CHAPTER 2

Antipsychotic Drugs
CLASSIFICATION
Conventional antipsychotics
1 2 3 4 5 6 1 2 3 4 5 6 7 1 2 3 4 5 6 Chlorpromazine Haloperidol Triuoperazine Sulpiride Pimozide Zuclopenthixol acetate Risperidone Olanzapine Quetiapine Amisulpride Aripiprazole Zotepine Clozapine Fluphenazine decanoate Flupenthixol decanoate Zuclopenthixol decanoate Haloperidol decanoate Pipotiazine palmitate IM risperidone

Atypical antipsychotics

Antipsychotic depot injections

11

12 Basic notes in psychopharmacology

CONVENTIONAL ANTIPSYCHOTICS
I CHLORPROMAZINE
(a) Mode of action
1 Dopamine antagonist; blocks D2-receptors in the mesolimbic cortical bundle which mediates the antipsychotic action of chlorpromazine. 2 It also has several other biochemical actions which mediate the side-eects of chlorpromazine: (i) Dopamine blocking activity at other sites (see later). (ii) Antiserotonergic activity. (iii) a1-Adrenergic receptor antagonist. (iv) Muscarinic M1-receptor antagonist. (v) Histamine H1-receptor antagonist.

(b) Indications
1 Schizophrenia: (i) Control and maintenance therapy in schizophrenia (usual maintenance dose 50 mg bd to 100 mg tds; maximum dose 1 g daily in divided doses). (ii) Chlorpromazine is more sedative and causes fewer extrapyramidal side-eects, cf haloperidol thus, chlorpromazine was the drug of choice for schizophrenia (before the advent of atypical antipsychotics). 2 Aective disorders: (i) Control of the psychotic components of psychotic depression. (ii) Usually brings the symptoms of acute mania under rapid control. 3 Persistent delusional disorder symptoms are sometimes relieved. 4 Obsessive compulsive disorders small doses of value when anxiolytic treatment is needed for more than the 24 weeks' duration for which benzodiazepines are prescribed. 5 Personality disorders may be given for short periods at times of unusual stress. 6 Chronic organic disorder alleviation of certain symptoms of dementia: (i) Anxiety. (ii) Overactivity. (iii) Delusions.

Antipsychotic Drugs

13

(iv) Hallucinations. NB: Care is needed to nd the optimal dose; in the elderly there are the special dangers of hypotension, atropinic eects and ECG changes therefore haloperidol is preferred to chlorpromazine in the elderly. 7 Behavioural disturbances tranquillization and emergency control. 8 Severe anxiety short-term adjunctive treatment. 9 Terminal disease. 10 Anti-emetic. 11 Intractable hiccup.

(c) Adverse eects

1 Extrapyramidal side-eects (EPSEs) mediated by dopamineblocking activity at D2-receptors in the nigrostriatal pathway: (i) Acute dystonic reactions. (ii) Akathisia. (iii) Pseudoparkinsonism. (iv) Tardive dyskinesia. 2 Hyperprolactinaemia mediated by dopamine-blocking activity at D2-receptors in the tubero-infundibular system galactorrhoea in both women and men. 3 Antiserotonergic side-eect: depression. 4 Antiadrenergic side-eects (due to blockade of a1-adrenergic receptor): (i) Postural hypotension. (ii) Failure of ejaculation. (iii) Sedation. 5 Anticholinergic side-eects (due to blockade of muscarinic M1receptors): (i) Dry mouth. (ii) Blurred vision. (iii) Constipation. (iv) Urinary retention. (v) Tachycardia. (vi) Impotence. (vii) Exacerbation of glaucoma. 6 Antihistaminergic side-eect (due to blockade of histamine H1receptors): sedation. NB: Sedation is mainly mediated through anti-adrenergic activity.

14 Basic notes in psychopharmacology

7 Impaired temperature regulation: (i) Hypothermia. (ii) Hyperpyrexia. 8 Neuroleptic malignant syndrome (NMS). 9 Bone marrow suppression leucopenia. 10 Skin photosensitivity and pigmentation. 11 Cardiac arrhythmias. 12 Cholestatic jaundice. 13 Seizures (due to lowering of the convulsive threshold). 14 Weight gain.

II HALOPERIDOL
(a) Mode of action
W 1 Greater dopamine blocking activity.a 2 Less antiadrenergic activity. cf chlorpromazine Y 3 Less anticholinergic activity.

(b) Indications
1 Mania. 2 Treatment of acute organic disorder during the daytime. 3 Bringing acutely disturbed behaviour under immediate control since it is less sedative and causes less postural hypotension than chlorpromazine. 4 Other non-aective psychoses.

(c) Adverse eects

1 2 3 4 5 6

W More EPSE. a Less sedation. cf chlorpromazine Y Less postural hypotension. Fewer anticholinergic side-eects. NMS. Danger of severe EPSE with haloperidol if a daily dose in excess of 20 mg is combined with lithium carbonate at a serum level of greater than 0.8 mmol/l. 7 ECG changes at high dose torsade de pointes. 8 Recently the maximum BNF recommended dose of haloperidol has been heavily reduced to: (i) 30 mg daily in divided doses if taken orally. (ii) 18 mg daily in divided doses as an intramuscular injection. This is due to EPSE at higher doses.

Antipsychotic Drugs

15

III TRIFLUOPERAZINE
(a) Mode of action
W 1 Greater dopamine blocking activity.a 2 Less antiadrenergic activity. cf chlorpromazine Y 3 Less anticholinergic activity. 1 Useful in psychotic patients where sedation is undesirable (i.e. retarded psychotic patients) since it is less sedative cf chlorpromazine. 2 Useful in psychotic patients with intractable auditory hallucinations; usual dose range 5 mg bd to 5 mg tds.

(b) Indications

(c) Adverse eects

1 2 3 4 More EPSE. Less sedation. Less postural hypotension. Fewer anticholinergic side-eects.

W b a b Y

cf chlorpromazine

IV SULPIRIDE
(a) Mode of action
1 Low doses thought to block presynaptic dopamine D3- and D4autoreceptors. 2 High doses blocks postsynaptic dopamine receptors; more specic blocker of D2-receptors cf D1-receptors.

(b) Indications
1 Low doses may have an alerting eect on schizophrenic patients with negative symptoms such as apathy and social withdrawal (optimum dosage 400 mg bd). 2 High doses useful in schizophrenic patients with orid positive symptoms such as delusions and hallucinations (optimum dosage 800 mg bd).

(c) Adverse eects

1 Less EPSE cf chlorpromazine. 2 Less sedation cf chlorpromazine. 3 Tendency to cause galactorrhoea.

16 Basic notes in psychopharmacology

V PIMOZIDE
(a) Mode of action
More specic blocker of D3- and D2-receptors cf chlorpromazine.

(b) Indication
Useful in monosymptomatic delusional psychosis it is claimed that pimozide has success in specically targeting monosymptomatic hypochondriacal delusions (dose range 416 mg daily). NB: Special caution is needed over rate of rise in daily doses.

(c) Adverse eects

' 1 Less EPSE. cf chlorpromazine 2 Less sedation. 3 Following reports of sudden unexplained death, CSM recommends: (i) An ECG prior to commencing treatment in all patients. (ii) ECGs at regular intervals in patients taking over 16 mg daily. (iii) A review of the need for pimozide if arrhythmias develop.

VI ZUCLOPENTHIXOL ACETATE
(a) Mode of action
Short-acting injection administered intramuscularly as an oily injection and rapidly released into the bloodstream.

(b) Indications
Useful for immediate management of acutely disturbed behaviour as an alternative to haloperidol since: 1 Zuclopenthixol acetate is more sedative than haloperidol. 2 These injections (maximum of four) are more easily administered to the patient, cf trying to persuade such a patient to comply with regular oral or intramuscular haloperidol.

(c) Cautions
1 Treatment duration should not exceed 2 weeks with a maximum dosage of 150 mg for each injection per 24 hours, and a maximum dosage of 400 mg for each course of injections. 2 Must not be used on neuroleptic-nave patients, i.e. haloperidol

Antipsychotic Drugs

17

should have been tried rst and been ineective before considering zuclopenthixol acetate.

ATYPICAL ANTIPSYCHOTICS
I RISPERIDONE
Introduced into the UK in 1993.

(a) Mode of action

1 Potent dopamine D2-receptor antagonist; in addition it has a regional preference for blocking D2-receptors in the mesolimbic cortical bundle, cf the nigrostriatal pathway. 2 Potent serotonin 5HT2A-receptor antagonist. 3 Low anity for serotonin 5HT2C-receptors. 4 Potent a1-adrenergic receptor antagonist. 5 No appreciable anity for muscarinic M1-receptors. 6 Low anity for histamine H1-receptors.

(b) Indications
1 Treatment of both the positive and negative symptoms of schizophrenia; it appears ecacious in treating both sets of symptoms equally well (usual dose range 4 mg od6 mg od for maintenance treatment in adults). Treatment of negative symptoms is mediated by blockade of serotonin 5HT2A-receptors. 2 Alleviation of aective symptoms associated with schizophrenia mediated by blockade of serotonin 5HT2A-receptors. 3 Useful in maintenance treatment of schizophrenic patients it has been given a licence such that it need only be taken once a day to prevent relapse of schizophrenia. 4 Licensed in the UK in 2004 for the treatment of mania in bipolar disorder: (i) either as monotherapy or in combination with an antimanic drug (lithium or valproate), no dose adjustment required. (ii) co-administration with carbamazapine in bipolar mania not recommended. (iii) when initiating treatment, the starting dose is 2 mg od on the rst day, which may be increased to 3 mg od on the second day in bipolar mania; due to high anity for a1adrenergic receptors. (iv) usual dose range 1 mg od6 mg od; continued use must be evaluated and justied on an ongoing basis.

18 Basic notes in psychopharmacology

5 Some evidence that it may be useful in the treatment of resistant depression* as an augmenting agent to SSRIs (by enhancing serotonergic accumulation within the synapse). NB: Risperidone is available in the UK as an oral preparation (including a quicklet which may be placed on the tongue and allowed to dissolve or dissolved in water); however IM risperidone, a long-acting intramuscular injection form of risperidone, was launched in the UK in 2002 (see later under antipsychotic depot injections).

(c) Adverse eects

1 Less EPSE (at doses up to and including 6 mg od), cf other antipsychotic drugs; this benet may be lost at doses of and over 8 mg od above this dose, it requires twice daily dosing, i.e. the next increment is 5 mg bd and this may be gradually increased up to a maximum of 8 mg bd. 2 Dose-dependent elevation in prolactin levels, although these are not necessarily related to the possible sexual side-eects. 3 Minimal weight gain due to low anity for serotonin 5HT2creceptors. 4 Postural hypotension therefore when initiating treatment, the starting dose is 2 mg od on the rst day, which may be increased to 4 mg od on the second day in schizophrenia or to 3 mg od on the second day in bipolar mania; both due to high anity for a1adrenergic receptors. 5 No appreciable anticholinergic side-eects. 6 Side-eects include agitation and insomnia due to possible low anity for histamine H1-receptors. 7 Some ECG changes (prolongation of the QTc interval). However, there is no requirement for routine ECG monitoring. 8 Not associated with agranulocytosis. 9 Gastrointestinal side-eects nausea, dyspepsia, abdominal pain. 10 More akathisia, cf chlorpromazine. 11 Associated with an increased risk of stroke in elderly patients with dementia thus, the CSM has advised that it should not be used for treating behavioural symptoms of dementia.

* Used but this indication is not currently licensed in the UK.

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19

II OLANZAPINE
Introduced into the UK in 1996.

(a) Mode of action

1 Potent dopamine D2-receptor antagonist; it preferentially blocks D2-receptors in the mesolimbic cortical bundle, cf the nigrostriatal pathway. 2 Potent serotonin 5HT2A-receptor antagonist. 3 High anity for serotonin 5HT2C-receptors. 4 Moderate anity for a1-adrenergic receptors. 5 High anity for muscarinic M1-receptors. 6 High anity for histamine H1-receptors.

(b) Indications
1 Treatment of both the positive and negative symptoms of schizophrenia, and aective symptoms associated with schizophrenia (usual dose 10 mg daily; dose range 520 mg for maintenance treatment). 2 Maintenance treatment of schizophrenia (once-per-day dosing). 3 Licensed in the UK in 2003 as monotherapy for the treatment of acute mania (starting dose 15 mg daily) and also for the prophylaxis of bipolar aective disorder (starting dose 10 mg daily). 4 It may also be used in combination with an antimanic drug for both the treatment of acute mania and the prophylaxis of bipolar aective disorder (starting dose 10 mg daily). 5 During treatment for acute mania and the prophylaxis of bipolar aective disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 520 mg/ day. 6 Some evidence that it may be useful in the treatment of resistant depression* as an augmenting agent to SSRIs (by enhancing serotonergic accumulation within the synapse). NB: Olanzapine is available in the UK as an oral preparation (including a velotab which may be placed on the tongue and allowed to dissolve or dissolved in water); however IM olanzapine, for use in rapid tranquillisation, was launched in the UK in 2004 (see next point). 7 The rapid tranquillisation of acutely disturbed or violent behaviour in patients with schizophrenia or manic episode, when oral therapy is inappropriate:
* Used but this indication is not currently licensed in the UK.

20 Basic notes in psychopharmacology

(i) the recommended initial dose of IM olanzapine is 10 mg. (ii) a second IM injection, 510 mg, may be repeated two hours later. (iii) the maximum daily dose of IM olanzapine is 20 mg. (iv) the maximum dose of IM olanzapine is 20 mg in 24 hours on 3 consecutive days. (v) recently it has been recommended that IM lorazepam can only be administered at a minimum of one hour after the administration of IM olanzapine, cf previously there had been some uncertainty about this as it had been common practice to administer IM lorazepam and IM haloperidol concurrently.

(c) Adverse eects

1 EPSE usually mild and transient if present responds to dose reduction or to an antimuscarinic drug. 2 Sometimes associated with elevation in prolactin level. However, associated clinical manifestations are rare, cf risperidone. 3 Signicant weight gain due to high anity for serotonin 5HT2creceptors; treatment-emergent diabetes mellitus does not appear to be associated with weight gain. 4 Some postural hypotension. However, treatment can be initiated at a therapeutic dose (10 mg daily) without the need to build up from a starting dose; due to moderate anity for a1-adrenergic receptors. 5 Anticholinergic side-eects: dry mouth may occur. 6 Side-eects include sedation due to high anity for histamine H1receptors. 7 Not generally associated with clinically signicant prolongation of the QTc interval. No requirement for routine ECG monitoring. 8 Not associated with agranulocytosis. 9 Transient, asymptomatic elevation of hepatic transaminases has been seen in association with olanzapine therapy. However, there is no CSM recommendation to routinely monitor LFTs (liver function tests). 10 Associated with an increased risk of stroke in elderly patients with dementia thus, the CSM has advised that it should not be used for treating behavioural symptoms of dementia.

Antipsychotic Drugs

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III QUETIAPINE
Introduced into the UK in 1997.

(a) Mode of action

1 2 3 4 5 6 Weak anity for dopamine D2-receptors similar to clozapine. Low anity for serotonin 5HT2A-receptors. Very low anity for serotonin 5HT2C-receptors. High anity for a1-adrenergic receptors. No appreciable anity for muscarinic M1-receptors. High anity for histamine H1-receptors.

(b) Indications
1 Treatment of the symptoms of schizophrenia (positive, negative and aective). 2 Maintenance treatment of schizophrenia (twice-per-day dosing; usual dose range 300450 mg daily in two divided doses for maintenance treatment; maximum 750 mg daily). 3 Licensed in the UK in 2003 for the treatment of acute mania either as monotherapy or in combination with an antimanic drug. NB: Quetiapine is currently only available in the UK as an oral preparation.

(c) Adverse eects

1 EPSE comparable with placebo across the dose range (up to, and including, the maximum dose of 750 mg daily in divided doses in schizophrenia) the only atypical antipsychotic currently available in the UK with this feature. 2 Prolactin level comparable with placebo across the dose range (up to, and including, the maximum dose). 3 Minimal weight gain due to very low anity for serotonin 5HT2creceptors. 4 Postural hypotension therefore when initiating treatment in schizophrenia, the starting dose is 50 mg daily in divided doses, which is then increased over six days to 600 mg daily in divided doses in adults; due to high anity for a1-adrenergic receptors. NB: When initiating treatment in acute mania, the starting dose is 100 mg daily in divided doses, which is then increased over ve days to 600 mg daily in divided doses in adults. The maximum dose for acute mania is 800 mg daily in divided doses. 5 No appreciable anticholinergic side-eects. 6 Side-eects include headaches and somnolence; latter due to high

22 Basic notes in psychopharmacology

7 8 9 10

anity for histamine H1-receptors. NB: No increase in somnolence above 100 mg daily as histamine receptors are saturated. Some ECG changes (prolongation of the QTc interval). However, there is no requirement for routine ECG monitoring. Not associated with agranulocytosis, cf clozapine. Some disturbance in LFTs. However, there is no requirement for the routine monitoring of LFTs. Requires twice daily dosing, cf risperidone (up to 8 mg daily) and olanzapine, which require once daily dosing; this may reduce compliance in patients taking quetiapine for the long-term treatment of schizophrenia.

IV AMISULPRIDE
Introduced into the UK in 1997.

(a) Mode of action

1 Blocks dopamine D3-receptors (mainly presynaptic) and dopamine D2-receptors (mainly postsynaptic); limbic selective. 2 No anity for serotonin 5HT2A-receptors. 3 No anity for serotonin 5HT2C-receptors. 4 No anity for a1-adrenergic receptors. 5 No anity for muscarinic M1-receptors. 6 No anity for histamine H1-receptors.

(b) Indications
1 Treatment of schizophrenic patients with orid positive symptoms or a mixture of positive and negative symptoms (usual dose range 200 mg bd to 400 mg bd; maximum dosage 600 mg bd); it can be initiated at 400 mg bd for orid positive symptoms. 2 Treatment of schizophrenic patients with predominantly negative symptoms (dose range 50 mg to 300 mg daily with an optimum dosage of 100 mg once a day). NB: Amisulpride is currently only available in the UK as an oral preparation.

(c) Adverse eects

1 Lower potential for causing EPSE, cf conventional antipsychotics; however, this benet is lost at the maximum dosage. 2 Reversible elevation in prolactin level associated with clinical manifestations; not dose dependent and comparable to conventional antipsychotics.

Antipsychotic Drugs

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3 Low weight gain due to lack of anity for serotonin 5HT2Creceptors. 4 Some postural hypotension. However, treatment can be initiated at a therapeutic dose (200 mg bd for positive symptoms with or without negative symptoms) without the need to build up from a starting dose; due to lack of anity for a1-adrenergic receptors. 5 No appreciable anticholinergic side-eects. 6 Side-eects include insomnia, anxiety and agitation. 7 Some ECG changes. However, there is no requirement for routine ECG monitoring. 8 Not associated with agranulocytosis, cf clozapine. 9 There is no requirement for the routine monitoring of LFTs. 10 May be the atypical antipsychotic of choice in patients with diabetes mellitus due to its lack of anity for serotonin 5HT2Creceptors. 11 Requires twice daily dosing, cf risperidone (up to 8 mg daily) and olanzapine, which require once daily dosing; this may reduce compliance in patients taking amisulpride for the long-term treatment of schizophrenia.

V ARIPIPRAZOLE
Introduced into the UK in 2004. Available as an orodispersible tablet in the UK in 2006.

(a) Mode of action

1 Partial agonist at dopamine D2-receptors: (i) Acts as a dopamine D2-receptor agonist on presynaptic autoreceptors. (ii) Acts as a dopamine D2-receptor antagonist on postsynaptic receptors. (iii) Aripiprazole acts as a dopamine system stabiliser in both hypodopaminergic and hyperdopaminergic conditions. As shown in animal models in vivo, stabilisation of the dopamine system is proposed to provide antipsychotic ecacy with minimal adverse eects. 2 Partial agonist at serotonin 5HT1A-receptors. (i) May protect against dopamine-mediated adverse eects. (ii) May provide anxiolytic activity. 3 High anity for serotonin 5HT2A-receptors. 4 Low anity for serotonin 5HT2C-receptors. 5 Low anity for a1-adrenergic receptors.

24 Basic notes in psychopharmacology

6 Low anity for muscarinic M1-receptors. 7 Low anity for histamine H1-receptors.

(b) Indications
1 Treatment of the positive symptoms of schizophrenia due to its action as a dopamine D2-receptor antagonist in the mesolimbic area (where dopamine is excessive). 2 Treatment of the negative symptoms of schizophrenia due to its action as a dopamine D2-receptor agonist in the mesocortical area (where dopamine is decient). NB: The usual starting dose is 1015 mg once daily with a maximum dose of 30 mg daily; aripiprazole is currently only available in the UK as an oral preparation.

(c) Adverse eects

1 EPSE comparable with placebo. 2 Prolactin level comparable with placebo. 3 Minimum weight gain due to lack of anity for serotonin 5HT2Creceptors. 4 Some postural hypotension. However, treatment can be initiated at a therapeutic dose (1015 mg) without the need to build up from a starting dose; due to low anity for a1-adrenergic receptors. 5 No appreciable anticholinergic side-eects. 6 Side-eects include nausea, akathisia, the risk of seizures and insomnia (thus, it is advisable to take it in the morning). 7 Not associated with ECG changes therefore no requirement for routine ECG monitoring. 8 Not associated with agranulocytosis, cf clozapine. 9 No requirement for the routine monitoring of LFTs. 10 No dose adjustments required in those with renal or hepatic impairment.

VI ZOTEPINE
Introduced into the UK in 1998.

(a) Mode of action

1 2 3 4 Moderate anity for dopamine D2-receptors. High anity for serotonin 5HT2A-receptors. High anity for serotonin 5HT2C-receptors. Low anity for a1-adrenergic receptors.

Antipsychotic Drugs

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5 Potent noradrenaline reuptake inhibitor. 6 Low anity for muscarinic M1-receptors. 7 High anity for histamine H1-receptors.

(b) Indications
1 Treatment of the symptoms of schizophrenia it has a general licence for this, i.e. it is not specically licensed for any individual set of symptoms (positive, negative or aective). However, it may have antidepressant eects due to its action as a potent noradrenaline reuptake inhibitor. 2 It is initiated in adults at the therapeutic dose of 25 mg tds; if further clinical improvement is required this may be increased to 50 mg tds; it may be further increased to a maximum of 100 mg tds if required. NB: Zotepine is currently only available in the UK as an oral preparation.

(c) Adverse eects

1 May have lower potential for causing EPSE, cf conventional antipsychotics. 2 Sometimes associated with elevation in prolactin levels. However, associated clinical manifestations are rare. 3 Signicant weight gain due to high anity for serotonin 5HT2Creceptors. 4 Some postural hypotension. However, treatment can be initiated at a therapeutic dose without the need to build up from a starting dose; due to low anity for a1-adrenergic receptors. 5 Dry mouth due to potent noradrenaline reuptake inhibition. 6 Side-eects include sedation due to high anity for histamine H1receptors. 7 Other side-eects include asthenia, constipation, tachycardia and seizures. 8 ECG changes (prolongation of the QTc interval) associated with a possible increased risk of toxicity. In view of this, CSM recommends an ECG prior to commencing treatment in patients at risk of arrythmias. Zotepine should therefore be used with caution in patients with clinically signicant cardiac disease. 9 Sometimes associated with neutropenia. Therefore if an infection occurs, a full blood count should be checked. 10 Sometimes associated with elevation in transaminases. Therefore in patients with known hepatic impairment, liver function tests should be monitored weekly for the rst three months.

26 Basic notes in psychopharmacology

11 Zotepine is uricosuric, therefore it should not be started within three weeks of resolution of an episode of acute gout. 12 Requires dosing three times a day, cf risperidone (up to 8 mg daily) and olanzapine, which require once daily dosing; this may reduce compliance in patients taking zotepine for the long-term treatment of schizophrenia.

VII CLOZAPINE
(a) Mode of action
1 2 3 4 5 6 7 8 Moderate anity for dopamine D2-receptors. More active at dopamine D4-receptors, cf other antipsychotics. High anity for serotonin 5HT2A-receptors. High anity for serotonin 5HT2C-receptors. High anity for a1-adrenergic receptors. High anity for muscarinic M1-receptors. High anity for muscarinic M4-receptors. High anity for histamine H1-receptors.

(b) Indications
The treatment of schizophrenia in patients unresponsive to, or intolerant of, conventional antipsychotic drugs; at least one drug from two chemically distinct classes should be given a full therapeutic trial before considering clozapine (the atypical antipsychotics may be used as rst-line treatment of schizophrenia); in addition, it may be worth considering a course of electroconvulsive therapy (ECT) before starting clozapine therapy, since this can be an eective treatment in resistant schizophrenia (particularly when a signicant aective component is present). NB: Clozapine treatment must only be instituted by psychiatrists registered with the Clozaril Patient Monitoring Service (CPMS).

(c) Adverse eects

1 Less EPSE, cf conventional antipsychotics. 2 Asymptomatic rise in serum prolactin. 3 Signicant weight gain due to high anity for serotonin 5HT2Creceptors; treatment-emergent diabetes mellitus does not appear to be associated with weight gain. 4 Postural hypotension with risk of collapse therefore treatment should be initiated with a starting dose and then gradually increased over 1421 days to 300 mg daily in divided doses; usual dose 200450 mg daily (max 900 mg daily).

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5 Anticholinergic side-eects: hypersalivation due to high anity for muscarinic M4-receptors in the salivary glands is common; other atropinic side-eects due to muscarinic M1-receptor blockade also occur. 6 Side-eects include sedation due to high anity for histamine H1receptors. 7 Other side-eects include ts and rare instances of myocarditis. 8 Some ECG changes. However, there is no requirement for routine ECG monitoring. 9 It causes agranulocytosis (life-threatening) in 23% of patients taking the drug its use is therefore restricted to patients registered with the Clozaril Patient Monitoring Service (CPMS) whereby the patient has regular full blood counts to detect any possible agranulocytosis; should this occur, the clozapine must be stopped. 10 No requirement for the routine monitoring of LFTs. 11 Requires twice daily dosing, cf risperidone (up to 8 mg daily) and olanzapine, which require once daily dosing; this may reduce compliance in patients taking clozapine for the long-term treatment of schizophrenia (as may the requirement for regular full blood counts).

ANTIPSYCHOTIC DEPOT INJECTIONS

A IN GENERAL
(a) Mode of action
Long-acting depot injections administered intramuscularly as an oily injection and slowly released into the bloodstream.

(b) Indications
1 For maintenance therapy of schizophrenia more conveniently given than oral antipsychotic preparations ensuring better patient compliance. 2 For prophylaxis of bipolar aective disorder in patients who have poor compliance with oral prophylactic medication (antimanic drugs) depot medication certainly protects against hypomanic relapse and some clinicians believe it also protects against a subsequent depressive relapse.

(c) Adverse eects

1 Initially patients should always be given a test dose injection to

28 Basic notes in psychopharmacology

ensure that the patient does not experience undue side-eects or any idiosyncratic reactions to the medication or formulation. 2 They may give rise to a higher incidence of EPSE cf oral antipsychotic preparations.

B MORE SPECIFICALLY 1 Fluphenazine decanoate

(a) Indications
1 Useful in treating agitated or aggressive schizophrenic patients. 2 May be useful for the control of aggressive patients (in view of its sedative nature).

(b) Adverse eect

Contraindicated in severely depressed states in view of its tendency to cause depression.

2 Flupenthixol decanoate
(a) Indication
Useful in treating retarded or withdrawn schizophrenic patients in view of its apparent alerting nature.

(b) Adverse eect

Not suitable for the treatment of agitated or aggressive schizophrenic patients since it can cause over-excitement in such patients in view of its alerting nature.

3 Zuclopenthixol decanoate
(a) Indications
1 Useful in treating agitated or aggressive schizophrenic patients. 2 May be useful for the control of aggressive patients (this specic indication is more clearly established for zuclopenthixol decanoate cf uphenazine decanoate) in view of its sedative nature (zuclopenthixol decanoate is more sedative than uphenazine decanoate).

(b) Adverse eect

Not suitable for the treatment of retarded or withdrawn schizophrenic patients since it may exacerbate psychomotor retardation in such patients in view of its sedative nature.

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4 Haloperidol decanoate
(a) Indication
Maintenance in schizophrenia and other psychosis; usually 4-weekly administration.

5 Pipotiazine palmitate (formerly known as pipothiazine palmitate)

(a) Indication
Maintenance in schizophrenia and other psychosis; 4-weekly administration.

(b) Adverse eect

Allegedly lower EPSE, cf other conventional antipsychotic depot injections.

6 IM risperidone
(a) Indication
1 The world's rst ever atypical antipsychotic long-acting intramuscular injection launched in the UK in 2002. 2 Licensed for the treatment of both the positive and negative symptoms of schizophrenia; it also alleviates aective symptoms associated with schizophrenia; 2-weekly administration. 3 May be the `depot' (long-acting intramuscular injection) of choice in patients with bipolar aective disorder who are poorly compliant with oral antimanic drugs.*

(b) Adverse eect

Less EPSE, cf other conventional antipsychotic depot injections.

* Used but this indication is not currently licensed in the UK.

CHAPTER 3

Antidepressant Drugs
CLASSIFICATION
Tricyclic antidepressants (TCAs)
1 2 3 4 5 Amitriptyline Imipramine Dosulepin Trazodone Clomipramine

Monoamine oxidase inhibitors (MAOIs) Reversible inhibitors of monoamine oxidase type A (RIMAs) Second-generation antidepressants
1 Lofepramine 2 Mianserin

Selective serotonin reuptake inhibitors (SSRIs)

1 2 3 4 5 6 Fluvoxamine Fluoxetine Sertraline Paroxetine Citalopram Escitalopram

Serotonin and noradrenaline reuptake inhibitors (SNRIs)

1 Venlafaxine 2 Duloxetine

Noradrenergic and specic serotonergic antidepressants (NaSSAs) Noradrenaline reuptake inhibitors (NARIs) Agomelatine 30