1. Anti-psychotics
Mainstay of pharmacological treatment for schizophrenia and related disorders
Diminish positive symptoms such as hallucinations, delusions, thought disorder
Some impact on negative symptoms such as lack of motivation, blunted affect, cognitive impairment
Important as a part of relapse prevention
Introduction
Antipsychotics are the foundation of pharmacological treatment of schizophrenia and other psychotic illnesses. Antipsychotic medications reduce positive symptoms such as hallucinations, delusions and thought disorder. They can also have some impact on negative symptoms such as poor motivation, blunted affect and cognitive impairment. Antipsychotics are very important in preventing relapses.
Antipsychotic actions are thought to be mediated by the blockade of dopamine transmission in various parts of the brain. Antagonism of other receptors, such as serotonin and histamine, also influence the activity of antipsychotic drugs.
Clinical Indications
Antipsychotics are prescribed for:
Acute Psychosis
Schizophrenia
Acute Mania
Organic Psychosis
Adjunct in psychotic depression
Severe behavioural disorders in children
Adjunct in anaesthesia
Adjunct in treatment of alcoholic hallucinosis
Tourette’s syndrome
Intractable nausea and vomiting (haloperidol, droperidol)
Intractable hiccup (chlorpromazine)
Delusional Disorders
Schizoaffective Disorders
Schizophreniform disorder, brief reactive psychosis or disorder not otherwise specified
Bipolar Disorder manic or mixed
Major Depressive Episode with psychotic features
Organic mental syndrome with psychotic features
Aggressive/disruptive behaviour in delirium, dementia or mental retardation (low doses)

2. Anti-psychotics
Antagonise dopamine receptors, resulting in anti-psychotic effects
Indications-schizophrenia, acute mania, psychotic depression,
Conventional and atypical
Both of equivalent efficacy when taken at recommended dosages
Atypicals have lower incidence of EPSE
Major and sub classes
There are two major types of antipsychotics:
1. Conventional or typical antipsychotics
2. Atypical antipsychotics

3. Dopamine Theory
The dopamine hypothesis of psychosis – overactivity of dopamine neurons in the mesolimbic pathway of the brain may mediate the positive symptoms of psychosis
Mesolimbic pathway responsible for pleasure, effects of drugs and alcohol and hallucinations and delusions
Figure 1: The Dopamine Hypothesis of Psychosis
Overactivity of the dopamine neurons in the mesolimbic pathway may mediate the positive symptoms of psychosis
(Stahl, S, (1999) Psychopharmacology of antipsychotics, Martin Dunitz, London)
All conventional antipsychotic drugs block dopamine D2 receptors. Antagonism of the dopamine D2 receptor results in the antipsychotic effects. Conventional antipsychotics block dopamine, muscarinic, histamine and alpha-adrenergic receptors.

4. Blockade Of D2 Receptors?
Nigrostriatal pathway
extrapyramidal side effects (EPS) and tardive dyskinesia D2
ANTAGONIST
Mesocortical pathway
enhanced negative and cognitive psychotic symptoms
Mesolimbic pathway
dramatic therapeutic action on positive psychotic symptoms
Tuberoinfundibular pathway
hyperprolactinemia (lactation, infertility, sexual dysfunction)
Nigrostriatal pathway - transmits dopamine from the substantia nigra (part of the mid brain) to the striatum (sub cortex). This pathway is associated with motor control. (Disorders for example: Parkinson’s)
Mesocortical pathway - transmits dopamine from Ventral Tegmental Area (mid brain) to frontal cortex (Disorder: Schizophrenia)
Mesolimbic pathway – transmits dopamine from VTA to nuclear Acumbens
Tuberoinfundibular pathway – transmits dopamine from hypothalmus to the pitutary gland (Disorder: hyperprolactinaemia)

5. Dopamine Receptors
Five subtypes – D2 most important in terms of psychosis
Blockade of mesolimbic receptors leads to reduced psychotic symptoms
Blockade of the mesocortical pathway leads to increased negative symptoms

6. Dopamine Receptors
Dopamine and acetylcholine have a reciprocal relationship-
Blockade of dopamine receptors increases the activity of acetylcholine
Over activity of acetylcholine causes EPSE
Blockade of dopamine causes movement disorders in the nigostriatal pathway
Long tem blockade causes “upregulation” and leads to Tardive Dyskinesia

7. Conventional or typical Antipsychotics
Have four actions – blockade of:
Dopamine 2
Muscarinic/cholinergc
Alpha adrenergic
Histamine
Figure 2: Conventional Antipsychotic
The figure represents a conventional or typical antipsychotic drug. Such drugs have at least four actions: blockade of dopamine, histamine, muscarinic and alpha-adrenergic receptors
(Stahl,S, (1999) Psychopharmacology of antipsychotics, Martin Dunitz, London)

8. Serotonin and Dopamine Interactions
Figure 5: Serotonin and Dopamine Interactions
This pathway regulates movement. Dopamine release from this pathway is regulated by serotonin. Dopamine and serotonin have a reciprocal relationship. Here, no serotonin is present at the receptor, therefore dopamine is being released.

9. The Dopamine Receptor Antagonist Hypothesis of Antipsychotic drug Action
Blockade of post synaptic dopamine receptors in the mesolimbic pathway is thought to mediate the efficacy of the drug and its ability to diminish positive symptoms
Figure 3: The Dopamine Receptor Antagonist Hypothesis of Antipsychotic Drug Action
Blockade of post synaptic dopamine receptors in the mesolimbic pathway is thought to mediate the efficacy of the drug and its ability to diminish positive symptoms (Stahl, S (1999) Psychopharmacology of antipsychotics, Martin Dunitz, London).

10. Receptor Affinity Low Affinity (loosely bound)
- Quetiapine, Olanzapine, Amisulpride, Clozapine
High Affinity (tightly bound)
- Chlorpromazine, Haloperidol, Flupenthixol, Fluphenazine
Tightly bound drugs lead to increased sensitivity to dopamine blockade so more likely to cause EPSE
The efficacy of the typical antipsychotic agents is strongly linked to their affinity for D2 receptors: the greater the affinity, the more potent the drug.

11. Atypical Antipsychotics
Pharmacologic Properties
5HT2A and D2 antagonism (as opposed to conventional drugs which are D2 without 5HT2A antagonism)
Atypicals – blockade of D2 and 5HT2A
Figure 4: Atypical Antipsychotics
These drugs are not just simply serotonin-dopamine antagonists. They have very complex pharmacologic properties. These agents act on multiple dopamine and serotonin receptors and the noradrenergic and cholinergic system.
(Stahl,S,(1999) Psychopharmacology of antipsychotics, Martin Dunitz, London)

12. Dopamine and Serotonin Receptors
Dopamine and serotonin have a reciprocal relationship
Serotonin opposes the release of dopamine in the nigrostriatal and tuberofundibular pathways
Figure 5: Serotonin and Dopamine Interactions
This pathway regulates movement. Dopamine release from this pathway is regulated by serotonin. Dopamine and serotonin have a reciprocal relationship. Here, no serotonin is present at the receptor, therefore dopamine is being released.

13. Dopamine and Serotonin Receptors
Action of atypicals – firstly binds to the D2 receptor
Secondly, binds to the 5HT2A receptor
The second action reverses the first – reverses the blockade of D2
Blocking 5HT2A disinhibits the dopamine neuron causing dopamine to pour out

14. Dopamine and Serotonin Receptors
The dopamine and serotonin then compete with the drug for the D2 receptor
Increased dopamine in the mesocortical pathway
Reduction in movement disorders/EPSE for atypical antipsychotics
Atypical Antipsychotics
Individual drugs act as antagonists at different dopamine receptor subtypes. All except amisulpride act as serotonin receptor antagonists. They are sometimes known as serotonin-dopamine antagonists (SDAs). The action of serotonin-dopamine antagonism differentiates atypical anti-psychotics from the conventional drugs. Atypical drugs are generally better tolerated and have less EPSE than conventional anti psychotics. Clozapine is the only antipsychotic considered to be of superior efficacy, but because of its adverse effect profile, it should only be used for treatment resistant patients.

15. Atypicals In reality – not simple serotonin-dopamine antagonists
Most complex pharmacological properties
Act on multiple serotonin and dopamine receptors, histamine, alpha adrenergic & cholinergic
Figure 2: Conventional Antipsychotic
The figure represents a conventional or typical antipsychotic drug. Such drugs have at least four actions: blockade of dopamine, histamine, muscarinic and alpha-adrenergic receptors
Stahl,S, (1999) Psychopharmacology of antipsychotics, Martin Dunitz, London)

16. Atypicals versus conventional
All equal efficacy (except Clozapine)
Consideration for:
Merits of high versus low affinity drugs
Cerebral selectivity of the drugs
Adverse effect profile
Dose necessary to achieve optimal D2 blockade
Patient tolerability, preference, response
Selected antipsychotics will target individual receptors
Adverse effects – to minimize adverse effects: prescribe tailored to suit the individual
Dose titrated individually to achieve therapeutic window
Consider previous response

17. Anti-psychotics
Conventional – eg chlorpromazine, haloperidol, stelazine, depots such as flupenthixol, zuclopenthixol, fluphenazine
Atypical – eg olanzapine, risperidone, quetiapine, amisulpride, clozapine, risperdal consta intramuscular injection, aripiprazole, paliperidone, ziprasidone
Also have effects on acetylcholine, histamine,serotonin receptors – varying adverse effects
The conventional antipsychotics are divided into several different classes according to their chemical structure:
Phenothiazines (chlorpromazine, fluphenazine, pericyazine, thioridazine, trifluoperazine)
Butyrophenones (droperidol, haloperidol)
Thioxanthines (flupenthixol, thiothixene, zuclopenthixol)
Diphenylbutylpiperidines (pimozide)
Zuclopenthixol, Haloperidol, Fluphenazine and Flupenthixol are all available in depot preparations. All antipsychotics competitively block dopamine D2 receptors. All conventional antipsychotic drugs are thought to be of equal efficacy when taken at the appropriate dose.
Typical/Conventional Antipsychotics available for use in Australia
Chlorpromazine
Droperidol (use limited due to serious cardiac adverse events and sudden death)
Flupenthixol Decanoate
Fluphenazine Decanoate
Haloperidol
Haloperidol Decanoate
Pericyazine

18. Atypical antipsychotics
The ‘newer” antipsychotics
Effectively treat psychotic symptoms
Lower incidence of extra pyramidal side effects than conventional agents
Have effects on dopamine, serotonin, histamine and muscarinic receptors
Pimozide ( Available only through Special Access Scheme (SAS) due to serious cardiac adverse effects and sudden death)
Thioridazine (use restricted due to serious cardiac adverse events and sudden death)
Thiothixene ( Not marketed in Australia but may be available through Special Access Scheme (SAS)
Trifluoperazine
Zuclopenthixol Acetate
Zuclopenthixol Decanoate
Zuclopenthixol Dihydrochloride
Conventional or Typical Antipsychotics:
The conventional antipsychotics are divided into several different classes according to their chemical structure:
Phenothiazines (chlorpromazine, fluphenazine, pericyazine, thioridazine, trifluoperazine)
Butyrophenones (droperidol, haloperidol)
Thioxanthines (flupenthixol, thiothixene, zuclopenthixol)
Diphenylbutylpiperidines (pimozide)
Zuclopenthixol, Haloperidol, Fluphenazine and Flupenthixol are all available in depot preparations. All antipsychotics competitively block dopamine D2 receptors. All conventional antipsychotic drugs are thought to be of equal efficacy when taken at the appropriate dose.

19. Atypical antipsychotics
Current atypicals in use in Australia are:
Amisulpride
Aripiprazole
Quetiapine
Olanzapine
Risperidone
Clozapine
Ziprasidone
Paliperidone
Atypical Antipsychotics available for use in Australia
Quetiapine
Risperidone
Clozapine
Olanzapine
Amisulpride
Aripiprazole
Ziprasidone
Paliperidone Extended Release
Indications
Schizophrenia and related psychosis
Acute mania
Behavioural disturbance in dementia

20. Therapeutic effects on symptoms
Agitation, sleep and appetite often respond in the first 1-2 weeks
Personal hygiene and basic interpersonal socialisation may take 2-3 weeks and psychotic symptoms can gradually decrease over 2-6 weeks
An effective trial should be at least 6-8 weeks at doses that are within the prescribed range
Therapeutic effect
Most antipsychotics are absorbed rapidly and are highly lipid soluble. There is widespread variability amongst patients in the pharmacokinetics of and responses to these drugs. The onset of the sedative properties of antipsychotic medications can be relatively fast, however, the impact on the target positive and negative symptoms may take several weeks. Symptoms often respond to antipsychotics in somewhat different time frames. Agitation, sleep and appetite often respond in the first 1-2 weeks whereas personal hygiene and basic interpersonal socialisation may be slower to respond (2-3 weeks), and psychotic symptoms can gradually decrease over 2-6 weeks. Residual symptoms may continue to improve at 6-12 weeks. An effective trial should be at least 6-8 weeks at doses that are within the prescribed range. Positive symptoms may respond to medication in 1-2 weeks. The lowest dose possible should be prescribed, followed by appropriate dose titration. Atypical and typical antipsychotics are of comparable efficacy, with the exception of Clozapine, which is thought to have superior efficacy. Atypical medications are thought to be better in treating the negative symptoms of schizophrenia and may also have a positive effect on cognitive dysfunction. Because their efficacy is at least equal to the conventional medications and they are relatively well tolerated, the atypical agents are widely advocated as first line treatment.
Usher, Foster & Bullock (2009)

21. How long should antipsychotics be taken for?
At least 6 months after an acute episode reduces relapse rates
If the person experiences another episode they may need antipsychotic medication for 2-5 years before ceasing use
For those with multiple episodes, they may need medication for much of their life
How long should antipsychotics be taken for?
Continuing antipsychotic drugs for at least 6 months after an acute episode reduces relapse rates. Some people will require anti-psychotic medication for long periods. Usually the medication is continued for 1-2 years after the person has achieved excellent recovery from their first episode, and is stable in life with regards to work or accommodation. If the person experiences another episode they may need anti-psychotic medication for 2-5 years before ceasing use. For those who have multiple episodes, they may need to use medication for much of their life. Indefinite continuation of maintenance therapy is required for the majority of people with schizophrenia.

22. Adverse Effects Sedation Postural hypotension
Anticholinergic effects – dry mouth, blurred vision, constipation, urinary hesitancy
Weight gain-clozapine, olanzapine
Metabolic effects-increased serum lipids, impaired glucose tolerance-clozapine, olanzapine, quetiapine
Side effects: Antipsychotics –Common-
Sedation: Sedation is associated with all antipsychotics. It tends to be most pronounced at the initiation of therapy or with upward dose titration. Starting at low doses and titrating up the dose slowly can reduce the impact of sedation. Clients should be advised to expect sedation in the early stages of treatment, and that this may affect their ability to drive or operate machinery safely.
Postural hypotension: Some antipsychotics are associated with postural hypotension. and this may increase the risk of falls particularly in aged persons. Advice should be provided in accordance with each client’s clinical presentation.
Anticholinergic effects: Most antipsychotic drugs possess some degree of anticholinergic activity (dry mouth, blurred vision, increased intraocular pressure, constipation and urinary hesitancy – older people may are more susceptible to delirium). The exceptions are: amisulpride, aripiprazole and risperidone. Blurred vision, Constipation
Nausea, Urinary retention, Sexual adverse effects, Extrapyramidal side effects
Weight gain: Most antipsychotic medications cause weight gain. Clozapine, olanzapine and to a lesser extent quetiapine are associated with weight gain. Baseline Body Mass Index (BMI) and weight should be taken prior to commencing antipsychotic medications for monitoring throughout treatment. Metabolic effects: Some antipsychotic medications are associated with abnormal glucose tolerance and increased serum lipids and place client at increased risk of diabetes, cardiovascular disease, risks that are augmented by obesity and lifestyle factors such as smoking and lack of exercise. It is recommended that fasting blood glucose and serum lipid measurements be measured around the onset of treatment in all cases and annually thereafter, but at least every 6 months in clients placed on clozapine or olanzapine Counselling in regard to diet, exercise and smoking cessation/reduction are important.

23. Adverse Effects
Hyperprolactinaemia-leads to galactorrhoea, amenorrhoea, decreased libido
Sexual dysfunction
QTc prolongation-leads to cardiac arrhythmias
EPSE-extrapyramidal side effects
Acute dystonias -laryngeal spasm, oculogyric crises
Akathisia-severe sense of agitation, inner restlessness in the limbs, especially the legs
Hyperprolactinemia: Raised prolactin may lead to gynaecomastia, galactorrhea, amenorrhoea, anovulation, impaired spermatogenesis, decreased libido, impaired sexual arousal, impotence and anorgasmia. These effects are dose dependent and associated to varying degrees with all antipsychotic drugs, with the possible exception of aripiprazole, clozapine and quetiapine. Routinely enquire about menstrual irregularities and sexual functioning.
Sexual dysfunction: Some antipsychotic medications can be associated with sexual dysfunction or sexual problems. Clinicians should ask questions early into treatment about sexual function.
QTc interval prolongation: Some antipsychotics may prolong the QTc interval which could lead to a life threatening condition called torsade de pointes. Thioridazine, pimozide, ziprasidone and droperidol are more likely to contribute to this condition. Women and people with hypokalemia, hypomagnesaemia, hypocalcaemia, renal failure, cardiac failure or a congenital disposition, are more susceptible to prolongation of the QTc interval. If a client’s history or family history suggests susceptibility, an electrocardiogram (ECG) should be done before starting treatment and there must be regular monitoring during treatment.
Extrapyramidal side effects: These effects are generally an indication that the dose of drug has exceeded the optimal therapeutic range for a given patient and should be reviewed.
Acute dystonia’s: Dystonia’s tend to develop within hours to days of antipsychotic administration and affect the face, neck and trunk. Dystonia’s such as an oculogyric crisis or opisthotonos can occur. Laryngeal spasm is also potentially fatal adverse effect. Young males are more susceptible to acute dystonia’s that others. Dystonia’s are treated with intramuscular antiparkinsonian (anticholinergic) medication such as benztropine.
Acute Dystonia
Symptoms commonly occur secondary to neuroleptic medication. Generally develops within minutes to days and often affect the face, trunk, neck or hands. Less common with atypical antipsychotics Laryngospasm (can cause death). Patient may complain of suffocation or be unable to speak (listen for stridor) Torticollis (head forced to one side) Retrocollis (head forced backwards) Protruding tongue with difficulty swallowing Opisthotonos (hyperextension of the back) Oculogyric crisis (eyes rolled upwards or laterally)

24. Acute Dystonias
Intervention
This is a serious medical condition. Refer for medical assessment and treatment urgently. Provide appropriate education and information to the patient. Ensure adverse effects are documented in the clinical record. Usually prescribed Benztropine 2mg IMI .

25. Adverse Effects Akathesia – a severe sense of psychomotor agitation
Parkinsonism -poverty of movement, tremor, rigidity, drooling, hypersalivation
Tardive dyskinesia-involuntary hyperkinetic movements, affects the mouth, lips, tongue, jaws with smacking, tongue writhing, sucking,chewing and tic like movements,limbs and trunk can be affected
Akathesia: is a severe sense of agitation restlessness which tends to be experienced in the limbs, especially the legs, It generally occurs within a few weeks of initiating treatment but can occasionally occur later in treatment. Consider a dose reduction or referral for medical review or switching to another antipsychotic medication.
Parkinsonism: Initially poverty of movement and rigidity may be seen and later tremor, drooling and hypersalivation may be evident. It is typically seen in the early weeks of treatment. Consider dose reduction or switching to another antipsychotic before using antiparkinsonian (anticholinergic) medication.
Tardive dyskinesia: Is a complex syndrome of involuntary hyperkinetic movements, usually large in amplitude, irregular, and worsened with distraction. It most frequently affects the mouth, lips, tongue and jaws, with smacking, tongue writhing, sucking or chewing movements and tic-like movements of the lips, eyes and facial muscles. The limbs and trunk can be affected with choreoathetoid movements. Anxiety increases the abnormal movements, which disappear in sleep. They can interfere with breathing, speaking and eating and are socially stigmatising. If detected early and if the antipsychotic medication can be reduced or ceased then tardive dyskinesia can often be fully reversible. Because of the lack of suitable management for established tardive dyskinesia, prevention is clearly preferred. Reference - Therapeutic Guidelines (2003) Psychotropic Therapeutic Guidelines Pty Ltd Version 5)

26. Adverse Effects Irreversible in some patients
Neuroleptic malignant syndrome-rare but potentially fatal – high temp, muscle rigidity, altered consciousness, raised creatinine kinase –cease medication
Can happen at anytime during treatment
30% patients will develop syndrome again on rechallenge
Neuroleptic Malignant Syndrome (NMS)
Neuroleptic malignant syndrome: All antipsychotics can cause this rare but potentially fatal adverse effect, which can develop at any time during treatment. It should be considered in any client who presents with high temperature, muscle rigidity, altered consciousness, autonomic instability and raised creatinine kinase. Other features can include neutrophilia and occasionally haemorrhagic tendency. If a client is suspected of or has neuroleptic malignant syndrome, they must attend the Emergency Department and have a review by a psychiatrist immediately.
Symptoms include hyperthermia, muscle rigidity, autonomic dysfunction and altered consciousness associated with antipsychotic medication. Signs are variable and my include tachycardia, tachypnoea, diaphoresis, labile BP, sialorrhea, nausea or dysphagia. Sometimes the patient will not feel unwell. Not all symptoms may be present and a high degree of suspicion should be maintained for NMS. Onset is hours to days. Higher incidence in young men, high dose antipsychotics, recent commencement or increased dose of antipsychotics, typical antipsychotics and concurrent lithium use (can occur with atypical antipsychotics). Typically white cell count, creatine kinase (CK) and LFTs are raised (clinical manifestations can be variable). If there is uncertainty, admission to a general hospital for observation would be advised.
Therapeutic Guidelines (2010) Psychotropic Therapeutic Guidelines Pty Ltd Version 5
Intervention
This is a serious medical condition. Consult a senior Medical Officer or Psychiatrist urgently and refer the patient for treatment. This is a life threatening condition requiring urgent medical attention. Immediate management includes ceasing antipsychotic medication, cooling, renal, respiratory and cardiovascular support and monitoring for electrolyte imbalance.
Consult with a psychiatrist as soon as possible and arrange a review of medications. Provide appropriate advice, education and information to the patient regarding the condition.

27. Depot Anti-psychotics
Used when concerns around compliance
Conventional-zuclopenthixol(useful for agitated,aggressive,disturbed behaviour) flupenthixol (may have mood elevating effects) fluphenazine -EPSE common
Typical-Risperdal Consta – onset of action 3 weeks, need oral Risperidone to supplement until peak plasma reached
Depot Formulations
Atypical Antipsychotics
Atypical antipsychotics, or the “newer” antipsychotics, effectively treat psychotic symptoms, but have a lower incidence of extra pyramidal side effects than conventional agents. The atypical antipsychotics have effects on dopamine, serotonin, histamine and muscarinic receptors. Current atypicals in use in Australia are:-Amisulpride, Aripiprazole, Quetiapine, Olanzapine, Risperidone, Clozapine, Ziprasidone, Paliperidone OralDepot Formulations
Some antipsychotics are also available in long acting or ‘depot’ formulations. These can be used when there are issues with medication adherence. The use of a small initial test dose is recommended for conventional antipsychotics. After the test dose is administered the patient should be closely monitored for adverse and/or allergic reactions and clinical response to the medication. Extrapyramidal side effects are common and the incidence is the same for all depot formulations. The pharmacokinetics of depot formulations are quite complex and it may take several months for the medication to reach steady state. Oral supplementation of antipsychotics may be required. Depot formulations are usually given at intervals of 2-4 weeks by deep intramuscular injection and deltoid muscle injection is an option with some specific products eg.Risperidone. Doses of depot medications should not be altered for minor reasons over short periods of time, as this can lead to adverse effects or compromise the control of symptoms.
New atypical long acting antipsychotics have become available recently eg. Risperidone, Olanzapine do not require a test dose if oral form of the drug has already been prescribed and administered. A long acting injection form of Paliperidone is available and Ariprazole are expected to be available in the near future.

28. Comparative Information for Anti-Psychotics
Chlorpromazine, Pericyazine
Most sedating, most potent anticholinergic effects, least likely to cause EPSE, most likely to cause orthostatic hypotension. Low potency antipsychotics
Trifluperazine, Fluphenazine
Moderately sedating, intermediate propensity to cause EPSE, some potential to cause orthostatic hypotension
Haloperidol, Droperidol, Thiothixene, Pimozide
Least sedating, almost no anticholinergic effects, most likely to cause EPSE, least likely to cause orthostatic hypotension, sometimes referred to as ‘high potency’ antipsychotics

29. Atypical antipsychotics
Amisulpride
Less potential for weight gain and sedation
Aripiprazole
May cause insomnia, less potential for hyperprolactinaemia
Clozapine
Effective treatment-resistant patients but has serious side-effects (blood dyscrasias, seizures, cardiomyopathy, myocarditis, orthostatic hypotension, sedation, weight gain).
Atypical agents have less potential for EPSE than conventional agents, but depends on dose. All antipsychotics can cause hyperprolactinaemia and EPSE
Reference: Australian Medicines Handbook (2010) Australian Medicines Handbook Pty Ltd)

30. Atypical antipsychotics
Olanzapine
Related to Clozapine may cause sedation, weight gain, peripheral oedema; increased risk of stroke and related mortality in elderly dementia patients
Quetiapine
Sedating and vasoactive, less potential for hyperprolactinaemia
Risperidone, Paliperidone
Orthostatic hypotension and hyperprolactinaemia, may be a problem; increased risk of stroke and related mortality in elderly dementia patients
Ziprasidone
Less potential for weight gain
Reference: Australian Medicines Handbook (2010) Australian Medicines Handbook Pty Ltd

31. Drug Interactions
Cytochrome P450 isoenzymes are significant in psychotropic drug interactions
Inducers or inhibitors of this pathway may produce clinically important drug interactions
May lead to increase or decrease of medications due to interactions
Interactions
Antipsychotics are involved in various drug interactions via the hepatic cytochrome P450 enzymes. Drugs that induce or inhibit these enzyme pathways can produce clinically significant drug interactions. There are clinically significant drug interactions with many drugs, including alcohol, benzodiazepines, SSRIs, nicotine (smoking) and carbamazepine.

32. Cytochrome P450
Examples
Fluvoxamine inhibits olanzapine and clozapine metabolism
Smoking induces Olanzapine metabolism
SSRIs inhibit most antipsychotics and therefore increase serum concentrations
Phenytoin reduces serum concentration of Quetiapine
Others – grapefruit juice, Antibiotics,

33. Clozapine Used when previously unresponsive to other antipsychotics
Serious adverse effect profile
Strict guidelines relating to commencement and monitoring
Significant risk of agranulocytosis
Trial at least 2 different standard antipsychotics at an adequate dose and for an adequate duration prior to commencing Clozapine
Clozapine is used in people who have been previously unresponsive to other antipsychotics. Clozapine has a serious adverse effect profile and requires strict monitoring. There are strict guidelines relating to the commencement and ongoing monitoring of Clozapine.
Agranulocytosis: Because of a significant risk of agranulocytosis, a potentially life-threatening adverse reaction, reserve clozapine for use in the treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with clozapine, it is strongly recommended that a patient be given at least 2 trials, each with a different standard antipsychotic drug product, at an adequate dose and for an adequate duration.
Patients who are being treated with clozapine must have a baseline white blood cell (WBC) and differential count before initiation of treatment and regular WBC counts during treatment and for 4 weeks after the discontinuation of clozapine.
Clozapine is available only through a distribution system that ensures monitoring of WBC and neutrophil counts prior to delivery of the next supply of medication.
Seizures: Seizures have been associated with the use of clozapine. Dose appears to be an important predictor of seizure, with a greater likelihood at higher clozapine doses. Use caution when administering clozapine to patients having a history of seizures or other predisposing factors. Advise patients not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others.
Myocarditis: Clozapine may be associated with an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. If myocarditis is suspected, promptly discontinue clozapine treatment.
Other adverse cardiovascular and respiratory effects: Orthostatic hypotension, with or without syncope, can occur with clozapine treatment. Rarely, collapse can be profound and be accompanied by respiratory or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation. In patients who have had even a brief interval off clozapine, start treatment with 12.5 mg once or twice/day
Because collapse, respiratory arrest, and cardiac arrest during initial treatment have occurred in patients who were being administered benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug (Drug Facts & Comparisons Pocket Version, 2007 Edition)

34. Use of antipsychotics with older persons
Various disorders treated with antipsychotics in the elderly – psychosis, bipolar affective disorder, delirium & dementia
Use extreme caution because of side effect profile
‘Start low & go slow’ (Malone et al 2007) & titrate over longer periods of time to reach the required dose
Avoid polypharmacy wherever possible
First and second generation antipsychotic medications are used to treat the various disorders in the older person including psychosis, bipolar affective disorder, delirium and dementia. Increasingly, the second generation or atypical antipsychotics have become more popular because of their reduced rate of EPSEs.
Adverse effects such as antimuscarinic anticholinergic and cardiovascular effects, sedation, tardive dyskinesia, stroke, cardiopulmonary events and death indicate they must be used with extreme caution with the elderly. The effect of sedation in this age group can be extended, increasing the likelihood of falls or other accidents (Malone et al 2007). When used, they should be administered at lower doses than in younger people and titrated over longer periods of time to reach the required dose. In other words, ‘start low, go slow’ (Malone et al, 2007) with older people when prescribing antipsychotics. Persons with dementia have been found to be particularly at risk of these medications and their use is not recommended (Kales et al 2007), an alarming fact given that the rate of prescription is reportedly high for persons with dementia living in aged care facilities (Alanen et al 2006). Few studies have been conducted on the safety of depot antipsychotics in the elderly. Of the typicals, low doses of Haloperidol and Fluphenazine are the preferred depot antipsychotic for use with the elderly as they tend to cause less sedation, postural hypotension and antimusarinic anticholinergic effect.Of the atypicals, Risperidone is the first to be approved as a long-acting injectable. To date it appears to have a favourable safety profile with the older person.
CAUTION ALERT Neuroleptic Malignant Syndrome in the older person
Even though it is more likely to occur in a younger age group, neuroleptic malignant syndrome (NMS) can also affect the older person. The risk is especially high for people with Parkinson’s disease or Lewy body dementia. Abrupt withdrawal of antipsychotic medications in this group may induce NMS. Antipsychotic medications should be avoided in these persons if at all possible. If antipsychotic medications must be used, quetiapine and clozapine are the more desirable choices because of their dopamine receptor occupancies (Malone et al 2004).
Avoid polypharmacy in the older person
Greater likelihood of falls, greater difficulty in adequately diagnosing mental illness, adverse medication reactions, especially if dosage not reduced and greater likelihood of interactions.
Guidelines for polypharmacy in the older person: start low, go slow, monitor for signs of improvement and titrate dose accordingly, assess regularly for adverse signs, educate about medication side effects and management strategies and include consumer and carer/ family in decisions.

35. Pregnancy & lactation Avoid antipsychotics if possible
Use the lowest effective dose
Neonatal adverse effects observed include generalised hypertonicity and dystonic reactions
Pregnancy
On the basis of limited available data, conventional or typical drugs appear to present no serious problems in pregnancy, with the possible exception of Chlorpromazine. There is evidence that this can cause a small increased risk of congenital abnormalities. However, large doses of any of these drugs can cause adverse effects in the neonate. Avoid if possible, or use the lowest effective dose. It should be noted that poorly controlled psychotic disorders may compromise maternal health and pregnancy outcomes. Neonatal adverse effects observed include generalised hypertonicity and dystonic reactions. The safety of atypical agents has yet to be established. On the basis of limited case report and studies there appears to be no deleterious effects to the foetus. There have been isolated cases of congenital abnormalities with the use of Clozapine. The most data available is for the use of olanzapine and no increased risk has emerged. The conventional agents are generally preferred. Supervised dose reduction and cessation 7-10 days prior to delivery should be considered.
Important Points to Consider Before Prescribing
Weighing up whether or not to prescribe psychotropic medication for your pregnant or breastfeeding patient is not a straightforward decision.  It can be fraught with concern and uncertainty around potential harmful medication effects on the pregnancy, fetus and infant; yet this must be balanced against the increasingly convincing evidence for the deleterious consequences of untreated maternal mental illness.  Each decision must be tailored to the individual patient and, where possible, include the father of the pregnancy in the decision-making.
 Historically, many doctors have avoided prescribing psychotropic medications in pregnancy or breastfeeding due to concerns about their safety, particularly for the unborn baby. Although psychotropic medication can pose potential risks in pregnancy and/or breastfeeding, it should always be noted that there is a baseline risk in the general population for giving birth to a child with any defect of 3-5%.

36. Pregnancy & lactation
The safety of atypical agents is yet to be established but preliminary reports there to be no deleterious effects to the foetus
Isolated cases of congenital abnormalities with the use of Clozapine
In addition, there is a growing body of literature to suggest that untreated maternal mental illness can have serious adverse outcomes on foetal well-being that may be equal to, or even surpass, any potential and largely unknown adverse effects of psychotropic medications.  For example, untreated ante-natal depression and/or anxiety is associated with poor maternal nutrition, poor antenatal attendance, increased smoking and alcohol use (as well as increased illicit substance use), and obstetric complications (eg spontaneous abortion, pre-eclampsia, increased uterine artery resistance, intra-uterine growth retardation, pre-term delivery, and low birth-weight babies).  Also, neonates born to depressed and/or anxious mothers tend to have smaller head circumferences, lower Apgar scores, higher cortisol levels at birth (which could lead to psychopathology later in life), and an increased need for special care nursery due to some medical complication (1,5-7,8-10)
There is also a greater likelihood that a woman with untreated antenatal depression and anxiety will go on to develop post-natal depression (PND).  In Australia, PND affects almost 16% of women giving birth every year (11), making it one of the most common complications of pregnancy (12).  It can have a devastating effect on the woman, including a reduced ability to care for and interact with her infant leading to a sense of inadequacy and failure as a mother.  At its worst, PND can lead to maternal suicide and/or infanticide, and can impact negatively on the mother-infant relationship as well as on the mother’s other familial relationships.  Increasingly, research suggests that women with PND are less attuned, less responsive, less focussed, and less able to provide stimulation to their infants.  These early mother-infant interactional problems can have longer-term detrimental impacts on the infant’s cognitive, emotional, behavioural and social development.  (13)
Therefore, the risks and benefits of prescribing psychotropic medications during pregnancy and/or lactation must always be weighed up against the risks and benefits of not prescribing.

37. Pregnancy & Lactation
No increased risk has emerged with the use of Olanzapine
The conventional agents are generally preferred
Supervised dose reduction and cessation 7-10 days prior to delivery should be considered
The psychotropic medication of choice in pregnancy &/or breastfeeding will depend upon:
The safety profile of the medication/s
The woman’s symptoms and their severity
Her history of mental illness (eg duration, hospitalizations)
Past treatments and responses to these
Therapeutic preferences, and
Her medical health during pregnancy
Discontinuing psychotropic medication prior to conceiving
Where circumstances might allow a woman to discontinue psychotropic medication prior to conceiving, (eg where her mental illness has been of ‘mild’ severity and where she has been symptom-free for more than one year), she should be informed about the possible risks and benefits of her treatment options.  Switching or changing a medication that has been effective always carries the risk of relapse. Importantly, women with major depression who discontinue their antidepressants in pregnancy have a 50-75% risk of relapse (4).  Ongoing consultation between the woman’s General Practitioner and/or a Psychiatrist is recommended, with close monitoring of her mental state.
 When to treat antenatal depression and/or anxiety with antidepressants
The decision in cases of mild depression is straightforward, as evidence is available in these cases for the efficacy of non-pharmacological treatmentsegpsychotherapy.  Similarly in women with severe depression, the risk of not treating far outweighs the risk of treating, for both mother and infant.
 It would be prudent to prescribe under the following circumstances:
●Where there are moderate to severe depressive symptoms, including vegetative symptoms, psychomotor agitation/retardation, and suicidal ideation and/or actual attempts
●Where there is co morbid panic/anxiety disorder or co morbid psychotic symptoms
●Where there is significant impairment in functioning eg inability to work, relationship breakdown
●A history of recurrent depression with hospitalizations

38. What other treatments are available?
Remember that antidepressant medication is only part of the
treatment for antenatal depression and anxiety. Also consider:
Psychological therapies
Exclude organic illness as a cause of mental health symptoms
Address any alcohol and/or illicit substance abuse
Assess the social situation
General lifestyle measures: adequate rest/sleep, balanced diet, exercise
The decision to treat should be made on an individual case basis
What other treatments are available
Remember that antidepressant medication is only part of the treatment for antenatal depression and anxiety. Also consider:
●Psychological therapies - such as Cognitive Behaviour Therapy, Interpersonal Therapy, Couples and Family Therapy.
●Exclude organic illness as a cause of mental health symptomseganaemia, hypothyroidism) 
●Address any alcohol and/or illicit substance abuse
●Assess the social situation and increasing social supports where appropriate (eg linking in with community groups; reviewing housing situation; enquiring about domestic violence)
●General lifestyle measures: adequate rest/sleep, balanced diet, exercise.
The decision to treat should be made on an individual case basis by considering the risks and benefits to both mother and foetus. Monotherapy is preferred because of the higher risk of congenital malformation associated with combination therapy.Olanzapine should be used at the lowest effective dose in pregnant women. Olanzapine crosses from the maternal to foetal compartments. The transfer depends significantly on binding characteristics, especially of albumin(1). 
When a planned or unplanned pregnancy occurs during olanzapine treatment, women may choose to continue the treatment. If it is considered the treatment of choice. The psychiatrist, obstetrician and general practitioner should discuss risk and benefit issues and document this discussion and the patient’s choice in her medical record. Olanzapine may induce maternal hyperglycaemia, impaired glucose tolerance and weight gain, which all predispose to unfavourable obstetric outcomes and pregnancy complications(2). Close monitoring is required throughout the pregnancy to prevent or manage metabolic complications such as excessive weight gain, increased serum triglyceride and cholesterol levels, glucose intolerance and /or gestational diabetes(3).Gestational diabetes had been reported in women with and without a family history of diabetes(4).Newhan et al suggest that babies born to mothers taking atypical antipsychotics during pregnancy may be at risk of being large for gestational age.  
Olanzapine has been associated with perinatal syndromes, which include physical and behavioural symptoms such as irritability, restlessness, excessive crying, hypertonia, tachycardia and seizures. These symptoms are presumed to be related to olanzapine use around the time of delivery. The incidence of such syndrome is low, and these symptoms usually resolve within a few days. 
Limited information is available regarding the long term effects of olanzapine on childhood development following in utero exposure in humans. Most studies have shown no significant differences on neurobehavioral development between exposed and non-exposed children.
The absolute dose transferred to the infant =1.2%(5)                                    
Half life = hours(5)
Peak concentration = 5-8 hours(6)                                                                                          
Milk/plasma ratio = 0.38(5)
Limited safety information is available on the use of olanzapine in breastfeeding mothers, each case should be considered individually. Use with extreme caution, especially in pre-term infants. Minimal single daily dose is preferred. Very small amounts of olanzapine are excreted into breastmilk. Monitor breastfed infants for any signs and symptoms of potential adverse effects such as drowsiness, poor feeding and changes in sleeping patterns.

39. Conclusion
Conventional and atypical antipsychotics are used as the foundation for pharmacological management of schizophrenia and related psychosis
All have equal efficacy, exception Clozapine
Atypicals generally better tolerated & have less EPSE
Atypicals first line treatment
Start lowest effective possible dose & titrate upwards
Ongoing monitoring & management of adverse effects
Caution numerous drug interaction & potential for neuroleptic malignant syndrome
Conclusion
Conventional and atypical antipsychotics are used as the foundation for the pharmacological management of schizophrenia and related psychosis. All antipsychotics are considered to be of equal efficacy, with the exception of Clozapine. The newer atypical agents are generally better tolerated and have less EPSE than the older conventional agents. Although the atypical agents have a broad adverse effect profile they are considered to be first line treatment in the management of psychotic disorders. Antipsychotics should be started at the lowest effective dose and titrated upwards and ongoing monitoring and management of adverse effects is required. Caution must be exercised with regards to the numerous drug interactions and the potential for neuroleptic malignant syndrome and other serious adverse effects.

40. Resources Therapeutic Guidelines – Psychotropic Version 5
Australian Medicines Handbook
MIMS online
Perinatal Psychotropic Medicine Information Service
Therapeutic Guidelines (2003) Psychotropic Therapeutic Guidelines Pty Ltd Version 5
Australian Medicines Handbook (2004) Australian Medicines Handbook Pty Ltd
Bryant, B, Knights, K and Salerno, E (2003), Pharmacology for Health Professionals, Mosby, Sydney
Belize S, (2000), Psychotropic Drug Directory, Quay Books, Wiltshire.
Doran, C (2003) Prescribing Mental Health Medication, Routledge, London
Stahl, S, (1999) Psychopharmacology of Antipsychotics, Martin Dunitz, London
Drug Facts & Comparisons Pocket Version, 2007 Edition)
Usher, Foster & Bullock (2009). Psychopharmacology for Health Professionals. Elsevier, Australia.