Dr Oluyemi Adekunte: MSc (ClinRes), MSc (MedEd), Fellow HEA, MRCPsych.
Dr Paul Wilkinson: MRCPsych, MD
This handbook has been developed to provide a broad overview of psychopharmacology, but with some specific details essential for Medical Undergraduate Education. It is important to note that management of psychiatric patients is based on ‘Biopsychosocial approach’ and the understanding of psychopharmacology should be viewed in this context. As in any condition, treatment varies across the lifespan i.e. children, young people, older adults and elderly people. This handbook largely focuses on treatment in the working age adult bracket but sections on other age groups are also provided.
Antipsychotics are effective in the treatment of schizophrenia and other ‘psychotic’ illnesses. They are also used as mood stabilisers and in augmenting antidepressants in the management of ‘Treatment Resistant Depression.
Historically, chlorpromazine (phenothiazine) was the first antipsychotic drug that was discovered. It was synthesised originally as an antihistamine/antihelminthic drug but was later found to have a sedative and antipsychotic effect.
One of the most enduring ideas in psychiatry is the ‘Classical Dopamine Theory’ of schizophrenia. This theory is based on the idea that schizophrenia results from increase in dopamine level in the mesolimbic system. There is further evidence that increased dopamine presynaptic activity in the Nigrostriatal pathway is also associated with psychosis. However, it is known that the dopaminergic system plays an essential role in the actions and therapeutic effects of antipsychotic agents. Some of the existing pharmacological evidence includes:
- Repeated exposure of healthy subjects to high doses of psychostimulants gradually leads to paranoid psychosis.
- Exposure of patients with schizophrenia to low doses of psychostimulants can cause relapse in psychotic symptoms or worsen psychotic symptoms.
- D2 receptor blockage is the only pharmacological property shared by all antipsychotic drugs.
The more the dopamine receptor binding affinity, the better the therapeutic effect and clinical potency of the antipsychotic agent. The importance of D3 and D4 receptor subtypes in schizophrenia remains unclear and uncertain. However, many antipsychotic agents also have effects on acetylcholine, noradrenaline, histamine and serotonin pathways leading to wide ranging side-effects.
- Affinity: How well does the drug bind to the receptor? – High, medium, or low affinity
- Intrinsic activity: What does the drug do when it binds to the receptor or the degree to which a drug activates a receptor?
- Occupancy: How many receptors are occupied by the drug?
Antipsychotics are broadly classified into two major groups – First Generation (FGAs) and Second-Generation (SGAs). While these terms are still relevant to our current practice, the current thinking is to move away from this artificial classification towards therapeutic consideration for individual drugs, efficacy, tolerability, side effect profile and effectiveness. Currently, there is an increasing shift towards ‘Neuroscience-Based Nomenclature’ classification. This classification system is based on contemporary pharmacological knowledge rather than clinical indications i.e antidepressants, antipsychotics, etc. For example, pimavanserin is an atypical antipsychotic but unlike other antipsychotics it is not a dopamine receptor antagonist. The question is: ‘Should it be classified as an antipsychotic agent?’
Major dopamine pathways:
[a]. Mesolimbic pathway: Linked to positive symptoms – delusions, hallucinations, disorganized speech/thinking and disorganized or catatonic behaviour
[b]. Mesocortical pathway: Linked to negative symptoms – Alogia, affective flattening, avolition etc.
[c]. Nigrostriatal pathway: Controls motor movement
[D]. Tuberoinfundibular pathway: Controls prolactin secretion.
|Receptors||Possible Clinical Implications|
|D2 partial agonist||Improved negative and positive symptoms, EPSE, prolactin changes.|
|5-HT1A partial agonist||Improved negative symptoms|
|5-HT2A antagonist||Sexual dysfunction; reduced EPSE and improved negative symptoms.|
|Alpha1-adrenergic antagonist||Postural hypotension, dizziness, reflex tachycardia|
|Histamine (H1) antagonist||Sedation, increased appetite, weight change, hypotension|
|Muscarinic (M1) antagonist||Minimal impact on blurred vision, dry mouth, constipation, urinary retention, sinus tachycardia|
EPSE – Extrapyramidal side effects. Tabitha Rogers (Services de sante, Royal Ottawa Healthcare group
- First Generation Antipsychotics – Characteristics
- Antipsychotic effects predominantly on D2 receptors (antagonism) – Requires about 70% D2 receptor occupancy for efficacy.
- Extrapyramidal side effects: Dystonia, drug-induced parkinsonism, akathisia, tardive dyskinesia (up to 78 % D2 receptor occupancy)
- Prolactin elevation.
- Muscarinic cholinergic blocking properties.
- Limited efficacy on negative symptoms
Examples: Chlorpromazine, haloperidol, trifluoperazine, fluphenazine, zuclopenthixol and flupentixol.
- Second Generation Antipsychotics (SGA) -Characteristics
- Lower D2 receptor affinity.
- High serotonin/dopamine binding ratio.
- Have greater efficacy for both positive and negative symptoms.
- Reduced risk for the development of extrapyramidal symptoms.
Examples: Clozapine, amisulpride, risperidone, olanzapine, quetiapine, and aripiprazole (Aripiprazole exhibits unique dopamine modulatory effects).
SGAs have been linked to the development of metabolic abnormalities more than the conventional agents. These abnormalities include –obesity (abdominal), elevated cholesterol/dyslipidaemia, elevated blood pressure and diabetes/glucose intolerance.
|Antipsychotic agent||Pharmacology||Efficacy||Side effects and interactions|
|Amisulpride||D2 and D3 receptors selective antagonism. 5-HT7 receptor antagonism. Limbic selective.||Acute and chronic schizophrenia. Negative symptoms at low doses.||Low EPSE. Less weight gain. Raised prolactin.|
|Aripiprazole *Higher Affinity and lower Intrinsic activity than dopamine at D2 receptors||D2 receptor partial agonism/antagonism. 5HT1A receptor partial agonism. 5HT2A and 5HT2C receptors antagonism. No anticholinergic effect.||Acute and chronic schizophrenia. Mood stabilisation. Control of agitation and behavioural disturbance in schizophrenia (short acting injectable). Available in Long Acting Injectable form (LAI).||Low EPSE. Less weight gain. Does not increase serum prolactin. No QTc changes.|
|Asenapine (rarely used in UK)||High affinity multi-serotonergic, dopaminergic, adrenoceptor and histaminergic receptors antagonism. Low affinity M1 receptors. 5HT1A receptor partial agonism.||Treatment of schizophrenia and acute mania||EPSE. Less weight gain. Low risk for prolactin elevation.|
|Lurasidone||Adrenergic, dopaminergic and serotonergic receptors antagonist. 5HT1A partial agonist.||Lowest ranked efficacious antipsychotic agent in schizophrenia treatment. Treatment of bipolar depression||EPSE Akathisia Low risk of QTc|
|Olanzapine||Multi-receptor antagonism (histaminergic, muscarinic, serotonergic, adrenergic and dopaminergic. D2 limbic receptor selectivity.||Treatment of positive, negative and mood symptoms of schizophrenia. Short-acting injection (SAI) effective in control of agitation and behavioural disturbance. Long-acting injection (LAI) – post injection monitoring necessary due to a possible post-injection syndrome.||Sedation. Weight gain. Metabolic syndrome. Dry mouth and constipation (anti-muscarinic).|
|Paliperidone||Metabolite of risperidone but with lesser bioavailability. Less affinity for D4 receptor than risperidone. 5HT2A, 5HT2C, D2, H1 and adrenergic receptor antagonism. Oral and LAI forms.||Treatment of schizophrenia||Severe EPSE Hyperprolactinaemia Weight gain Lower risk of QTc changes.|
|Risperidone||5HT2A, 5HT2C, D2, and adrenergic receptor antagonism. Low – moderate H1 affinity. Oral and LAI forms.||Schizophrenia. Acute treatment of mania.||Akathisia and dystonia. Weight gain. Hyperprolactinemia. Tachycardia.|
|Ziprasidone||D2 receptor antagonism. Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A. NB: Lacks anticholinergic effects||Positive and negative symptoms of schizophrenia||Acute withdrawal syndrome. Sleepiness, weight gain and headache QTc prolongation|
Important points to note:
- To be taken with food (at least 350 calories)
- Efficacy is not affected by meal quantity and it is not dependent on meal fat content.
- It should be administered sublingually to optimize bioavailability due to its significant first-pass metabolism.
- Water or meal intake has no effect on bioavailability after 10 minutes of sublingual dose
- Side effects include dysgeusia and oral hypoesthesia.
- Use with food optimises absorption
Primarily, antipsychotic medications are used in the treatment of schizophrenia, mania and other psychoses includingpsychotic depression and schizoaffective disorder. They are also useful as augmenting agents in the treatment of obsessive-compulsive disorder and in the control of severely disturbed behaviour in various contexts (e.g. rapid tranquillisation for extreme agitation and/or anxiety).
Liquid, tablet, orodispersible (thin formulations which dissolve on the tongue) and short or long-acting (depot) injections.
- Extrapyramidal side-effects (EPSEs).
- Neuroleptic malignant syndrome (NMS).
- Prolonged QT (a risk factor for occasionally fatal ventricular arrhythmia). If >500, refer for cardiological assessment.
- Hyperprolactinaemia (with osteoporosis) and sexual dysfunction.
- Metabolic syndrome – weight gain, diabetes, dyslipidaemia (elevated triglyceride and low HDL cholesterol level) and hypertension.
- Decreased seizure threshold.
- Anticholinergic effects – constipation etc.
- Hyponatraemia (syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
- Agranulocytosis and myocarditis (clozapine)
Clozapine and related side effects:
It is licensed for treatment-resistant schizophrenia. Clozapine can improve positive/negative symptoms of psychosis, affective symptoms, cognitive symptoms and manic symptoms (in treatment resistant bipolar disorder).
These effects are due to its receptor affinity binding profile – histaminergic, muscarinic, adrenergic, serotonergic and dopaminergic receptors.
All patients MUST be registered with clozapine monitoring service. Patients on clozapine should have full blood count performed weekly for the first 18 weeks from dose commencement (when the risk of neutropenia/agranulocytosis is greater), fortnightly until 52 weeks of treatment and then monthly thereafter if haematologically stable.
Clozapine is titrated from a relatively low dose (12.5mg).
If treatment is missed for more than 48 hours, re-titration is recommenced to reduce the risk of severe side effects. However, progression through the protocol may need to be more rapid compared with drug-naïve patients.
A plasma level of at least 350ug/l should be the aim for adequate trial. About 30% of patients who have previously been refractory to treatment improve sufficiently after 6 weeks’ treatment with clozapine and up to 60% respond after 1 year.
Clozapine side effects:
- Neutropenia/agranulocytosis – Concomitant use of lithium can increase the white cell-count.
- Myocarditis and cardiomyopathy: ECT is required before treatment commencement.
It requires regular blood tests due to its side-effect profile especially bone marrow suppression.
Monitoring Guidance –Clozapine (Secondary care prescribing responsibility)
|Baseline||10-16 weeks||6 months||12 months||Ongoing|
|Weight / BMI / waist circumference||ü||To be checked as often as required or after 10-16 weeks , 6 months, 12 months and then annually.||To be checked as often as required or after 10-16 weeks , 6 months, 12 months and then annually.||To be checked as often as required or after 10-16 weeks , 6 months, 12 months and then annually.||To be checked as often as required or after 10-16 weeks , 6 months, 12 months and then annually.|
|Lipids (ideally fasting)||ü||ü||ü||ü||Annually|
|Random Blood Gluclose (Ideally fasting)||ü||ü||ü||ü||Annually|
|ECG||ü||ü||Repeat if clinically required or if there are concerns||Repeat if clinically required or if there are concerns||Repeat if clinically required or if there are concerns|
|U & Es||ü||ü||ü||Annually|
|FBC||Baseline then monitoring should continue as per the clozapine monitoring protocol. Additional monitoring may be required.||Baseline then monitoring should continue as per the clozapine monitoring protocol. Additional monitoring may be required.||Baseline then monitoring should continue as per the clozapine monitoring protocol. Additional monitoring may be required.||Baseline then monitoring should continue as per the clozapine monitoring protocol. protocol. Additional monitoring may be required.|
|Prolactin||Only if clinical symptoms are present and as the risk of this occurring with Clozapine is low then other causes should be considered.||Only if clinical symptoms are present and as the risk of this occurring with Clozapine is low then other causes should be considered.||Only if clinical symptoms are present and as the risk of this occurring with Clozapine is low then other causes should be considered.|
|BP and Pulse||Baseline thendaily during titration (see Trust initiation guidelines), weekly until 18 weeks then monthly on an ongoing basis (minimum of 3 monthly). Tachycardia is often a symptom warranting further investigation.||Baseline thendaily during titration (see Trust initiation guidelines), weekly until 18 weeks then monthly on an ongoing basis (minimum of 3 monthly). Tachycardia is often a symptom warranting further investigation..||Baseline thendaily during titration (see Trust initiation guidelines), weekly until 18 weeks then monthly on an ongoing basis (minimum of 3 monthly). Tachycardia is often a symptom warranting further investigation.||Baseline thendaily during titration (see Trust initiation guidelines), weekly until 18 weeks then monthly on an ongoing basis (minimum of 3 monthly). Tachycardia is often a symptom warranting further investigation.||Baseline thendaily during titration (see Trust initiation guidelines), weekly until 18 weeks then monthly on an ongoing basis (minimum of 3 monthly). Tachycardia is often a symptom warranting further investigation..|
|EEG||At baseline, only if the patient has a history of seizures and monitor as necessary if seizures occur.||At baseline, only if the patient has a history of seizures and monitor as necessary if seizures occur||At baseline, only if the patient has a history of seizures and monitor as necessary if seizures occur||At baseline, only if the patient has a history of seizures and monitor as necessary if seizures occur|
|CPK||At Baseline and then if NMS suspected||At Baseline and then if NMS suspected||At Baseline and then if NMS suspected||At Baseline and then if NMS suspected||At Baseline and then if NMS suspected|
|Serum level Clozapine (0.35-0.6mg/L)||ü||Can be helpful in checking concordance with prescription and reason for inefficacy, Check levels when maintenance does is reached, after any dose change and if the service user starts or stops smoking.||Can be helpful in checking concordance with prescription and reason for inefficacy, Check levels when maintenance does is reached, after any dose change and if the service user starts or stops smoking.||Can be helpful in checking concordance with prescription and reason for inefficacy, Check levels when maintenance does is reached, after any dose change and if the service user starts or stops smoking.|
Table information extracted from: Medication monitoring guidelines Author Clare Gaskell on behalf of the Drug and Therapeutics Committee.
Treatments of specific side effects
- Dystonic reactions: Oculogyric spasm and torticollis.
- Higher risks in the early stages of treatment or after an increase in dose.
- It may also occur on drug withdrawal.
- Use oral, IM or IV anticholinergics e.g. procyclidine 5-10mg).
- Drug Induced parkinsonism: Tremor, bradykinesia and rigidity.
- Treated with anticholinergic agent but not as a routine.
- Most patients will cope with the symptoms without active treatments.
- Note that anticholinergics can cause dry mouth, blurred vision, constipation, cognitive impairment and can exacerbate tardive dyskinesia.
- Akathisia: Subjective unpleasant state of motor restlessness. It has been linked to violence and suicide.
- Responds poorly to anticholinergics but can be treated by changing to a drug with lower liability for akathisia – usually an atypical.
- Use of a non-selective beta-blocker such as propranolol, small dose of clonazepam or the antihistamine cyproheptadine have been suggested and tried.
- Tardive dyskinesia: This involves a wide variety of movements – lip-smacking, chewing, tongue protrusion, choreiform hand movements, pelvic thrusting and severe orofacial movements caused by super-sensitivity of dopamine receptors due to prolonged therapy with dopamine-blocking drugs.
- Reduction/discontinuation of any anticholinergics
- Reduction of antipsychotic dose to the minimum that is effective
- Substituting older drugs with atypical antipsychotics
- Introduction of clozapine – believed to have little or no association with TD.
- Use of tetrabenazine and sodium valproate.
- Medications recently approved by FDA – deutetrabenazine and valbenazine.
NB: All patients treated with antipsychotics are at risk of developing TD but patients with affective illness, diabetes and learning disabilities are more prone to it. Females and the elderly are also more likely to be affected.
Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH).
This is commonly associated with the use of haloperidol, risperidone, quetiapine, olanzapine and clozapine. Mild to moderate hyponatraemia presents as confusion, epilepsy, cramps, nausea, headache and lethargy. As the plasma sodium falls, these symptoms become increasingly severe and seizures and coma can develop.
Antipsychotic related serum prolactin elevation occurs in about 40% of men and 60% of women.
This can often lead to galactorrhoea, gynaecomastia, hypogonadism, infertility, oligomenorrhoea/amenorrhoea and sexual dysfunction. A measurement of serum prolactin can be a useful indicator that the antipsychotic drug is being taken and is reaching CNS dopamine receptors.
- Risperidone and paliperidone have potent prolactin-elevating effect.
- Olanzapine has a transient minimal effect
- Quetiapine, aripiprazole and clozapine have no important effect on prolactin
Reduced seizure threshold:
Seizure is a recognised side-effect of antipsychotic therapy – the higher the dose, the greater the risk and clozapine has the highest risk.
Mediated through adrenergic a1-blockade. It is a particular risk when phenothiazine is prescribed for the elderly or when high doses of antipsychotics are used. The atypical antipsychotics clozapine, risperidone, quetiapine and sertindole all have important affinity for a1-receptors, making dosage titration necessary.
Dry mouth, blurred vision, urinary retention and constipation.
Clozapine has been associated with severe constipation which may result in intestinal obstruction. Anticholinergic effects may also have a detrimental impact on cognitive functioning.
Antipsychotics with potent anticholinergic effects – chlorpromazine and clozapine are not advisable in patients with closed-angle glaucoma.
SGAs are less likely to cause anticholinergic side effects – olanzapine and quetiapine only have mild/transient side effects of this kind.
Metabolic syndrome: Central obesity, diabetes/glucose intolerance, hyperlipidaemia and elevated BP.
Clozapine tends to have the highest risk of weight gain, followed by olanzapine, quetiapine, risperidone and aripiprazole.
The likely mechanism is insulin resistance but this does not seem to be clearly dose-related. In some cases, ongoing treatment with oral hypoglycaemic agent or insulin is required, even if treatment with clozapine or olanzapine is discontinued. Advice should be given on the management of increased appetite, diet and exercise, and weight should be monitored regularly.
Neuroleptic Malignant Syndrome (NMS)
A life-threatening medical emergency with a mortality of around 20%. It occurs in approximately 0.5% of patients newly treated with antipsychotics.
Clinical features, which evolve rapidly over 24-72 hours, include hyperthermia, muscular rigidity, decreased conscious level and labile blood pressure.
Laboratory findings include elevated creatine kinase (CK), leucocytosis, abnormal liver function tests and myoglobinuria.
Mortality: 10 – 20 %
The usual cause of death includes: pulmonary embolism, Disseminated Intravascular Coagulopathy, aspiration and renal failure secondary to rhabdomyolysis.
NMS Risks factors:
Rapid antipsychotic dose increase, intramuscular medication, medical illness, male gender, dehydration etc.
Treatment of NMS:
- Antipsychotic agent discontinuation.
- Supportive treatment (hydration, antipyretics etc)
- Dopamine agonists (bromocriptine, dantrolene) may help with reduction in muscle spasm and to reverse anti-dopaminergic effects.
- Transfer to the nearest medical facility for management – Treatment in ICU may be required.
- Investigations: serum CPK (raised in NMS) while temperature, pulse, and blood pressure should be closely monitored.
ANTIDEPRESSANTS AND NEUROSTIMULATION
The earliest effective antidepressants were discovered mostly by chance. Iproniazid was an antituberculous drug while imipramine was a chlorpromazine analogue (synthesised as an antihistamine).
Historically, monoamines deficiency in the CNS was causally linked to the development of depression. The monoamine hypothesis predicts an impairment in the central monoaminergic pathway. The lesion may be in the form of absolute concentration deficiencies of serotonin (5-HT) and/or norepinephrine. Studies have provided evidence of correlation between deficiencies and depressive symptom. However, the monoamine hypothesis has not satisfactorily explained the similarity in efficacy of different agents acting differentially on monoamine pathway. Due to these shortcomings, the hypothesis has been modified over several years with the focus now targeting receptor regulation and second messenger signalling. Alternative neurobiological systems been proposed include – Hypothalamic-Pituitary Axis (HPA) hypothesis and Glutamate/neuplasticity hypothesis’.
Classification of Antidepressants
Essentially, all effective antidepressants enhance the synaptic activities of one or more monoamines – serotonin (5HT), nor-adrenaline (NA) and dopamine (DA) consistent with monoamine hypothesis, which proposes that they are depleted in depression.
- Selective Serotonin Reuptake Inhibitors (SSRI) – Fluvoxamine, fluoxetine, sertraline, citalopram, escitalopram and paroxetine.
- First line antidepressants in the treatment of depression.
- Although they are structurally different, they share in common the selective serotonin (5-HT) re-uptake blockage.
- SSRIs are metabolised in the liver by cytochrome p450 enzyme and some including fluoxetine has an active metabolite.
- Although in low concentration, they are secreted in the breast milk differently (highest with fluoxetine and citalopram, lowest with sertraline and paroxetine).
- Some are also prone to discontinuation syndrome especially those with short half-life (paroxetine). Fluoxetine is least likely to cause discontinuation syndrome due to longer half-life.
- They are safer in overdose compared with tricyclic antidepressants (TCA).
- GIT symptoms: Nausea, vomiting and diarrhoea.
- Sexual dysfunction (highest risks with paroxetine)
- Hyponatremia (highest risks in elderly)
- Bleeding (due to platelet 5-HT depletion)
- Worsened thoughts of hurting self or others. Proven in under 26s. Possible in other ages
- Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
Examples are: Venlafaxine, Des-venlafaxine and Duloxetine
|Venlafaxine||Selective 5-HT and Norepinephrine (NE) Reuptake Inhibitors (NE re-uptake inhibition at doses above 150mg/day)||Side effects are similar to SSRI. increase BP (dose dependent) Seizure (in overdose) Discontinuation syndrome|
|Duloxetine (Also, effective in treating neuropathic and musculoskeletal pains)||Selective 5-HT and Norepinephrine (NE) Reuptake Inhibitors (same affinity for both receptors. (NA re-uptake inhibition at doses above 60mg/day)||As above. Liver disease – avoid use with alcohol. Fatigue.|
|Desvenlafaxine A synthetic form of active metabolite of venlafaxine. It has greater NA:5-HT transporter inhibition ratio than venlafaxine||Selective 5-HT and NARI (NA re-uptake inhibition at doses above 50mg/day)|
Note: Adequate trials of SNRIs to recruit the norepinephrine transporters should reach: duloxetine-120 mg, venlafaxine-225 mg, desvenlafaxine-100 mg
- Noradrenaline Re-uptake Inhibitors (NARIs) – Reboxetine and (TCA lofepramine).
- They boost noradrenaline and dopamine in prefrontal cortex.
- Less efficacious than SSRI and SNRIs.
*Lofepramine is a TCA but unlike typical TCA, it is less toxic in overdose and binds to monoamine receptors with low affinity.
- Alpha2 – Adrenoceptor Antagonists – Mirtazapine, Mianserin (older drug) –
- Increases NA transmission by blocking negative feedback on alpha 2 receptors.
- It increases serotonin transmission by blocking alpha 2 heteroreceptors on serotonergic neurones.
- It also blocks the serotonin receptors that are responsible for some of the SSRI side effects of insomnia, nausea and sexual dysfunction.
- Side effects include increase appetite, weight gain and sedation.
- Can be safely used in combination with other antidepressants especially SSRIs and SNRIs to treat ‘Treatment Resistant Depression’.
Mianserin is commonly associated with blood dyscrasia and requires blood count monitoring when used.
- Tricyclic Antidepressants (TCA)
The tricyclics gained the name because their chemical structure contains 3 rings.
More sedating: Amitriptyline, clomipramine, dosulepin (dothiepin)
Less sedating: Imipramine, lofepramine and nortriptyline.
Tertiary amines (amitriptyline, imipramine and lofepramine) have strong affinity for 5-HT reuptake blockage.
Secondary amines (nortriptyline and desipramine) are more potent on NA reuptake receptor.
While this group of antidepressants are very efficacious, they all have significant unwanted pharmacological effects-
- Antimuscarinic effects: Blurring vision, dry mouth, retention of urine and constipation.
- Anti-histaminic action: Weight gain, sedation etc.
- Alpha1 adrenergic action: Dizziness, orthostatic hypotension etc.
- Blockage of voltage-sensitive sodium channels (heart and brain). – In overdose they can lead to coma, seizure, cardiac arrhythmias, cardiac arrest and death. This is the main reason why they are no longer used as 1st line treatment of depression.
Other side effects:
- Manic switch if used in the treatment of bipolar disorder patients. This has been linked to the boost in the NA neurotransmission.
- Discontinuation syndrome: Gastrointestinal symptoms, agitation, anxiety and vivid dreams.
- Neurotoxicity: Movement disorders, delirium etc
- Cardiotoxicity: Arrhythmias prolonged QTc and ST elevation in some cases.
TCAs are metabolised in the liver. The tertiary amines are metabolised to secondary amines. There is evidence that the clinical effects of TCAs are dose-dependent and the side effects are dose-related. Thus, titration to an effective dose is essential. The cardio-toxic side effects make it less commonly used in elderly patients
TCA use is contraindicated in the following conditions – arrhythmias, recent MI, heart block, mania, hypomania and acute porphyria.
- Monoamine Oxidase Inhibitors (MAOIs)
- MAOIs facilitate the release and storage of 5-HT and NA
- They are present both in the periphery (GIT) and CNS.
- Due to their significant adverse effects, they are mostly used by specialists after unsuccessful trials of other antidepressant medications.
- MAOIs inhibit MAO-A (metabolises 5-HT, NA, DA) and MAO-B (metabolises DA, phenylethylamine). They both metabolise tyramine.
- Irreversible MAOIs: Phenelzine, tranylcypromine, isocarboxazid and selegiline (selective MAO-B inhibitor).
- Reversible MAOIs (RIMA): Moclobemide – It causes less potentiation of the pressor effects of tyramine. It has a better tolerability and does not need specialist supervision.
MAOIs are mostly used in the treatment of severe depression, treatment resistant depression and atypical depression. They are easily absorbed on administration (orally) but toxic level is linked with slow acetylation.
Important side effects:
- Hypertensive reaction/crisis caused by tyramine containing foods (cheese, yeast extracts) and indirect sympathomimetic drugs (phenylephrine).
- Postural hypotension (especially in elderly).
- Cardiovascular disease and central nervous system disease.
- Enhances melatonin MT1 and MT2 receptor functions
- Blocks 5-HT2c receptors.
- It has been hypothesised that it boosts the effects of DA and NA in the pre-frontal cortex.
- Agomelatine has a short half-life and often used at night, thus most side effects- GIT symptoms, sedation, nausea and dizziness are rare.
- Elevated liver enzymes and rarely hepatoxicity.
- In addition to its effects on 5-HT transporter, it is also a serotonin modulator and stimulator.
- It improves cognitive function in depressed patients.
- Common side effects:nausea, dry mouth, headache and hyperhidrosis.
- Incidence of sexual dysfunction caused by vortioxetine is only slightly higher than in people on placebo.
- Serotonin reuptake inhibitor and like vortioxetine, it is also a serotonin modulator and stimulator.
- Side effects include nausea, diarrhoea and insomnia. Risks of suicide and withdrawal symptoms have been reported.
- More active enantiomer of milnacipran. It is a NSRI (Noradrenaline-Serotonin Reuptake Inhibitor)
- Compared with SNRIs, levomilnacipran has much more balanced reuptake inhibitors of serotonin and norepinephrine.
- It has better receptor selectivity, improved tolerability and greater potency.
- NICE guidelines
- Antidepressants are not recommended in mild depression – watchful waiting, problem-solving and exercise are more effective
- When an antidepressant is prescribed, a generic SSRI is recommended as first choice
- All patients should be informed about the withdrawal effects of antidepressants
- For severe or resistant depression, a combination of antidepressant and CBT is recommended
- Patients with two prior episodes and functional impairment should be treated for at least 2 years.
- In children and young people, fluoxetine is the only antidepressant with the evidence that shows that benefits outweigh risks in the treatment of moderate to severe depression
- When prescribed in children and young people, antidepressant should be closely monitored for suicidal behaviour, self‑harm or hostility, particularly at the beginning of treatment.
Acute neuropsychiatry presentation, which sometimes may resemble neuroleptic malignant syndrome but is caused by raised CNS serotonin activity. It may be due to simultaneous prescription of more than one antidepressant or interaction between agents that increase 5-HT functions (SSRI with MAOI). Symptoms include agitation, sweating, confusion, myoclonus, nystagmus, headache, tremor, pyrexia, mood changes and fits. Discontinuation of the agent/s and supportive measures are usually enough for treatment.
Antidepressant discontinuation symptoms
This is a clinical syndrome that has given the impression that antidepressants are addictive. While some physiological processes and adaptations to the agents may have occurred, symptoms are not known to include tolerance and craving as seen in cases of typical addiction.
Antidepressant with potent anticholinergic side effects is more implicated in this syndrome. Symptoms mostly develop within the first 5 days of stopping an established treatment especially those with a short half-life. Symptoms are often mild and self-limiting and may resolve over 2 weeks. If severe, recommence the antidepressant agent and taper off at a slower rate. Switching over or starting fluoxetine with longer half-life may suffice in some cases and then withdrawing it.
|TCAs||SSRIs and related|
|Discontinuation Symptoms||Common Flu-like symptoms (chills, myalgia, excessive sweating, headache, nausea), insomnia, excessive dreaming. Occasionally Movement disorders, mania, cardiac arrhythmia||Common Flu-like symptoms, ‘shock-like’ sensations. Dizziness exacerbated by movement, insomnia, excessive (vivid) dreaming, irritability, crying spells Occasionally Movement disorders, Problems with concentration and memory.|
|Drugs most commonly associated with discontinuation symptoms||Amitriptyline Imipramine||Paroxetine Venlafaxine|
[A]. Electroconvulsive Therapy (ECT)
ECT is a therapeutic procedure that involves induction of seizure by applying an electrical stimulus to the brain. It is delivered in a controlled clinical setting, after induction of general anaesthesia and application of a muscle relaxant.The exact mechanism of action is still under investigation. ECT is one of the most effective treatments for MDD. Response rates can reach 70% to 80%, with remission rates 40% to 50%.
Hypotheses for mechanism of action include seizure-induced changes in neurotransmitters, neuroplasticity and functional connectivity. For example, ECT can increase levels of brain-derived neurotrophic factor (BDNF), which may contribute to the antidepressant effect.
There are no absolute contraindications for ECT.
The following conditions may be associated with an increased safety risk: space-occupying cerebral lesion, increased intracranial pressure, recent myocardial infarction, recent cerebral haemorrhage.
*Electrode placements: Bilateral (bitemporal or bifrontal) and right unilateral (RUL).
*Seizure threshold: Minimum intensity to produce a generalized seizure.
*Index course: Number of ECT treatments required to achieve response and/or remission. It ranges between 6 and 15.
ECT is usually delivered 2 to 3 treatments per week during the index course.
The main predictor of nonresponse to ECT is the degree of resistance to previous treatments.
Factors that influence good response:
- Patients with psychotic features.
- Shorter duration of illness.
- Lesser depression severity.
Problems associated with ‘Consent for ECT’
- Incapable patient
- Perceived coercion
NICE guidance recommends ECT for use in the acute treatment of moderate to severe depression, mania or catatonia in patients who have failed in responding to other treatments. It is effective in the treatment of patients with severe depression with psychosis and psychomotor retardation.
- Adverse effects relating to use of general anaesthesia.
- Confusion, headache and nausea.
- Cognitive impairment: Increased incidence with bilateral application than unilateral application of electric current. The applied dose and patient factors are also important risks factors. The memory impairment usually resolves within weeks but some may experience it as a permanent phenomenon.
[B]. Repetitive Transcranial Magnetic Stimulation (rTMS)
rTMS makes use of powerful (1.0-2.5 Tesla), focused magnetic field pulses to noninvasively generate electrical currents in neural tissue. The pulses are delivered through an inductor coil applied against the scalp. Unlike ECT, anaesthesia is not required. The mechanism of action is under investigation. However, the mechanisms proposed are at cell-molecular and network levels.
Stimulus intensity is based on individually determined Resting Motor Threshold (RMT). RMT is the minimum intensity to elicit muscle twitches at relaxed upper or lower extremities, either by visual inspection or electromyography. Most common intensity in all trials to date is 110-120% RMT.
There are 2 stimulation frequencies used in rTMS.
- High-frequency (5-20 Hz): Excitatory
- Low-frequency (1-5 Hz): Inhibitory.
The most effective treatment protocols appear to involve high frequency stimulation of the dorsolateral prefrontal cortex (DLPFC).
Adverse Effects Associated with rTMS.
• Scalp pain during stimulation and transient headache after stimulation
• The most serious rTMS adverse event is seizure induction.
Absolute contraindication: Metallic hardware (e.g. cochlear implants, brain stimulators or electrodes, aneurysm clips) anywhere in the head, except the mouth.
Relative contraindications: Include presence of cardiac pacemaker, implantable defibrillator, a history of epilepsy and brain lesion.
rTMS has a safe cognitive profile compared with ECT.
Starting a new antidepressant with rTMS results in higher response and remission rates than rTMS alone.
Sedatives were among the first psychopharmacological agents. Chloral hydrate and paraldehyde were introduced in the 19th century. Despite significant adverse effects reported, barbiturates appeared to be the anxiolytic drug of choice until the benzodiazepines were introduced. Benzodiazepines (BZD) became a preferred drug of choice after barbiturates due to a higher therapeutic index but for the problems with withdrawal symptoms, dependence and tolerance.
In the post-benzodiazepine era, buspirone – a 5-HT1A partial agonist became popular. This progressed to the introduction of SSRIs for the treatment of anxiety disorders and they are now currently recommended as first-line treatment. SNRIs have also become effective in the treatment of generalised anxiety disorders (GAD). In addition, pregabalin (non-BZD anxiolytic) has also been licenced for GAD treatment.
|Anxiolytic agent||Pharmacology||Clinical effects||Adverse effects|
|Benzodiazepines||GABAA receptors agonist. No enzyme induction. Phase 1 metabolism to form active metabolites. [N.B: Lorazepam, temazepam and oxazepam undergo direct phase 2 reactions].||Anxiolytic Hypnotic Anticonvulsant||Drowsiness and dizziness. Confusion (elderly). Cleft lip/palate and respiratory depression (avoid in pregnancy). Cognitive and psychomotor impairment. Tolerance and cross-tolerance with alcohol. Withdrawal and discontinuation symptoms.|
|Antidepressants||5-HT reuptake blockage.||SSRIs: 1st line pharmacological treatment for anxiety disorders. Clomipramine: OCD||See individual agent above.|
|Buspirone (Azapirones)||5-HT1A-receptor partial agonist. Short elimination half-life||Effective in GAD Less effective in treating acute anxiety or social phobia. Not a good augmenting agent with SSRI in anxiety disorders.||Nausea, dizziness and akathisia.|
|Pregabalin||Has affinity for voltage-gated Ca2+. Eliminated unchanged via kidneys.||Effective in treating GAD and social phobia. Useful in augmentation strategy for antidepressant treated anxiety disorders||Well tolerated. Discontinuation syndrome. Drug of abuse. Deranged liver function. Vertigo, dizziness and weight gain.|
|Beta Blockers||Blockage of beta adrenoceptors.||Reduction in the physical symptoms of anxiety. Akathisia and lithium induced fine tremor.||Bradycardia and hypotension. Bronchospasm (in asthma patients),|
Benzodiazepines vary in their duration of action:
- Short acting agents – lorazepam and temazepam: Have greater potential for abuse and dependence, but may be safer in acute situations.
- Long-acting – diazepam.
The non-benzodiazepine ‘Z drugs’ (zopiclone, zaleplon and zolpidem) are not used as anxiolytics though they act on the benzodiazepine receptor. They are commonly prescribed as hypnotics and have little to offer over benzodiazepines.
Other points to note:
- Benzodiazepines can be used for short-term management of severe anxiety. Longer-term anxiety is better managed by psychotherapy, changing the environmental situation or by other medications (e.g. SSRIs).
- Buspirone can be used in the longer-term, but may be less efficacious than alternative strategies and is rarely used in clinical practice.
- For those addicted to benzodiazepines, conversion is required to a long-acting drug (i.e. diazepam) before starting on a very slow reducing regimen.
- Most benzodiazepines undergo Phase I Metabolism (Oxidation, reduction, hydrolysis and demethylation by CYP450).
- Phase II Metabolism (Conjugation). Lorazepam, oxazepam and temazepam.
Lithium is a naturally occurring alkaline metal. Among other uses, it is widely found in spa waters which were recommended for mania treatment as long ago as the second century by Soranus of Ephesus. John Cade, an Australian psychiatrist who started to use it to treat manic patients, pioneered its modern use. There is evidence that it reduces suicide mortality.
Lithium mechanism of action is due to its ability to alter the signal induced by multiple neurotransmitter system (i.e. dopamine, serotonin and noradrenaline), but the specific mode of action is still unconfirmed. Its therapeutic effect has been attributed to a number of reasons that include:
- Ability to block neuronal calcium channels.
- Boosting of the activities of Na+/K+ ATPase
- Interactions with intracellular ‘second messengers’.
- Facilitation of growth hormone response to cholinergic agonist.
- Neuroprotective effects on neuronal functions.
Lithium is absorbed in upper GIT, unbound in serum, reaches its peak serum level in about 3 hours and it achieves steady-state plasma concentration after 5 days. Its excretion is primarily through the kidney in an unchanged form. It comes in different preparations (carbonate, citrate etc.) with different bioavailability. Different preparations should not be substituted dose for dose. For prescription purposes, trade name should be used.
It is effective in acute mania and as the first-line maintenance treatment of bipolar disorder. It reduces both the number and severity of relapses of bipolar affective disorder and offers some protection against antidepressant-induced hypomania.
Intermittent treatment with lithium may worsen the natural course of bipolar illness (NB: an increased risk of manic relapse is seen in the first few months after discontinuing lithium, even in patients who have been symptom-free for as long as 5 years). The risk of relapse may be reduced by decreasing the dose of lithium gradually over a period of 1 month or longer. It is less effective in the treatment of mixed affective states and rapid cycling. It should be used cautiously with antipsychotic medication due to a possible neurotoxic adverse effect.
Lithium and antidepressants are probably equally effective in the prophylaxis of recurrent depressive disorder. It is effective in augmenting the effect of antidepressants in patients with refractory unipolar depression. It can be used in combination with antipsychotics in the treatment of schizo-affective disorder. It may also help to decrease self-mutilating behaviour, aggression, suicidal ideation, completed suicide and impulsivity.
Lithium adverse effects:
The adverse effects can relate to serum concentration. The higher the serum concentration, the more likely some of the adverse effects will occur
- Weight gain.
- Nausea and diarrhoea.
- Polyuria, polydipsia and thirst.
- Renal impairment
- Hypothyroidism (and possibly hyperthyroidism)
- Teratogenicity: Ebstein’s anomaly
- Worsening of psoriasis.
- Toxicity: Lithium has a narrow therapeutic index. While toxicity can still occur in some patients within the therapeutic range (adults: 0.6-1.0 mmol/ℓ, elderly: 0.4-0.8 mmol/ℓ), signs of toxicity usually appear at a serum concentration of >1.2mmol/L. The investigation of choice in neurotoxicity is ‘EEG’ which shows ‘diffuse slowing of cortical activity’.
Predictors of good response to lithium:
- Good concordance/compliance with use.
- History of remission with lithium.
- Family history of bipolar disorder and response/remission to lithium.
- Full remission between episodes.
- Few prior episodes
Predictors of poor response to lithium:
- Rapid cycling
- Poor concordance
- Illicit drug use.
- More than 3 previous episodes.
- Prior to starting lithium treatment, the following tests should be carried out: serum electrolyte, urea and creatinine, thyroid function and ECG.
- Start at 400 mg once daily – taken at night (200 mg in the elderly).
- Check serum concentration level after 5-7 days, then every 5-7 days until the required level is reached (adults: 0.6-1.0 mmol/ℓ, elderly: 0.4-0.8 mmol/ℓ).
- Blood should be taken about 12 hours (12-16) after the last dose.
- Once stable, check level every 3-6 months.
- Check U&Es and TFTs every 6 months.
- Take particular note of creatinine level, TSH level and any polyuria.
Lithium and Breast milk.
- It is not advisable to prescribe lithium to breastfeeding mothers.
- It can lead to lethargy, hypotonia, hypothermia, cyanosis and electrocardiography changes in the infant.
The mode of action of anticonvulsants in stabilising mood is not well established. One hypothesis is that they boost the actions of GABA in the central nervous system.
Valproate is available in the UK in three forms:
*Sodium valproate – Epilim
*Valproate semi sodium – Depakote (sodium valproate + valproic acid).
Both valproate semisodium and sodium valproate are metabolised to valproic acid, which is responsible for the pharmacological activity of all three preparations. It is now been increasingly used as first-line monotherapy.
Valproate is effective in the treatment of:
- Mania (more effective in non-psychotic patients)
- Rapid cycling bipolar disorder.
- Maintenance treatment of bipolar disorder.
- Blood dyscrasia: Thrombocytopenia, leucopoenia, red cell hypoplasia.
- Weight gain
- Nausea, vomiting and diarrhoea.
- Loss of hair
- Headache, confusion and lethargy.
Many side effects of valproate are dose-related (peak plasma level-related) and they increase in frequency and severity when the plasma level is >100mg/ℓ.
Practicalities in clinical use:
- Contra-indicated in women of childbearing age.
- Evidence of dose-response effects: Use loading dose to enhance response in severe mania.
- Preparations do not have same dose equivalence.
- Monitor liver functions, FBC and clotting profiles of patients
- Pregnancy test: Valproate is an established teratogen. The risk of foetal malformations is 7.2%, in particular neural tube defects
Carbamazepine is effective (more as adjuncts to other agents) for the prophylaxis of bipolar disorder, which has been unresponsive to lithium. It is not as equally effective as lithium in preventing relapse.
Highlights of carbamazepine are in its interactions with other drugs. It induces the metabolism of
- Psychotropic medications – antidepressants, antipsychotics, valproate etc.
- Oral contraceptive agents leading to failure.
- Blood dyscrasia: Leucopenia.
- Skin reactions: More serious reactions are Steven-Johnson syndrome and toxic epidermal necrolysis.
- Hepatoxicity, liver failure and cholestatic jaundice.
- Teratogenicity (Secondary to folate deficiency): Spina bifida.
- Drowsiness, headache and diplopia.
- Drowsiness, ataxia and nausea.
- Discontinue carbamazepine at the first sight of new skin rashes and investigate if they are related to carbamazepine use.
- Immediate release formulations are less tolerated than extended release.
- Monitoring of blood, skin and liver are advised during the use of carbamazepine.
- Not an effective antimanic agent but has a modest antidepressant activity.
- Although used as an adjunctive treatment, it is known to prevent depressive relapse in patients with bipolar disorder.
- Rashes and more serious reactions – Steven-Johnson syndrome: Slow titration can reduce the likelihood of dermatological reactions.
- Flu-like symptoms
- Aseptic meningitis
- Ataxia and blurred vision.
Medication Treatment of Acute Mania:
- STOP antidepressant medication.
- Atypical Antipsychotics: Risperidone, quetiapine, olanzapine, aripiprazole, paliperidone, ziprasidone, asenapine, cariprazine, haloperidol
- Mood Stabilisers: Lithium and Valproate.
Medication Treatment of Acute Bipolar Depression:
Quetiapine, lithium, lamotrigine, lurasidone, divalproex, combined olanzapine-fluoxetine, ECT, cariprazine etc
Maintenance Treatment in Bipolar Disorder
- Atypical Antipsychotics: Quetiapine, olanzapine, aripiprazole, ziprasidone, Asenapine.
- Mood Stabilisers: Lithium, Valproate, Lamotrigine (Depression only) 2nd Line: Carbamazepine
- Mood stabiliser + antipsychotic
Methods to Improve Medication Adherence
- Education about the medication
- Involve the family and carers
- Simple dosing regimens (once daily)
- Use of dosette boxes or blister packs
- Use of oral dispersible medications or liquid formulations
- Long acting injectables
DRUGS FOR THE TREATMENT OF ALCOHOL AND SUBSTANCE MISUSE.
Alcohol is legal and readily available. Its effect is facilitated via GABAA and glutaminergic pathways.
Alcohol is metabolised to acetaldehyde through the action of alcohol dehydrogenase and it undergoes zero order elimination. Acetaldehyde is subsequently converted to Acetate by acetaldehyde dehydrogenase. Disulfiram blocks the action of acetaldehyde dehydrogenase.
- Treatment of alcohol intoxication:
Supportive with airway protection
Intramuscular thiamine, followed by glucose treatment.
- Treatment ofAlcohol Withdrawal
Benzodiazepines are effective in the treatment of alcohol withdrawal – lorazepam, diazepam, chlordiazepoxide. Benzodiazepines modulate GABAA receptors activities.
A typical chlordiazepoxide regime for treatment of alcohol withdrawal (the dose/regime of chlordiazepoxide treatment will vary depending on the severity of alcohol withdrawal)
|Day 1||20mg qds|
|Day 2||15mg qds|
|Day 3||10mg qds|
|Day 4||5mg qds|
|Day 5||5mg bd|
In liver impairment, lorazepam, oxazepam and temazepam arepreferred since they are not subject to Phase 1 reactions in the liver.
Thiamine and vitamin Bco: Longstanding drinkers are prone to vitamin deficiency due to poor appetite.
Parenteral thiamine is recommended in alcohol dependence to avert the development of Wernicke’s encephalopathy. Carbamazepine can be used as an alternative if benzodiazepines are contraindicated.
Other medications used in the treatment of alcohol dependence:
- It inhibits aldehyde dehydrogenase resulting in the accumulation of acetaldehyde in the body.
- Beneficial if administered under supervision (It is advisable for the patient to be in a supportive relationship)
- It is not an anti-craving agent.
The consumption of alcohol on top of disulfiram causes adverse reactions:
- Nausea and vomiting.
Contra-indications to disulfiram use include:
- Severe liver failure
- Cardiac disease
- Psychosis (inhibition of dopamine-beta-hydroxylase theoretically worsening psychosis or causes psychosis).
- NMDA receptor antagonist, which reduces craving for alcohol.
- Increases both abstinence rate and ‘time to first drink’
- Can also reduce the chances that an episode of alcohol consumption leads to full relapse.
- It has minimal to no liver metabolism – higher renal elimination.
- An opiate antagonist, effective in the treatment of alcohol and opiate dependence.
- Reduces craving and relapses in alcohol dependent people.
- Increases abstinence in alcohol dependent patients by preventing a rush of endorphins associated with drinking.
- Potential risks of hepatoxicity.
- Double-blind RCTs support use in alcoholism with behavioral interventions i.e relapse prevention.
- A long acting full ‘mu’ opioid agonist with a ½ life of approximately 36 hours.
- The ½ life is reduced to about 24 hours after a period of regular use as a result of cytochrome P450 enzyme induction.
- Effective with harm reduction for IV opioid use
- It is recommended for use in pregnancy
- It prolongs QTc at doses usually above 100mg/daily.
- Typical dosing of 60-120 mg/day
- Respiratory depression in overdose.
- A partial mu-agonist and partial antagonist (kappa).
- High affinity for opioid receptors and can be combined with naloxone to minimise the incidence of recreational IV use.
- It does not cause dysphoria.
- ½ life > 24 hours.
- Risk of fatal respiratory depression is low compared with methadone.
- There is a risk of precipitated withdrawal symptoms – described as intense withdrawal symptoms resulting from a sudden reduction of overall opioid effect on commencing buprenorphine.
- An alpha2 agonist
- Licensed for alleviation of somatic symptoms during opiate withdrawal.
- It is associated with hypotension and bradycardia.
It acts on nicotinic acetylcholine receptors – Alpha 4, Beta 2 receptors are most related to nicotine dependence.
Agents approved for smoking cessation:
- Nicotine Replacement Therapy (NRT)
- Full agonist
- Oral absorption is reduced by acidic pH (e.g. coffee)
- Formulations: Transdermal patch, gum, lozenge and Inhaler.
- Side Effects: Localized skin reactions with patch, sleep disturbance and nausea.
- Alpha-4, beta-2, nicotinic acetylcholine receptor partial agonist
- It alleviates the symptoms of nicotine craving and withdrawal through its agonist activity.
- Side Effects: Nausea and possibly depression & suicidality
- Bupropion – An antidepressant
- Nicotinic antagonist
- Noradrenaline and dopamine Re-uptake Inhibitors (antidepressant action)
- Sometimes preferred in depressed smokers
- Side effects: Induces weight loss and seizures (contraindicated in anorexia nervosa/eating disorders and seizure history). Psychosis due to effects on dopamine system. Sleep disturbance.
DRUGS FOR THE TREATMENT OF DEMENTIA AND COGNITIVE IMPAIRMENT
Drugs that are currently licensed for the treatment of cognitive deficits in dementia are
- Acetylcholinesterase inhibitors (AChEI): Donepezil, Galantamine and Rivastigmine
These medications are essentially for symptom relief rather than cure or for alteration of clinical course.
AChEIs inhibit the action of acetylcholinesterase from metabolising acetylcholine, thereby sustaining the level and duration of action of the neurotransmitter.
The neurochemical changes in Alzheimer’s disease include – Loss of cholinergic neurons in the nucleus basalis of Meynert, decline in Choline Acetyl Transferase activity and depletion of acetylcholine, especially in moderate to severe stage.
Treatment with AChEI should only be initiated by specialists in the care of patients with dementia (psychiatrists, neurologists and geriatricians). Patients should be reviewed every 6 months with MMSE score, global, functional, and behavioural assessment. Carers’ views should also be sought each time.
Memantine is an NMDA receptor antagonist and is designed to stop excitatory cell death in Alzheimer’s and vascular dementia.
|Agents||Mechanism of Action||Adverse effects|
|Donepezil||Selective reversible AChE inhibitor||GI side effects. Seizure Sinoatrial and atrioventricular blocks. Caution with concomitant cytochrome enzymes inducers and inhibitors.|
|Galantamine||Reversible AChE inhibitor||As above|
|Rivastigmine||Irreversible AChE inhibitor||As above|
|Memantine||Non-competitive NMDA receptor antagonist.||Hallucination Confusion.|
|Inhibition||AChE||AChE||AChE and BuChE|
|Half-life||70 hours||7-8 hours||1-2 hours|
|Doses per day||1||1||2||1|
|Starting Dose||5 mg QAM||8 mg QAM||1.5 mg BID||5 mg|
|Monthly Increment||5 mg QAM||8 mg||1.5 mg BID||5mg|
|Maximum||10 mg||24mg||6 mg BID||10 mg|
|Given with food||Irrelevant||Recommended||Inc bio-availability|
|Elimination||Liver||Liver & Kidneys||Kidneys|
*Massoud et al. Int Psychogeriatric 2010:372-8; Blennow et al. Lancet 2006: 387-403
[A]. Cholinesterase inhibitors:
- Cardiac: Bradycardia (<50), LBBB.
- Peptic ulcer disease
- Medications: anticholinergic medications
- Creatinine clearance < 30 mL/min
Pharmacological Management of Neuropsychiatric Symptoms (NPS)
- Dangerous and distressing behaviours that are negatively impacting social relationships and which has not responded to comprehensive non-pharmacologic treatment plan.
- Behaviours that require emergency treatment to allow investigation of underlying problems.
NPS with psychotic features:
- Atypical antipsychotics (Increased risk of death and stroke).
NPS without Psychotic symptoms
- Atypical antipsychotics
Other potential harms of antipsychotic treatment
- Increased risks of EPSE
- Further Impairment in cognition
- QTc prolongation with arrhythmia
- Metabolic effects:
DRUGS FOR THE TREATMENT OF ATTENTION DEFICIT / HYPERACTIVITY DISORDER (ADHD)
Appropriate psychological, social and behavioural interventions should be put in place during management of patients with ADHD. Medication (with or without behavioural treatment) is the most effective treatment for core symptoms. However, the combination of medication and behavioural treatment is the most effective approach for problems associated with ADHD.
Where drug treatment is considered appropriate, stimulants (methylphenidate and dexamfetamine) and atomoxetine are recommended as options for management.
- Methylphenidate (MPH)
- Ritalin, Ritalin SR
- Biphentin – Long acting
- Concerta – Long acting
- Dexedrine/Dexedrine spansule (d-amphetamine)
- Adderall XR: Mixed salts amphetamine (d-amphetamine and amphetamine salts in a ratio of 3:1) – Long acting
- Vyvanse (Lisdexamfetamine) – Long acting: It is a pharmacologically inactive prodrug with low abuse potential. It becomes active in the body after its conversion to ‘d-amphetamine’.
Use of Long-Acting formulations improve compliance and facilitate a more consistent coverage throughout the day.
Common adverse effects of stimulants (Methylphenidate and d-amphetamine).
- Decreased appetite
- Sleep disturbance.
- Stomach upset
NB: Side effects improve with time
Other concerns with use of stimulant:
- Growth suppression
- Abuse potential
- Cardiovascular effects
Points to note and explore before initiating patients on stimulants
- Cardiac risk assessment of individual patients including physical examination. This includes heart rate and blood pressure.
- Detail history that includes personal and family history to identify those at risk of sudden cardiac death.
- Cardiology referral for patients with suspected heart disease or identified risk factors for sudden death.
Monitoring of patients on stimulants
- Height and weight – preferably with growth charts
- HR and BP – During clinical encounters and with dose changes.
- Rating scales (Parent and teacher) to monitor medication response and adverse effects.
Atomoxetine is a ‘selective norepinephrine reuptake inhibitor (NRI) that is useful when patients are non-responsive to stimulants or there are significant side effects to stimulants. It is also effective in patients with comorbid anxiety and when there is a risk of stimulant’s abuse/diversion.
Compared with stimulants, atomoxetine has little or no long-term effect on growth in children and it has no appetite suppressant effect. However, it has smaller effect size with lower response rate.
- Increased BP and HR: Should be avoided in patients with symptomatic cardiovascular diseases, moderate to severe hypertension or severe cardiovascular.
- Drug-drug interactions vis cytochrome P450 enzymes.
- Response using rating scales
- HR and BP at baseline and subsequent clinic encounters
- Height and weight on grow charts.
- Suicidal ideation
- Routine blood tests are not needed.
Short-term management of disturbed and violent behaviours in psychiatry settings and emergency department.
1) Talk to the patient.
- Do not get too close and make sure the patient is not between you and the door.
- Speak in a calm quiet voice and reassure the patient that you are there to help them. Listen to what they have to say.
- Make sure that only one person is speaking to the patient and that the situation does not attract an audience of other patients which may be over-stimulating for the patient.
2) Oral medications.
- Benzodiazepine – lorazepam: It is a short acting benzodiazepine and has a less prolonged effect on behaviour. Any serious side effects are likely to be less long lasting. It has a high abuse potential.
- Haloperidol: Typical antipsychotic medication
- Risperidone: Atypical antipsychotic medication
- Olanzapine: Atypical antipsychotic medication
- Combinations: Oral risperidone plus oral lorazepam.
- Promethazine is sometimes used in adolescents
Avoid antipsychotics in Lewy body dementia (LBD) due to the risks of serious extrapyramidal side effects and neuroleptic malignant syndrome.
3) Parenteral routes.
- The IV route should not be used except in the most desperate of situations.
- IM haloperidol (5-10mg) alone or with IM lorazepam (1-2mg). Up to two further doses of haloperidol may need to be given at 30-60 min intervals if insufficient effect is observed.
- IM/Oral procyclidine can be used to reverse acute dystonic reactions.
- Olanzapine IM 5-10 mgs has been used as an alternative: This should not be combined with benzodiazepine (leave at least one hour between giving one if the other has been given).
- Using the combination rather than either individual drug alone may allow lower doses of each drug (e.g. 5mg of haloperidol and 1 mg of lorazepam).
- If using IM lorazepam, you should be sure about the availability of flumazenil (the antidote to benzodiazepine overdose) and equipment for airway management in the event of severe respiratory depression.
4) Rapid tranquillisation in the elderly
• Use lower doses (e.g. 1mg of haloperidol and 0.5 mg of lorazepam).
• Olanzapine and Risperidone: Less commonly used due to increased risk of stroke.
• Avoid antipsychotics in known cases of LBD.
PSYCHOTROPIC USE DURING PREGNANCY AND LACTATION
Prescribing in Breast Feeding
General principles of prescribing psychotropic in breast-feeding:
- In each case, the benefits of breast-feeding to the mother and infant must be weighed against the risk of drug exposure in the infant.
- Premature infants and infants with renal, hepatic, cardiac or neurological impairment are at a greater risk from exposure to drugs.
- The infants should be monitored for any specific adverse effects of the drugs as well as for feeding patterns, growth and development.
- It is usually inappropriate to withhold treatment to allow breast-feeding. Treatment of maternal illness is the highest priority
• Use the lowest effective dose
• Avoid polypharmacy
• Time the feeds to avoid peak drug levels in the milk.
Summary of recommendations
|Class of drugs||Recommended drugs|
|Antidepressants||Paroxetine, sertraline Tricyclic antidepressants (except Doxepin)|
|Mood-stabilisers||Avoid if possible. valproate|
|Sedatives||Lorazepam for anxiety; zolpidem for sleep|
Relative infant dose: The most used and reliable measure to assess the safety of a medication use in breastfeeding. Less than 10% is considered safe for breastfeeding
- Sertraline: 0.5-3%
- Paroxetine: 1.4% – withdrawal symptoms
- Escitalopram: 4.6-7.7%
- Avoid medications with long ½-life e.g aripiprazole.
- Prescribing in Pregnancy.
- If feasible, avoid all drugs in first trimester.
- Antipsychotic agent: Most experience with chlorpromazine, trifluoperazine and olanzapine.
- Antidepressant agent: More experience with amitriptyline, imipramine and fluoxetine.
- Paroxetine in first trimester is associated with foetal heart defects.
- Fluoxetine is the SSRI with the lowest known risk during pregnancy.
- SNRI: Venlafaxine is the most studied but has a higher risk of withdrawal symptoms due to a short ½-life.
- Persistent Pulmonary Hypertension of the Newborn: Increased risk with SSRI – Incidence: 2-6/ 1000 life newborns (rare), absolute risk for SSRI <1%
- Risk of QTc prolongation: SSRI (Citalopram and Escitalopram), Trazodone, SNRI (except Duloxetine), Domperidone and TCA (except Nortriptyline).
- Doxepine is not advisable in pregnancy due to the increased risk of respiratory depression. It has a significant anti-histaminic side effect.
Lithium use in women
- Lithium increases the rate of foetal heart defects to around 60 in 1000, compared with the risk of 8 in 1000 in the general population. It is estimated that lithium increases the risk of Ebstein’s anomaly (a major cardiac malformation) from 1 in 20,000 to 10 in 20,000.
- It should not be routinely prescribed for women, particularly in the first trimester of pregnancy (because of the risk of cardiac malformations in the foetus) or during breastfeeding (because of the high levels in breast milk).
- If a woman taking lithium is planning a pregnancy and she is well and not at high risk of relapse, she should be advised to stop taking the drug because of the risk of cardiac malformations in the foetus.
- If pregnancy is confirmed in the first trimester, and the woman is well and not at high risk of relapse, lithium should be stopped gradually over 4 weeks; it should be explained that this may not remove the risk of cardiac defects in the foetus.
- If the pregnant woman is not well or is at high risk of relapse, the following should be considered:
- switching gradually to an antipsychotic medication (or)
- Stopping lithium and restarting it in the second trimester – especially if the woman is not planning to breastfeed and her symptoms have responded better to lithium than to other drugs in the past (or)
- Continuing with lithium if she is at high risk of relapse.
If the pregnant woman continues taking lithium, serum lithium levels should be checked every 4 weeks, then weekly from the 36th week, and less than 24 hours after childbirth; the dose should be adjusted to keep serum levels towards the lower end of the therapeutic range, and the woman should maintain adequate fluid intake.
Women taking lithium should deliver in hospital and be monitored during labour by the obstetric team. Monitoring should include fluid balance, because of the risk of dehydration and lithium toxicity (in prolonged labour, it may be appropriate to check serum lithium levels).
Carbamazepine and lamotrigine use in women.
Carbamazepine is estimated to increase the risk of neural tube defects and carries a risk of other major foetal malformations including gastrointestinal tract problems and cardiac abnormalities. Lamotrigine carries the risk of oral cleft (estimated at nearly 9 in 1000 exposed foetuses).
If a woman who is taking carbamazepine or lamotrigine is planning a pregnancy or has an unplanned pregnancy, healthcare professionals should advise her to stop taking these drugs because of the risk of neural tube defects and other malformations in the foetus. If appropriate an alternative drug (such as an antipsychotic) should be considered.
Lamotrigine should not be routinely prescribed for women who are breastfeeding because of the risk of dermatological problems in the infant, such as Stevens–Johnson syndrome.
|Carbamazepine||Neural tube defects|
|Valproate 0.9-40% of mother’s dose in breastmilk Increased half-life in newborn due to very high hepatic metabolism required 5mg Folic acid daily, throughout pregnancy||Neural table defects Hypospadias Low birth weight Neurocognitive developmental delay|
|Benzodiazepines||Cleft palate Floppy baby syndrome|
|Lithium||Heart defects e.g. Ebstein’s anomaly. Risks are highest in 2-6 weeks after conception. Fœtal echocardiography in 1st trimester and high-resolution echo|
Special considerations arising from the use of psychotropic drugs during early pregnancy or while breastfeeding:
If a pregnant woman was taking drugs with known teratogenic risk (lithium, valproate, carbamazepine, lamotrigine and paroxetine) at the time of conception and/or in the first trimester, healthcare professionals should:
- Confirm the pregnancy as quickly as possible.
- Offer appropriate screening and counselling about the continuation of the pregnancy, the need for additional monitoring and the risks to the fetus if the woman continues to take medication.
- Undertake a full paediatric assessment of the newborn infant.
- Monitor the infant in the first few weeks after delivery for adverse drug effects, drug toxicity or withdrawal (for example, floppy baby syndrome, irritability, constant crying, shivering, tremor, restlessness, increased tone, feeding and sleeping difficulties and, rarely, seizures). NB: If the mother was prescribed antidepressants in the last trimester, these may result from serotonergic toxicity syndrome rather than withdrawal.
Pregnant women with a mental disorder who have sleep problems should initially be given general advice about sleep hygiene (including bedtime routines, the avoidance of caffeine, and the reduction of activity before sleep). For women with serious and chronic problems, low-dose chlorpromazine or low-dose amitriptyline may be considered.
Discussions about treatment options with a woman with a mental disorder who is planning a pregnancy, pregnant or breastfeeding should cover:
- The risk of relapse or deterioration in symptoms and the woman’s ability to cope with untreated or subthreshold symptoms.
- Severity of previous episodes, response to treatment and the woman’s preference.
- The possibility that stopping a drug with known teratogenic risk after pregnancy is confirmed may not remove the risk of malformations.
- The risks from stopping medication abruptly.
- The need for prompt treatment because of the potential impact of an untreated mental disorder on the foetus or infant.
- The increased risk of harm associated with drug treatments during pregnancy and the postnatal period, including the risk in overdose.
- Treatment options that would enable the woman to breastfeed if she wishes, rather than recommending she does not breastfeed.
When prescribing a drug for a woman with a mental disorder who is planning a pregnancy, pregnant or breastfeeding. Prescribers should:
- Choose drugs with lower risk profiles for the mother and the foetus or infant
- Start at the lowest effective dose, and slowly increase it; this is particularly important where the risks may be dose related.
- Use monotherapy in preference to combination treatment.
- Clozapine should not be routinely prescribed for women who are pregnant (because there is a theoretical risk of agranulocytosis in the foetus) or for women who are breastfeeding (because it reaches high levels in breast milk and there is a risk of agranulocytosis in the infant).
When stopping a drug in a woman with a mental disorder who is planning a pregnancy, pregnant or breastfeeding, take into account:
- NICE guidance on the specific disorder.
- The risk to the foetus or infant during the withdrawal period.
- The risk from not treating the disorder.
Explaining the risks of treatments
- When considering treatment choices for mental disorders during pregnancy and breastfeeding, or when a pregnancy is planned, it is important to place risks from drug treatment in the context of the individual woman’s illness. It should also be noted that the background risk of foetal malformations in the general population is between 2% and 4%.
- Acknowledge the uncertainty surrounding the risks.
- Explain the background risk of fetal malformations for pregnant women without a mental disorder.
- Describe risks using natural frequencies rather than percentages (for example, 1 in 10 rather than 10%).
- If possible, use decision aids in a variety of verbal and visual formats that focus on an individualized view of the risks
- Provide written material to explain the risks (preferably individualised) and, if possible, audio-taped records of the consultation.
Women taking antipsychotics who are planning a pregnancy should be told that the raised prolactin levels associated with some antipsychotics (notably amisulpride, risperidone and sulpiride) reduce the chances of conception. If prolactin levels are raised, an alternative drug should be considered.
If a pregnant woman is taking clozapine, switching to another drug and careful monitoring should be considered.
When deciding whether to prescribe olanzapine to a woman who is pregnant, risk factors for gestational diabetes and weight gain, including family history, existing weight and ethnicity, should be taken into account.
Depot antipsychotics should not be routinely prescribed to pregnant women because there is relatively little information on their safety and their infants may show extrapyramidal symptoms several months after administration of the depot.
Anticholinergic drugs should not be prescribed for the extrapyramidal side effects of antipsychotic drugs except for acute short-term use. Instead, the dose and timing of the antipsychotic drug should be adjusted, or the drug changed.
Valproate use in women
- Valproate should not be routinely prescribed for women of child bearing potential. If there is no effective alternative, the risks of taking valproate during pregnancy, and the importance of using adequate contraception, should be explained.
- It increases the risk of neural tube defects (mainly spina bifida and anencephaly) from around 6 in 10,000 pregnancies in the general population to around 100 to 200 in 10,000.
- It also has effects on the child’s intellectual development.
- Many pregnancies are unintended and/or not confirmed until after the 28th day (when the neural tube closes) so care is needed when prescribing the drug.
- It should not be prescribed to women younger than 18 years because of the risk of polycystic ovary syndrome and increased risk of unplanned pregnancy in this age group.
- If a woman who is taking valproate is planning a pregnancy, or is pregnant, she should be advised to stop taking the drug. Where appropriate in the treatment of bipolar disorder, an alternative drug (usually an antipsychotic) should be considered.
- If there is no alternative to valproate, doses should be limited to a maximum of 1 gram per day, administered in divided doses and in the slow release form, with 5 mg/day folic acid. However, it is not clear how the serum level of valproate affects the risk of abnormalities.
MEDICINES MONITORING GUIDELINES
From CPFT Medicines Monitoring Guidelines 2015
Monitoring guidance – Antipsychotics
ü = recommended for all antipsychotics (including clozapine)
For additional information about additional clozapine monitoring requirements please see separate CPFT guideline on Clozapine Prescribing and initiation and the Clozapine Policy.
|Baseline||0-3Months||12 months then annually|
|Weight/BMI/waist circumference1||ü||ü Weekly for the first six weeks then at 3 months||ü|
|BP/Pulse2||ü||üAt 3 months||ü|
|ECG||Cannot see if this is a 3 or a tick?||Repeat if over BNF maximum doses prescribed, or if other clinical indication||Repeat if over BNF maximum doses prescribed, or if other clinical indication|
|Blood glucose (preferably fasting) and HbA1 Cannot see what the small numbers are.||ü||ü At 3 months||ü|
|Blood lipids (preferably fasting)||ü||ü At 3 months||ü|
|Prolactin4||ü||ü At 3 months||ü|
|FBC5||ü||Mandatory FBC tests for clozapine in line with monitoring service schedule (through-out treatment)||ü|
|U&Es5||ü||This box is intentionally left blank||ü|
|LFTs5||ü||This box is intentionally left blank||ü|
|TFTs||Quetiapine only||This box is intentionally left blank||This box is intentionally left blank|
- Consideration should be given to more frequent monitoring of weight, blood glucose and lipids for patients taking clozapine or olanzapine as per BNF recommendations if clinically indicated: see current BNF for more details.
- Frequent blood pressure and pulse monitoring is advices by the BNF during *Not sure if this is close or dose? titration for most antipsychotics: see current BNF for more details.
- A baseline ECG should be offered if:
- Specified in the summary of product characteristics (SPC) e.g. haloperidol, clozapine.
- A physical examination has identified specific cardiovascular risk (e.g diagnosis of high blood pressure)
- There is a personal history of cardiovascular disease
- The service user is being admitted as an inpatient
- If over BNF maximum doses are to be prescribed (see next page)
- No need to measure prolactin annually if not affected in first year, future monitoring if clinically indicated.
- FBC (apart from clozapine), U&Es and LFTs are not routinely recommended, they should be undertaken if clinically required for an individual patient. The BNF advises they should be done for most antipsychotics: see current BNF for more details.
MONITORING GUIDELINES – Mood stabilisers
For additional information about lithium please see separate CPFT guidelines on Lithium Prescribing and Monitoring
|Baseline||0-3 months||6 months||12 months then annually|
|Weight/BMI/waist circumference||Lithium Valproate Carbamazepine||This box is intentionally left blank||Lithium Valproate Carbamazepine||Lithium Valproate Carbamazepine|
|ECG||Lithium – if cardiac disease or risk factors||This box is intentionally left blank||This box is intentionally left blank||This box is intentionally left blank|
|FBC1||Valproate Carbamazepine Lamotrigine Lithium||This box is intentionally left blank||Valproate Carbamazepine||Valproate Carbamazepine|
|U&E’s2||Valproate Carbamazepine Lamotrigine||This box is intentionally left blank||Every 6 months Lithium Carbamazepine||Every 6 months Lithium Carbamazepine|
|LFTs||Valproate Carbamazepine Lamotrigine||This box is intentionally left blank||Valproate Carbamazepine||Valproate Carbamazepine|
|TFTs||Lithium||This box is intentionally left blank||Every 6 months Lithium Carbamazepine||Every 6 months Lithium Carbamazepine|
|Serum Li level||Lithium – frequently during dose titration (see CPFT guidance)||Every 3 months3 Lithium||Every 3 months3 Lithium|
- Valproate may increase bleeding time: check FBC and coagulation tests before any surgery.
- For lithium – request calcium and calculation of EGFR.
- See CPFT Lithium Monitoring Guidelines – in some circumstances, monitoring every six months after first year.
Monitoring guidance – Antidepressants
There are very few specific monitoring recommendations for antidepressants with the exception of the following:
- Citalopram and escitalopram – consider baseline ECG in patients with cardiac disease. Correct electrolyte disturbances prior to treatment. Monitor serum magnesium, especially in elderly patients who are taking diuretics or proton pump inhibitors. If cardiac symptoms develop, or dose prescribed is above licensed maximum, monitor ECG.
- Venlafaxine – Any pre-existing high blood pressure should be treated before venlafaxine is started. Monitor BP at baseline, after 3 months, after any dose increase above 200mg, and then annually.
- Mirtazapine – FBC and weight at baseline, then if clinically indicated.
- Duloxetine – BP, pulse, LFTs, and FBC at baseline, then if clinically indicated.
Anderson I and McAllister-Williams (Edited) 2016. Fundamentals of Clinical Psychopharmacology (BAP) – 4th Edition:
Stahl S (2008). Stahl’s Essential Psychopharmacology – Neuroscientific Basis and Practical Applications 3rd Edition
Stahl S (2014). Stahl’s Essential Psychopharmacology – Prescriber’s Guide 5th Edition
Taylor D, Paton C and Kapur S (2015). The Maudsley: Prescribing Guidelines in Psychiatry 12th Edition WILEY Blackwell.
UK committee on safety of medicines 2004 Herrmann and Lanctot, 2005 Gill et al, BMJ 2005
The Canadian Journal of Psychiatry / La Revue Canadienne de Psychiatrie 2016, Vol. 61(9) 504-505
Journal of psychopharmacology 2018 vol 32 (5).
Multimodal Treatment Study of Children With ADHD (MTA Group, Arch Gen Psychiatry, 1999
Psychopharmacology update: focus on newer medications and uses. Pierre Blier, MD, Ph.D Professor, Psychiatry and Cellular & Molecular Medicine University of Ottawa 2018.
Antipsychotics lecture slides by Tabitha Rogers, Royal Ottawa health Care Group 2018
Recommended further reading
Bazire S (2016). Psychotropic drug directory (2016): The professionals Pocket handbook and Aide Memoire.
Schaefer C, Peters P, Miller R. (eds.) (2014) Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd Edition, London, Academic Press.
MIMS handbook of psychiatry: treatment approaches, drug-class overview, generic / trade names. Vol. I – 2012/13 Author: J R Snyman; MIMS (South Africa).