – hallucinations, delusions
Mesocortical – negative/cognitive symptoms
Nigrostriatal – movement
Tuberoinfindibular - prolactin
In some cases, a high cost to doing business. Desired efeect in the Mesolimbic pathway but noticeable side effects in the other dopamine pathways.

24. Imagine the “Ideal Antipsychotic”
Decrease Dopamine in Mesolimbic
Increase Dopamine in Mesocortical
No Disruption of Dopamine in Nigrostriatal and Tuberoinfindibular Pathways

25. Typical Antipsychotics
Four Main Actions:
D2 receptor blockade (antagonists)
Side Effect Profile:
M1 muscarinic blockade (anti-cholinergic)
Alpha1 adrenergic blockade
H1 histaminic blockade
In addition, to binding to dopamine receptors, antipsychotics also have important activity at other receptors, giving them their side effect profile and accounting for some of the differences seen in tolerability among the individual agents.

26. Muscarinic Receptor Blockade
Anti-cholinergic side effects
Drowsiness
Dry-mouth
Blurred vision
Constipation
Confusion
Urinary retention
Those conventional agents that cause more EPS are the agents with weaker anticholinergic properties. Those agents with fewer EPS are the agents with stronger anticholinergic properties
We spoke about the importance of Ach activity recently, when looking at the Nigrostriatal pathway. Hopefully, you recall that Doapmine recptor blockade results in Ach over activity…we get drug induced parkisonism and we fix that by using an Ach drug, to suppress Ach activity. Each of the typical antipsychotics have some intrinsic anticholinergic properties already………….you can imagine that if a particular drug is by its nature very anti cholinergic you will see less problems in the Nigrostriatal pathway. You already have an anticholingeric medicine on board, this will help with the Ach over activity that can occur in this pathway.

27. Adrenergic Blockade Alpha1 adrenergic blockade: Drowsiness
Orthostatic hypotension
Dizziness

28. Histamine Blockade
H1 Blockade:
Drowsiness
Weight gain

29. Typical Antipsychotics
Classified into groups based on potency or affinity for post synaptic D2 receptors
Low-potency
Mid-potency
High-potency
Affinity for D2 receptors influences likelihood to produce EPS
Chlorpromazine was introduced in the early 50’s, the mechanism was largely unknown until the late 60’s and 70’s that we began to understand the the therapeutic effects were related to D2 blockade. These medications are classified into different groups based on their affinity for these D2 receptors.

30. Low Potency Typicals
Chlorpromazine (Thorazine) – first introduced in mid 1950s as anti-histamine which improved psychosis in schizophrenic patients. Mechanism for this not understood until years later.
Less likely to cause EPS, but more likely to produce other side effects: sedation, orthostatic hypotension, etc…

31. High Potency Typicals Haloperidol (Haldol)* Fluphenazine (Prolixin)*
Trifluoperazine (Stelazine)
Greater association with EPS due to greater affinity for D2 receptors and less intrinsic anti-cholinergic properties
* Available in Decanoate preparations, administered intramuscularly
Decanoate are long acting preparations. Haldol injection every 4 weeks. Prolixin injection every two weeks. Often used in cases where compliance is a key issue. In cases of medication over objection, where we ask a judge to order treatment over objection, cases where dangerousness, this ensure the patient is atking medication. You can cheek your pills

32. Neuroleptic Malignant Syndrome
Potentially fatal reaction to neuroleptics
Estimated incidence %
Muscle rigidity, fever, autonomic instability, decreased level of consciousness, elevated CPK
STOP antipsychotic
Administer dopamine agonists and muscle relaxants
Rare but potentially fatal reaction to treatment with antipsychotics, more likely with older agents. Often early in treatment or with recent dose increases.

33. Seizures All antipsychotics decrease the seizure threshold.
This is dose dependent so avoid rapid increase in dose and high dose therapy

35. Atypical Antipsychotics
Defined by either 5-HT2A antagonism or fast dissociation from D2 receptors.
Due to differences in binding, some atypicals are less likely to cause EPS and TD than typicals.
Many variations among the atypicals.

36. Atypical Antipsychotics
Serotonin inhibits dopamine release in the four key dopamine pathways
Blockade of Serotonin receptors promotes dopamine release
More dopamine available to compete with the atypical for a Dopamine receptor – potentially reversing some of the effects of dopamine blockade
Let us discuss what happens if you block not only the D2 receptors but also the Serotonin 2A receptors in each of those four key dopamine pathways.

37. Atypicals and Mesolimbic Pathway
In this pathway, Serotonin2A receptor blockade does NOT reverse the effects of D2 blockade.
Positive symptoms are effectively reduced
In this pathway, we are lucky that serotonin blockade fails to reverse the effects of dopamine blockade.

38. Atypicals in Mesocortical Pathway
Greater number of Serotonin2A receptors than D2 receptors
Dopamine release > Dopamine blockade
Increased levels of Dopamine may improve negative symptoms and cognitive functioning
More serotonin receptors than dopamine receptors so if you think of this as a tug of war, there is proportionally less dopamine blockade. We are always looking at the balance between the two. Dopamine release due to serotonin blockade wins over dopamine blockade.

39. Atypicals in Nigrostriatal Pathway
Blockade of Serotonin2A receptors increases dopamine levels
More Dopamine is available to compete for post synaptic receptors, partially reversing blockade and decreasing EPS
<1% incidence of TD
As we said serotonin inhibits dopamine release. So if we are doing the opposite then, blocking serotonin receptors we are promoting dopamine release. With more dopamine we are able to reverse some of the D2 blockade. We have less EPS and TD less common but we are finding does still occur.

40. Atypicals in Tuberoinfundibular Pathway
Dopamine decreases Prolactin levels
Serotonin increases Prolactin levels
Depending on the atypical, serotonin blockade mitigates the effects of dopamine blockade to varying degrees
In summary with the conventional antipsychotic dopamine release is always blocked. You have the resulting side effects from decreasing dopamine levels. With the atypical antipsychotics, with involvement of serotonin sometimes dopamine release wins out over the dopamine blockade minimizing some of the side effects seen with the older agents. Effect not always robust enough to prevent elevated prolactin levels

41. Four Dopamine Pathways
Mesolimbic – Effects of Dopamine blockade not reversed
Mesocortical – Dopamine release greater then Dopamine blockade
Nigrostriatal – Effects of Dopamine blockade partially reversed
Tuberoinfundibular – Effects of Dopamine blockade partially reversed

42. Risperidone (Risperdal)
Dosed from mg daily
Available in liquid form and long-acting form
More likely to lead to hyperprolactinemia
Other common side effects include sedation, weight gain and orthostatic hypotension
Also now available in longer acting preparation but still not commonly used, problems with reimbursement through insurance companies that is now starting to get worked out. Our first atypical with a longer acting preparation.

44. Olanzapine (Zyprexa) Dosed from 2.5 – 20mg
Rapidly dissolving form (Zydis) & injectable
Common side effects include weight gain, sedation, orthostatic hypotension and anti-cholinergic side effects
Commonly results in elevated serum glucose and triglyceride levels
Lacks EPS at even high doses, generally tends to be well tolerated, some people do not gain weight. In other cases the weight gain can be dramatic.

46. Quetiapine (Seroquel)
Effective dose range is from mg
Significant blockade at H1 receptors causing significant sedation and weight gain
Low incidence of EPS makes it a first line treatment for psychosis in Parkinson’s
Frequent off-label use for insomnia and anxiety

47. Ziprasidone (Geodon) Dosed from 40mg – 160mg in two divided doses
Less likely to cause weight gain
More likely to cause sedation and orthostatic hypotension
Initial concerns regarding QTc prolongation have led to differences in package labeling

48. Aripiprazole (Abilify)
Unique mechanism of action: Antagonist at Serotonin2A receptors but partial agonist at D2 receptors
Partial Agonist – block a receptor if it is over stimulated and stimulate same receptor when needed
Dose ranges from 5-30mg daily
Most common side effect is akathisia

49. Clozapine (Clozaril) Nothing typical about it (except D2 blockade)
First antipsychotic without EPS or TD
No elevation in prolactin levels
Blockade at Serotonin2A and D2
Interacts with at least 9 different neurotransmitter systems making it the most complex antipsychotic

50. Clozapine Slow titration needed due to side effect profile
Recommended dose range from mg/day
Common side effects
Sedation
Weight gain
Increased salivation
Metabolic syndrome

51. Clozapine Serious side effects: Seizures Cardiorespiratory arrest
Agranulocytosis
Weekly blood counts for first 6 months and then bi- weekly WBC count
Agranulocytosis occurs in 0.5 to 2% of patients

52. Clozapine
The absolute neutrophil count (ANC) at or above 1500/mm3 to initiate or continue on medication in the general population.
Need to monitor for signs and symptoms of infection
Patient adherence is critical

53. Why Clozapine?
Treatment Refractory patients – may have improved efficacy over all other atypicals
Reduce risk of suicide
Improve pre-existing tardive dyskinesia
Not a first line agent given side effect profile but some individuals will have profound improvement in symptoms

54. Atypical Antipsychotics
Amount of blockade at Serotonin2A and D2 receptors varies
Activity at other serotonin and dopamine receptor subtypes varies
Activities at other receptors differs also
These differences give each atypical a unique profile with different side effects

55. Antipsychotic Receptor Blockade
Haloperidol
70-90% D2 blockade
Risperidone
60% Serotonin2A blockade
50% D2 blockade
Clozapine
85-90% Serotonin2A blockade
30-60% D2 blockade

56. Antipsychotics and QTc
Atypicals (except aripiprazole) can cause QTc prolongation, not torsades
Typicals (especially Haldol) prolong QTc and can cause torsades. Increased risk with IV administration.
(IV administration not FDA approved but common practice in ICU setting.)

57. Antipsychotics and the Black Box
2003 Atypicals can cause potentially fatal Diabetes Mellitus
2005 Atypicals when used in elderly with dementia and related psychosis and treated with antispychotics have an increased risk of death
2008 Above warning extended to Typicals

58. Atypical Antipsychotics
All atypicals require monitoring for the development of a Metabolic Syndrome
Weight Gain
Dyslipidemia
Glucose Intolerance

59. Metabolic Syndrome BMI = weight (kg) / height squared (m2)
Normal
Overweight
Obesity ≥ 30
Clinically significant weight gain with increase from 5-7% warrants clinical intervention.

60. Metabolic Syndrome Greatest Risk Clozapine Olanzapine
Intermediate Risk Risperidone
Quetiapine
Lowest Risk Ziprasidone
Aripiprazole

61. Time Course of Antipsychotic Response
Certain target symptoms may diminish in first few days (or hours):
Agitation
Psychomotor excitement
Improvement in psychotic symptoms typically occurs in the following order over 3-5 weeks:
Thought disorder
Hallucinations – decreased intensity, frequency
Delusions – new misinterpretations are first affected

62. Are Atypicals More Effective Than Typicals?
NIMH funded CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study
Largest (1463 patients) and longest (18 months) study of chronic schizophrenia patients
Phase I results published September 22, in New England Journal of Medicine

63. Efficacy of 4 atypicals compared to perphenazine (Trilafon)
All medications are efficacious but discontinuation of treatment also common (74% dropout rate).
Is the use of atypicals justified given comparable efficacy to typicals but much higher cost?
Newer medications compared with each other as well as to Trilafon. Looked at how the drugs affected symptoms but also daily functioning. For 18 months looked at how they functioned day to day, how much support they needed and how long they chose to stay on the medications. Initial headlines implied newer drugs not better over older agents. Reality was more that all treatments work but each one has own advantages and drawbacks. What we learned is where we still need to go. Although the older medications remain effective treatments, concerns about TD remains biggest liability. Most people still believe that the atypicals are first line agents and considered the gold standard.

65. Secondary Analyses I
Fewer patients in the olanzapine group than in the other four groups were hospitalized for an exacerbation of schizophrenia.
More patients discontinued perphenazine owing to extrapyramidal effects.
Quetiapine was associated with a higher rate of anticholinergic effects.

66. Secondary Analyses II
More patients discontinued olanzapine owing to weight gain or metabolic effects.
Patients in the olanzapine group gained more weight than patients in any other group, with an average weight gain of 2 lbs per month.
Olanzapine had effects consistent with the potential development of the metabolic syndrome (Increased HbA1C, Total cholesterol, TAG)
Ziprasidone was the only study drug associated with improvement in each of these metabolic variables.
Only risperidone was associated with a substantial increase in prolactin levels.
There were no substantially different effects of the medications on the QT interval on electrocardiography, and torsades des pointes did not develop in any patients.

67. Acute treatment: Considerations in drug selection
Prior response
Side effect profile
Patient preference
Route of administration
Cost?