Psychotropic drugs

Chapter 20 Psychotropic drugs



David Nutt, Simon Davies, Sue Wilson, Blanca Bolea-Alamanac



Synopsis


Psychiatric disorders are some of the most common illnesses. Advances in drug treatment have revolutionised the practice of psychiatry over the past six decades. This chapter considers the following drug groups:



• Antidepressants.


• Antipsychotics (‘neuroleptics’).


• Mood stabilisers.


• Drugs for anxiety and sleep disorders.


• Drugs for dementia.


• Drugs for attention deficit/hyperactivity disorder.




Diagnostic issues


Older classifications of psychiatric disorder divided diseases into ‘psychoses’ and ‘neuroses’. The term ‘psychosis’ is still widely used to describe a severe mental illness with hallucinations, delusions, extreme abnormalities of behaviour including marked overactivity, retardation and catatonia, usually with lack of insight. Psychotic disorders include schizophrenia, severe depression and mania. Psychosis may also be due to illicit substances or organic conditions. Clinical features of schizophrenia are subdivided into ‘positive symptoms’, which include hallucinations, delusions and thought disorder, and ‘negative symptoms’ such as apathy, flattening of affect and poverty of speech.


Disorders formerly grouped under ‘neuroses’ include anxiety disorders (e.g. panic disorder, generalised anxiety disorder, obsessive–compulsive disorder, phobias and post-traumatic stress disorder), eating disorders (e.g. anorexia nervosa and bulimia nervosa), depression (provided there are no ‘psychotic’ symptoms) and sleep disorders.


Also falling within the scope of modern psychiatric diagnostic systems are organic mental disorders (e.g. dementia in Alzheimer’s disease), disorders due to substance misuse (e.g. alcohol and opiate dependence; see Ch. 11), personality disorders, disorders of childhood and adolescence (e.g. attention deficit/hyperactivity disorder, Tourette’s syndrome), and mental retardation (learning disabilities).



Drug therapy in relation to psychological treatment


No account of drug treatment strategies for psychiatric illness is complete without considering psychological therapies. Psychotherapies range widely, from simple counselling (supportive psychotherapy) through psychoanalysis to newer techniques such as cognitive behavioural therapy.


As a general rule, psychotic illnesses (e.g. schizophrenia, mania and depressive psychosis) require drugs as first-line treatment, with psychotherapy being adjunctive, for instance in promoting drug compliance, improving family relationships and helping individuals cope with distressing symptoms. By contrast, for depression and anxiety disorders, such as panic disorder and obsessive–compulsive disorder, forms of psychotherapy are available that provide alternative first-line treatment to medication. The choice between drugs and psychotherapy depends on treatment availability, previous history of response, patient preference and the ability of the patient to work appropriately with the chosen therapy. In many cases there is scope and sometimes advantage to the use of drugs and psychotherapy in combination.


Taking depression as an example, an extensive evidence base exists for the efficacy of several forms of psychotherapy. These include cognitive therapy (which normalises depressive thinking), interpersonal therapy (which focuses on relationships and roles), brief dynamic psychotherapy (a time-limited version of psychoanalysis) and cognitive analytical therapy (a structured time-limited therapy that combines the best points of cognitive therapy and traditional analysis).


All doctors who prescribe drugs engage in a ‘therapeutic relationship’ with their patients. A depressed person whose doctor is empathic, supportive and appears to believe in the efficacy of the drug prescribed is more likely to take the medication and to adopt a hopeful mindset than if the doctor seemed aloof and ambivalent about the value of psychotropic drugs. Remembering that placebo response rates of 30–40% are common in double-blind trials of antidepressants, we should never underestimate the importance of our relationship with the patient in enhancing the pharmacological efficacy of the drugs we use.



Antidepressant drugs


Antidepressants can be broadly divided into four main classes (Table 20.1), tricyclics (TCA, named after their three-ringed structure), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and novel compounds, some of which are related to TCAs or SSRIs. Clinicians who wish to have a working knowledge of antidepressants would be advised to be familiar with the use of at least one drug from each of the four main categories tabulated. A more thorough knowledge-base would demand awareness of the distinct characteristics of the subgroups of novel compounds (e.g. serotonin and noradrenaline/norepinephrine reuptake inhibitors (SNRIs), mirtazapine, reboxetine and agomelatine) and differences between individual SSRIs and TCAs. As antidepressants are largely similar in their therapeutic efficacy, awareness of profiles of unwanted effects is of particular importance.


Table 20.1 Classification of antidepressants











Tricyclics Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors
Dosulepin
Amitriptyline
Lofepramine
Clomipramine
Imipramine
Trimipramine
Doxepin
Nortriptyline
Protriptyline
Desipramine		 Fluoxetine
Paroxetine
Sertraline
Citaloprama
Escitaloprama
Fluvoxamine		 Phenelzine
Isocarboxazid
Tranylcypromine
Moclobemide (RIMA)












Novel compounds
Mainly noradrenergic Mainly serotonergic  
Reboxetine (NaRI) Trazodoneb
Nefazodoneb,c		  






Mixed
Venlafaxine (SNRI)
Mirtazapine (nassa)b
Duloxetine (SNRI)
Milnacipran (SNRI)d
Agomelatine

RIMA, reversible inhibitor of monoamine oxidase; NaRI, noradrenaline/norepinephrine reuptake inhibitor; SNRI, serotonin and noradrenaline/norepinephrine reuptake inhibitor; NaSSA, noradrenaline/norepinephrine and specific serotonergic antidepressant.


a Escitalopram is the active S-enantiomer of citalopram.


b Trazodone, nefazodone and mirtazapine have been classed as ‘receptor blocking’ antidepressants based on their antagonism of postsynaptic serotonin receptors (trazodone, nefazodone, mirtazapine) and presynaptic α2-receptors (trazodone, mirtazapine).


c Nefazodone has additional weak SSRI activity but has now been withdrawn due to risk of hepatitis.


d Not available in the UK.


An alternative categorisation of antidepressants is based solely on mechanism of action (Fig. 20.1). The majority of antidepressants, including SSRIs, TCAs and related compounds, are reuptake inhibitors. Certain novel agents, including trazodone and mirtazapine, are receptor blockers, whereas MAOIs are enzyme inhibitors.


image

Fig. 20.1 Flow chart of the evolution of antidepressant drugs, and classification by mechanism of action.


The first TCAs (imipramine and amitriptyline) and MAOIs appeared between 1957 and 1961 (see Fig. 20.1). The MAOIs were developed from antituberculous agents that unexpectedly improved mood. Imipramine was a chlorpromazine derivative that showed antidepressant rather than antipsychotic properties. Over the next 25 years the TCA class enlarged to more than 10 agents with heterogeneous pharmacological profiles, and further modifications of the original three-ringed structure gave rise to the related (but pharmacologically distinct) antidepressant trazodone.


In the 1980s an entirely new class of antidepressant arrived with the SSRIs: The first was zimelidine but unfortunately this was withdrawn due to associations with Guillain–Barré syndrome. Next came fluvoxamine, followed by fluoxetine (Prozac®). Within 10 years, the SSRI class accounted for half of antidepressant prescriptions in the UK. Further developments in the evolution of antidepressants have been novel compounds such as the SNRIs (e.g. venlafaxine and duloxetine), reboxetine, mirtazapine and agomelatine, and a reversible MAOI, moclobemide.




Mechanism of action


The monoamine hypothesis proposes that, in depression, there is deficiency of the neurotransmitters noradrenaline/norepinephrine and serotonin in the brain which can be restored by antidepressants. Drugs that alleviate depression also enhance monoamine availability and release (Fig. 20.2), increasing activity at postsynaptic receptors. It is relevant that (older) antihypertensive agents, e.g. reserpine, which reduced the availability of noradrenaline/norepinephrine, caused depression.


image

Fig. 20.2 Mechanism of action of antidepressant drugs at the synapse.


SSRIs act, as their name indicates, predominantly by preventing serotonin reuptake by blocking the cell-surface serotonin transporter; with little effect on noradrenaline/norepinephrine reuptake. Tricyclic antidepressants and reboxetine inhibit noradrenaline/norepinephrine reuptake, but tricyclic effects on serotonin reuptake vary widely; desipramine and protriptyline have no effect, whereas clomipramine is about five times more potent at blocking serotonin than noradrenaline/norepinephrine reuptake. SNRIs are capable of inhibiting reuptake of both transmitters. However, for venlafaxine a dose of at least 150 mg/day is required for noradrenaline/norepinephrine uptake blockade to be exerted. Mirtazapine also achieves an increase in noradrenergic and serotonergic neurotransmission, but through antagonism of presynaptic α2-autoreceptors (receptors that mediate negative feedback for transmitter release, i.e. an autoinhibitory feedback system). Other novel antidepressants include trazodone, which blocks several types of serotonin receptor (including the 5HT2A and 5HT2C receptors) as well as α-adrenoceptors and histaminergic receptors and acts as a partial agonist at the 5HT1A receptor, and agomelatine which acts both as an agonist of melatonin receptors and a blocker of the serotonin 5HT2C receptor, the combined effects of these actions leading to a rise in frontal cortex dopamine availability.


MAOIs increase the availability of noradrenaline/norepinephrine and serotonin by preventing their destruction by the monoamine oxidase type A enzyme in the presynaptic terminal (see Ch. 21, Table 21.3). The older MAOIs, phenelzine, tranylcypromine and isocarboxazid, bind irreversibly to monamine oxidase by forming strong (covalent) bonds. The enzyme is thus rendered permanently ineffective such that amine metabolising activity can be restored only by production of fresh enzyme, which takes weeks. These MAOIs are thus called ‘hit and run’ drugs as their effects greatly outlast their detectable presence in the blood.


But how do changes in monoamine transmitter levels produce an eventual elevation of mood? Raised neurotransmitter concentrations produce immediate alterations in postsynaptic receptor activation, leading to changes in second-messenger (intracellular) systems and to gradual modifications in cellular protein expression. Antidepressants increase a cyclic AMP response element binding (CREB) protein, which in turn is involved in regulating the transcription of genes that influence survival of other proteins, including brain-derived neurotrophic factor (BDNF), which exerts effects on neuronal growth.


Although the monoamine hypothesis of depression is conceptually straightforward, it is in reality an oversimplification of a complicated picture. Other systems that are implicated in the aetiology of depression (and which provide potential targets for drug therapy) include the hypothalamic–pituitary–thyroid axis and the hypothalamic–pituitary–adrenal (HPA) axis. The finding that 50% of depressed patients have raised plasma cortisol concentrations constitutes evidence that depression may be associated with increased HPA drive.


Drugs with similar modes of action to antidepressants find other uses in medicine. Bupropion (amfebutamone) inhibits reuptake of both dopamine and noradrenaline/norepinephrine. It was originally developed and used as an antidepressant but is now more frequently used to assist smoking cessation (see p. 321). It is also prescribed in attention deficit hyperactivity disorder (see p. 345). Sibutramine, licensed as an anorectic agent, is a serotonin and noradrenaline/norepinephrine reuptake inhibitor (SNRI).



Pharmacokinetics


The antidepressants listed in Table 20.1 are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect. Where there is a failure of response, measurement of plasma concentration can be useful as the failure may be attributable to low plasma levels due to ultra-rapid metabolism (though it is often not available). Antidepressants in general are metabolised principally by hepatic cytochrome P450 enzymes. Of the many isoenzymes identified, the most important in antidepressant metabolism are CYP P450 2D6 (Table 20.2A) and CYP 3A4 (Table 20.2B). Other important P450 enzymes are CYP 1A2 (inhibited by the SSRI fluvoxamine, induced by cigarette smoking; substrates include caffeine and the atypical antipsychotics clozapine and olanzapine) and the CYP 2 C group (inhibition by fluvoxamine and fluoxetine, involved in breakdown of escitalopram and moclobemide). Sometimes several CYP enzymes are capable of mediating the same metabolic step. For example, at least six isoenzymes, including CYP 2D6, 3A4 and 2 C9, can mediate the desmethylation of the SSRI sertraline to its major metabolite.


Table 20.2A Psychotropic (and selected other) drugs known to be CYP 2D6 substrates, inhibitors and inducers









CYP 2D6 inhibitors
Antidepressants
Paroxetine
Fluoxetine














CYP 2D6 substrates    
Antidepressants Antipsychotics Miscellaneous
Paroxetine
Fluoxetine
Citalopram
Sertraline
Venlafaxinea
Duloxetine
Amitriptyline
Clomipramine
Desipramine
Imipramine
Nortriptyline
Reboxetine		 Chlorpromazine
Haloperidol
Zuclopenthixol
Perphenazine
Risperidone		 Dexfenfluramine
Donepezil
Opioids
Codeine
Hydrocodone
Dihydrocodeine
Tramadol
Ethyl morphine
MDMA (ecstasy)
β-Blockers
Propranolol
Metoprolol
Timolol
Bufaralol
Carvidelol

A substrate is a substance that is acted upon and changed by an enzyme. Where two substrates of the same enzyme are prescribed together, they will compete and, if present in sufficient quantities, the metabolism of one or other, or both, drugs may also be inhibited, resulting in increased plasma concentration and possibly in enhanced therapeutic or adverse effects. An enzyme inducer accelerates the metabolism of co-prescribed drugs that are substrates of the same enzyme, reducing their effects. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects.


a CYP 2D6 is involved only in the breakdown of venlafaxine to its active metabolite and therefore implications of 2D6 interactions for efficacy are of limited significance.


Table 20.2B Psychotropic (and selected other) drugs known to be CYP 3A4 substrates, inhibitors and inducers












CYP 3A4 inhibitors  
Antidepressants Other drugs
Fluoxetine
Nefazodone		 Cimetidine
Erythromycin
Ketoconazole (grapefruit juice)














CYP 3A4 substrates    
Antidepressants Anxiolytics, hypnotics and antipsychotics Miscellaneous
Fluoxetine
Sertraline
Amitriptyline
Imipramine
Nortriptyline
Trazodonea		 Alpraxolam
Aripiprazole
Buspirone
Diazepam
Midazolam
Triazolam
Zoplicone
Haloperidol
Zuclopethixol
Quetiapine
Sertindole		 Buprenorphine
Carbamazepine
Cortisol
Dexamethasone
Methadone
Testosterone
Calcium channel blockers
Diltiazem
Nifedipine
Amlodipine
Other drugs
Amiodarone
Omeprazole
Oral contraceptives
Simvastatin











CYP 3A4 inducers  
Antidepressants Miscellaneous
St John’s wort Carbamazepine
Phenobarbital
Phenytoin

A substrate is a substance that is acted upon and changed by an enzyme. Where two substrates of the same enzyme are prescribed together, they will compete and, if present in sufficient quantities, the metabolism of one or other, or both, drugs may also be inhibited, resulting in increased plasma concentration and possibly in enhanced therapeutic or adverse effects. An enzyme inducer accelerates the metabolism of co-prescribed drugs that are substrates of the same enzyme, reducing their effects. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects.


a mCPP (meta-chlorophenylpiperazine), the active metabolite of trazodone, is a CYP 2D6 substrate; observe for unwanted effects when trazodone is co-administered with the 2D6 inhibitors fluoxetine or paroxetine.


Several of these drugs produce active metabolites that prolong their action (e.g. fluoxetine is metabolised to norfluoxetine, t½ 200 h). The metabolic products of certain TCAs are antidepressants in their own right, e.g. nortriptyline (from amitriptyline), desipramine (from lofepramine and imipramine) and imipramine (from clomipramine). Half-lives of TCAs lie generally in a range from 15 h (imipramine) to 100 h (protriptyline), and those for SSRIs from 15 h (fluvoxamine) to 72 h (fluoxetine).


Around 7% of the Caucasian population have very limited CYP 2D6 enzyme activity. Such ‘poor metabolisers’ may find standard doses of TCAs intolerable, and it is often worth prescribing them at a very low dose. If the drug is then tolerated, plasma concentration assay may confirm the suspicion that the patient is a poor metaboliser. There is also a genetic polymorphism influencing CYP 2 C19 activity which has a clinically important effect on metabolism of escitalopram.



Therapeutic efficacy


Provided antidepressant drugs are prescribed at an adequate dose and taken regularly, 60–70% of patients with depression should respond within 3–4 weeks. Conventional meta-analyses have shown little evidence that any particular drug or class of antidepressant is more efficacious than others, but there are some possible exceptions to this general statement:



• Venlafaxine, in high dose (> 150 mg/day) and Escitalopram may have greater efficacy than other antidepressants.


• Amitriptyline appears to be slightly more effective than other TCAs and also SSRIs for severe depression, but this advantage is compromised by its poor tolerability and lack of safety in overdose relative to more modern agents.


• The older MAOIs (e.g. phenelzine) may be more effective than other classes in ‘atypical’ depression, a form of depressive illness where mood reactivity is preserved, lack of energy may be extreme and biological features are the opposite of the normal syndrome, i.e. excess sleep and appetite with weight gain.



Selection


An antidepressant should be selected to match individual patients’ requirements, such as the need or otherwise for a sedative effect, or the avoidance of antimuscarinic effects (especially in the elderly). In the absence of special factors, the choice rests on the weight of evidence of efficacy, the tolerability, the safety in overdose and the likelihood of an effective dose being reached. SSRIs and other newer drugs (e.g. mirtazapine and venlafaxine) are highlighted as best meeting these needs.



Mode of use


Antidepressants usually require 3–4 weeks for the full therapeutic effect to be achieved. When a minimal response is seen, an antidepressant can usefully be extended to 6 weeks to see whether further benefit is achieved. By contrast, patients may experience unwanted effects, especially ‘jitteriness’ or ‘activation’ symptoms such as increased anxiety and irritability, soon after starting treatment (they should be warned about this possibility), but such symptoms usually diminish with time. Some drugs have the advantage that they can be started at a dose which would be considered adequate for the therapeutic effect (e.g. most SSRIs) but in contrast many others, including all tricylic antidepressants, need to be started at a low and generally tolerable starting dose to the therapeutic dose. For example, imipramine should be started at 25–50 mg/day, with gradual increments to a recognised ‘minimum therapeutic’ dose, around 125 mg/day (140 mg/day for lofepramine). Low starting doses are particularly important for elderly patients. Only when the drug has reached the minimum therapeutic dose and been taken for at least 4 weeks can response or non-response be adequately established. However, some patients do achieve response or remission at subtherapeutic doses, for reasons of drug kinetics and limited capacity to metabolise, the self-limiting nature of depression, or by a placebo effect (reinforced by the experience of side-effects suggesting that the drug must be having some action).


For SSRIs dose titration is often unnecessary as the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not usually required, and administration is by a single morning or evening dose. Evidence suggests that patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs. Of the novel compounds, trazodone usually requires titration to a minimum therapeutic dose of at least 200 mg/day. Response to reboxetine, venlafaxine and mirtazapine may occur at the starting dose, but some dose titration is commonly required. Venlafaxine is licensed for treatment-resistant depression by gradual titration from 75 to 375 mg/day. There is some need for dose titration when using MAOIs. Unlike other drug classes, reduction to a lower maintenance dose is recommended after a response is achieved if unwanted effects are problematical.



Changing and stopping antidepressants


When an antidepressant fails through lack of efficacy despite an adequate trial or due to unacceptable adverse effects, a change to a drug of a different class is generally advisable. For a patient who has not responded to an SSRI it is logical to try a novel compound such as venlafaxine, mirtazapine or reboxetine, or sometimes a tricylic antidepressant. Any of these options may offer a greater increase in synaptic noradrenaline/norepinephrine than the ineffective SSRI.


Evidence also suggests that patients failing on one SSRI may respond to a different drug within the class, an approach that is particularly useful where other antidepressant classes have been unsuccessful previously, are contraindicated, or have characteristics that the patient or doctor feels are undesirable. Awareness of biological differences between drugs within a class may also be helpful when patients cannot tolerate other drug classes. For instance, among SSRIs, paroxetine has the most affinity for the serotonin transporter and fluoxetine the least, while among TCAs, clomipramine has more important serotonergic enhancing effects than the others.


When changing between antidepressant doses, a conservative approach would be to reduce the first antidepressant progressively over 2 or more weeks before starting the new drug. The gradual reduction is particularly important with paroxetine and venlafaxine which are known to cause ‘discontinuation syndromes’ if stopped abruptly, and less important with fluoxetine due to its long half-life active metabolite which offers ‘built-in’ protection against withdrawal problems. A more proactive approach would involve ‘cross-tapering’ the second antidepressant – i.e. starting it while the first antidepressant is being reduced and gradually titrating the dose up. However, an important exception concerns changes to or from MAOIs, which must be handled with great caution due to the dangers of interactions between antidepressants (see below). Therefore MAOIs cannot safely be introduced within 2 weeks of stopping most antidepressants (3 weeks for imipramine and clomipramine; combination of the latter with tranylcypromine is particularly dangerous), and not until 5 weeks after stopping fluoxetine, due to its long half-life active metabolite. Similarly, other antidepressants should not be introduced until 2–3 weeks have elapsed from discontinuation of MAOI (as these are irreversible inhibitors; see p. 313). No washout period is required when using the reversible MAOI, moclobemide.


When a patient achieves remission, the antidepressant should be continued for at least 9 months at the dose that returned mood to normal. Premature dose reduction or withdrawal is associated with increased risk of relapse. In cases where three or more depressive episodes have occurred, evidence suggests that long-term continuation of an antidepressant offers protection, as further relapse is almost inevitable in the next 3 years.


When ceasing use of an antidepressant, the dose should be reduced gradually to avoid discontinuation syndromes (symptoms include anxiety, agitation, nausea and mood swings). Discontinuation of SSRIs and venlafaxine are associated additionally with dizziness, electric shock-like sensations and paraesthesia. Short t½ drugs that do not produce active metabolites (e.g. paroxetine, venlafaxine) and TCAs are most likely to cause such problems.



Augmentation


The development of many new antidepressants in recent years has reduced the need to use augmentation strategies. Nevertheless augmentation, i.e. the addition of a second drug to an existing antidepressant, can be used when two or more standard antidepressants have successively failed to alleviate depressive symptoms despite treatment at an adequate dose for an adequate time. Some of the augmentations discussed may even be used earlier than this if there is an indication or justification for the augmenting drug specific to the individual patient.


One strategy which has come to prominence is to augment (or combine) an SSRI or SNRI antidepressant with the novel antidepressant mirtazapine. The initial justification for this combination stems from mirtazapine’s unorthodox mechanism of action – the idea being that the presynaptic adjustments effected by mirtazapine could act additively or even synergistically with the monoamine reuptake inhibition of SSRIs and SNRIs. A second justification is more practical – mirtazapine is known to improve the quality of sleep and serotonin reuptake inhibitors may initially disrupt this, thus mirtazapine can be added both to boost the antidepressant effect and to address an unresolved problem with sleep. An evidence base does exist both for mirtazapine–venlafaxine and mirtazapine–fluoxetine co-prescription in depression, with both combinations reported as providing significantly higher remission rates than fluoxetine alone. Ease of initiation of these combinations, along with the evidence of enhanced effectiveness, means that these are currently the most commonly used augmentation strategies for treatment of depression in psychiatry inpatients in the UK.


Another important augmentation strategy employs the mood stabiliser lithium carbonate. Controlled trials suggest that up to 50% of patients who have not responded to standard antidepressants can respond after lithium augmentation but the evidence is stronger for augmenting tricyclics than for augmenting SSRIs. Addition of lithium requires careful titration of the plasma concentration up to the therapeutic range, with periodic checks thereafter and monitoring for toxicity (see p. 331).


More recently, augmentation of SSRIs with atypical antipsychotics has been effective in clinical trials. Trial evidence is strongest using olanzapine, and also exists for quetiapine, risperidone and aripiprazole. Antipsychotics also have important potential for side-effects which must be taken into account before their introduction (see p. 322).


Tri-iodothyronine (T3) also aids antidepressant action, and most evidence points to added benefit with TCAs. When co-prescribing TCAs with thyroid hormone derivatives, be aware that the combination of lofepramine with the levo isomer of thyroxine is contraindicated. The amino acid L-tryptophan and the β-adrenoceptor blocker pindolol may also be used to augment. Tryptophan increases 5-hydroxytryptamine (5HT) production, and pindolol may act by blocking negative feedback of 5HT on to 5HT1A-autoreceptors.



Other indications for antidepressants


Antidepressants may benefit most forms of anxiety disorder, including panic disorder, generalised anxiety disorder, post-traumatic stress disorder, obsessive–compulsive disorder and social phobia (see p. 331). SSRIs are recognised as first-line drug treatment for all five of these anxiety disorders.


Fluoxetine is effective in milder cases of the eating disorder bulimia nervosa, in higher doses (60 mg/day) than are required for depression. This effect is independent of that on depression (which may coexist), and may therefore involve a different mode of action. Antidepressants appear to be ineffective in anorexia nervosa. Antidepressants also have a role in pain control. The SNRI drug duloxetine is licensed for diabetic neuropathy while considerable trial evidence exists for use of the original tricyclic antidepressants imipramine and amitriptyline for the control of chronic pain.



Adverse effects


As most antidepressants have similar therapeutic efficacy, the decision regarding which drug to select often rests on adverse effect profiles and potential to cause toxicity.



Selective serotonin reuptake inhibitors


SSRIs have a range of unwanted effects including nausea, anorexia, dizziness, gastrointestinal disturbance, agitation, akathisia (motor restlessness) and anorgasmia (failure to experience an orgasm). They lack direct sedative effect, an advantage over older drugs in patients who need to drive motor vehicles or need to work or study. SSRIs can disrupt the pattern of sleep with increased awakenings, transient reduction in the amount of rapid eye movement (REM) and increased REM latency, but eventually sleep improves due to improved mood. SSRIs lack the side-effects of postural hypotension, antimuscarinic and antihistaminergic effects seen with TCAs. In contrast to both TCAs and mirtazapine, SSRIs may induce weight loss through their anorectic effects, at least in the short term. SSRIs are relatively safe in overdose.





The serotonin syndrome


is a rare but dangerous complication of SSRI use and features restlessness, tremor, shivering and myoclonus, possibly leading on to hyperpyrexia, convulsions and delirium. The risk is increased by co-administration with drugs that enhance serotonin transmission, especially MAOIs, the antimigraine triptan drugs and St John’s wort. The combination of fluoxetine or paroxetine with tramadol can also cause serotonin syndrome. These SSRIs inhibit the metabolism of tramadol to its active metabolite (which is responsible for the pain relief), leaving a build-up of unmetabolised tramadol which has sufficient serotonergic activity itself to interact with the SSRIs and enhance the risk of serotonin syndrome.



Novel compounds





Venlafaxine


produces unwanted effects that resemble those of SSRIs with a higher incidence of nausea. Sustained hypertension (due to blockade of noradrenaline/norepinephrine reuptake) is a problem in a small proportion of patients at high dose, and blood pressure should be monitored when more than 200 mg/day is taken. Venlafaxine appears to have some association with cardiac arrhythmias but whether this is to a degree that is clinically significant is unclear.



Duloxetine


may cause early nausea, which tends to subside quickly. Other unwanted effects are somnolence, dizziness and constipation.



Mirtazapine


has benefits in rarely being associated with sexual dysfunction and in improving sleep independent of mood but it may cause unwanted sedation and weight gain.



Trazodone


is an option for depressed patients where heavy sedation is required. It also has the advantages of lacking antimuscarinic effects and of being relatively safe in overdose. Males should be warned of the possibility of priapism (painful penile erections), attributable to the drug’s blockade of α1-adrenoceptors.



Agomelatine


is given at night when it appears to resynchronise circadian rhythms and therefore promotes improved sleep. Like mirtazapine it is rarely associated with sexual dysfunction, but its use necessitates early liver function tests.



Tricyclic antidepressants


The commonest unwanted effects are those of antimuscarinic action, i.e. dry mouth, constipation, blurred vision and difficulty with accommodation, raised intraocular pressure (glaucoma may be precipitated) and bladder neck obstruction (may lead to urinary retention in older males).


Patients may also experience: postural hypotension (through inhibition of α-adrenoceptors), which is often a limiting factor in the elderly; interference with sexual function; weight gain (through blockade of histamine H1 receptors); prolongation of the QTc interval of the ECG, which predisposes to cardiac arrhythmias especially in overdose (use after myocardial infarction is contraindicated).


Some TCAs (especially trimipramine and amitriptyline) are heavily sedating through a combination of antihistaminergic and α1-adrenergic blocking actions, and this presents special problems to those whose lives involve driving vehicles or performing skilled tasks. In selected patients, sedation may be beneficial, e.g. a severely depressed person who has a disrupted sleep pattern or marked agitation.


There is great heterogeneity in adverse-effect profiles between TCAs. Imipramine and lofepramine cause relatively little sedation, and lofepramine is associated with milder antimuscarinic effects (but is contraindicated in patients with severe liver disease). When comparing SSRIs and TCAs for dropouts (a surrogate endpoint for tolerability), most meta-analyses show a small benefit in favour of SSRIs, although the older tricyclics imipramine and amitripyline are overrepresented in these meta-analyses.





Overdose


Depression is a risk factor for both parasuicide and completed suicide, and TCAs are commonly taken by those who deliberately self-harm. Dosulepin and amitriptyline are particularly toxic in overdose. Lofepramine is at least 15 times less likely to cause death from overdose; clomipramine and imipramine occupy intermediate positions.


Clinical features of overdose reflect the pharmacology of TCAs. Antimuscarinic effects result in warm, dry skin from vasodilatation and inhibition of sweating, blurred vision from paralysis of accommodation, papillary dilatation and urinary retention.


Consciousness is commonly dulled, and respiration depression and hypothermia may develop. Neurological signs including hyperreflexia, myoclonus, divergent strabismus and extensor plantar responses may accompany lesser degrees of impaired consciousness and provide scope for diagnostic confusion, e.g. with structural brain damage. Convulsions occur in a proportion of patients. Hallucinations and delirium occur during recovery of consciousness, often accompanied by a characteristic plucking at bedclothes.


Sinus tachycardia (due to vagal blockade) is a common feature but abnormalities of cardiac conduction accompany moderate to severe intoxication and may proceed to dangerous tachyarrhythmias or bradyarrhythmias. Hypotension may result from a combination of cardiac arrhythmia, reduced myocardial contractility and dilatation of venous capacitance vessels.


Supportive treatment suffices for the majority of cases. Activated charcoal by mouth is indicated to prevent further absorption from the alimentary tract and may be given to the conscious patient in the home prior to transfer to hospital. Convulsions are less likely if unnecessary stimuli are avoided, but severe or frequent seizures often precede cardiac arrhythmias and arrest, and their suppression with diazepam is important. Cardiac arrhythmias do not need intervention if cardiac output and tissue perfusion are adequate. Correction of hypoxia with oxygen, and acidosis by intravenous infusion of sodium bicarbonate are reasonable first measures and usually suffice.



Reboxetine


is not structurally related to tricyclic agents but like lofepramine and desipramine acts predominantly by noradrenergic reuptake inhibition. Pseudo-antimuscarinic effects, particularly urinary hesistancy and dry mouth, trouble a minority of patients, postural hypotension may occur, as may impotence in males. It is relatively safe in overdose.



Monoamine oxidase inhibitors


Adverse effects include postural hypotension (especially in the elderly) and dizziness. Less common are headache, irritability, apathy, insomnia, fatigue, ataxia, gastrointestinal disturbances including dry mouth and constipation, sexual dysfunction (especially anorgasmia), blurred vision, difficult micturition, sweating, peripheral oedema, tremulousness, restlessness and hyperthermia. Appetite may increase inappropriately, causing weight gain.



Interactions


Antidepressant use offers considerable scope for adverse interaction with other drugs and it is prudent always to check specific sources for unwanted outcomes whenever a new drug is added or removed to a prescription list that includes an antidepressant.



Pharmacodynamic interactions




• Most antidepressants (including SSRIs and tricylics) may cause central nervous system (CNS) toxicity if co-prescribed with the dopaminergic drugs entacapone and selegiline (for Parkinson’s disease). SSRIs increase the risk of the serotonin syndrome when combined with drugs that enhance serotonin transmission, e.g. the antimigraine triptan drugs which are 5HT1-receptor antagonists, and the antiobesity drug sibutramine.


• Most antidepressants lower the convulsion threshold, complicate the drug control of epilepsy and lengthen seizure time in electroconvulsive therapy (ECT). The situation is made more complex by the capacity of carbamazepine to induce the metabolism of antidepressants and of certain antidepressants to inhibit carbamazepine metabolism (see below).


• SSRIs are known to interfere with platelet aggregation and may increase the risk of gastrointestinal bleeding, especially in those with existing risk factors.


• Trazodone and many tricyclics cause sedation and therefore co-prescription with other sedative agents such as opioid analgesics, H1-receptor antihistamines, anxiolytics, hypnotics and alcohol may lead to excessive drowsiness and daytime somnolence.


• The majority of tricyclics have undesirable cardiovascular effects, in particular prolongation of the QTc interval. Numerous other drugs also prolong the QTc interval, e.g. amiodarone, disopyramide, procainamide, propafenone, quinidine, terfenadine, and psychotropic agents such as pimozide and sertindole. Their use in combination with TCAs that prolong QTc enhances the risk of ventricular arrhythmias.


• Tricylics potentiate the effects of catecholamines and other sympathomimetics, but not those of β2-receptor agonists used in asthma. Even the small amounts of adrenaline/epinephrine or noradrenaline/norepinephrine in dental local anaesthetics may produce a serious rise in blood pressure.



Pharmacokinetic interactions


Metabolism by cytochrome P450 enzymes provides ample opportunity for interaction of antidepressants with other drugs by inhibition of, competition for, or induction of enzymes. Tables 20.2A and 20.2B indicate examples of mechanisms by which interaction that may occur when relevant drugs are added to, altered in dose or discontinued from regimens that include antidepressants.





Enzyme inhibition


In depressive psychosis, antidepressants are commonly prescribed with antipsychotics and there is potential for enhanced drug effects with paroxetine + perphenazine (CYP 2D6), fluoxetine + sertindole (3A4) and fluvoxamine + olanzapine (1A2). Rapid tranquillisation with zuclopenthixol acetate (see p. 325) of an agitated patient who is also taking fluoxetine or paroxetine can result in toxic plasma concentrations with excessive sedation and respiratory depression due to inhibition of zuclopenthixol metabolism by CYP 2D6 and CYP 3A4. P450 enzyme inhibition by fluoxetine or paroxetine may also augment effects of alcohol, tramadol (danger of serotonin syndrome) methadone, terfenadine (danger of cardiac arrhythmia), -caine anaesthetics and theophylline.



Enzyme-inducing drugs


e.g. carbamazepine and several other antiepilepsy drugs, accelerate the metabolism of antidepressants, reducing their therapeutic efficacy and requiring adjustment of dose. Epilepsy is a particularly common co-morbid illness in patients who have both psychiatric illness and learning disabilities, and the combination of an anticonvulsant and an antidepressant or major psychotropic drug is to be anticipated. Depression and hypertension are both such common conditions that some co-morbidity is inevitable. Panic disorder (an indication for an antidepressant drug) is associated with hypertension.1 An antidepressant that is an enzyme inhibitor may exaggerate antihypertensive effects of metoprolol (metabolised by CYP 2D6), or diltiazem or amlodipine (3A4).



Monoamine oxidase inhibitors





Hypertensive reactions


Patients taking MAOIs are vulnerable to highly dangerous hypertensive reactions. Firstly, as MAOIs increase catecholamine stores in adrenergic and dopaminergic nerve endings, the action of sympathomimetics that act indirectly by releasing stored noradrenaline/norepinephrine is augmented. Secondly, patients taking a MAOI are deprived of the protection of the MAO enzyme present in large quantities in the gut wall and liver. Thus orally administered sympathomimetics that would normally be inactivated by MAO are absorbed intact. (Note that enhanced effects are not as great as might be expected from adrenaline/epinephrine, noradrenaline/norepinephrine and isoprenaline, which are chiefly destroyed by another enzyme, catechol-O-methyltransferase, in the blood and liver.)



Symptoms


include severe, sudden throbbing headache with slow palpitation, flushing, visual disturbance, nausea, vomiting and severe hypertension. If headache occurs without hypertension it may be due to histamine release. The hypertension is due both to vasoconstriction from activation of α-adrenoceptors and to increased cardiac output consequent on activation of cardiac β-adrenoceptors. The mechanism is thus similar to that of the episodic hypertension in a patient with phaeochromocytoma.



The rational and effective treatment


is an α-adrenoceptor blocker (phentolamine 5 mg i.v.), with a β-blocker later added in case of excessive tachycardia.



Patient education


It is essential to warn patients taking MAOIs of possible sources of the hypertensive reaction.



Many simple remedies


sold direct to the public, e.g. for nasal congestion, coughs and colds, contain sympathomimetics (ephedrine, phenylpropanolamine).



Foods likely to produce hypertensive effects in patients taking MAOIs include:



• Cheese, especially if well matured.


• Red wines (especially Chianti) and some white wines; some beers (non- or low-alcohol varieties contain variable but generally low amounts of tyramine).


• Yeast extracts (Marmite, Oxo, Bovril).


• Some pickled herrings.


• Broad bean pods (contain dopa, a precursor of adrenaline/epinephrine).


• Over-ripe bananas, avocados, figs.


• Game.


• Stale foods.


• Fermented bean curds including soy sauce.


• Fermented sausage, e.g. salami, shrimp paste.


• Flavoured textured vegetable protein (Vegemite).


This list may be incomplete and any partially decomposed food may cause a reaction. Milk and yoghurt appear safe.



Foods


to avoid are those that contain sympathomimetics, most commonly tyramine, which acts by releasing noradrenaline/norepinephrine from nerve vesicles. Degradation of the protein, casein, by resident bacteria in well matured cheese can produce tyramine from the amino acid tyrosine (hence the general term ‘cheese reaction’ to describe provocation of a hypertensive crisis).


Stale foods present a particular danger, as any food subjected to autolysis or microbial decomposition during preparation or storage may contain pressor amines resulting from decarboxylation of amino acids.


The newer drug moclobemide offers the dual advantages of selective MAO-A inhibition; in theory, this should avoid the ‘cheese’ reaction by sparing the intestinal MAO, which is mainly MAO-B, and of being a competitive, reversible inhibitor. Whereas the irreversible inhibitors inactivate the MAO enzyme and can therefore continue to cause dangerous interactions in the 2–3 weeks after withdrawal, until more enzyme can be synthesised, the reversible nature of MAO inhibition means it is incomplete except during peak plasma concentrations. As the inhibition is competitive, tyramine can then displace the inhibitor from the active site of the MAO enzyme. Consequently there are fewer dietary restrictions for patients using moclobemide, although hypertensive reactions have been reported.



MAOI interactions with other drugs


The mechanisms of many of the following interactions are obscure, and some are probably due to inhibition of drug-metabolising enzymes other than MAO enzyme, as MAOIs are not entirely selective in their action. Effects last for up to 2–3 weeks after discontinuing the MAOI.


Antidepressants. Combination with tricyclic antidepressants has the potential to precipitate a hypertensive crisis complicated by CNS excitation with hyperreflexia, rigidity and hyperpyrexia.


MAOI–SSRI combinations may provoke the life-threatening ‘serotonin syndrome’ (see above). Strict rules apply regarding washout periods when switching between MAOIs and other drugs (see above, Changing antidepressants, p. 316). Very occasionally, MAOIs are co-prescribed with other antidepressants, but as many combinations are highly dangerous such practice should be reserved for specialists only and then as a last resort.


Narcotic analgesics. With co-prescribed pethidine, respiratory depression, restlessness, even coma, and hypotension or hypertension may result (probably due to inhibition of its hepatic demethylation). Interaction with other opioids occurs but is milder.


Other drugs that cause minor interactions with MAOIs include antiepileptics (convulsion threshold lowered), dopaminergic drugs, e.g. selegiline (MAO-B inhibitor) may cause dyskinesias, antihypertensives and antidiabetes drugs (metformin and sulphonylureas potentiated). Concomitant use with bupropion/amfebutamone (smoking cessation), sibutramine (weight reduction) and 5HT1-agonists (migraine) should be avoided. Because of the use of numerous drugs during and around surgery, an MAOI is best withdrawn 2 weeks before, if practicable.



Overdose


with MAOIs can cause hypomania, coma and hypotension or hypertension. General measures are used as appropriate with minimal administration of drugs: chlorpromazine for restlessness and excitement; phentolamine for hypertension; no vasopressor drugs for hypotension, because of risk of hypertension (use posture and plasma volume expansion).



St John’s wort


The herbal remedy St John’s wort (Hypericum perforatum) has found favour in some patients with mild to moderate depression. The active ingredients in the hypericum extract have yet to be identified, and their mode of action is unclear. Several of the known mechanisms of action of existing antidepressants are postulated, including inhibition of monoamine reuptake and the MAO enzyme, as well as a stimulation of GABA receptors. Much of the original research into the efficacy of St John’s wort was performed in Germany, where its use is well established. Several direct comparisons with tricyclic antidepressants have shown equivalent rates of response, but the interpretation of these studies is complicated by the fact that many failed to use standardised ratings for depressive symptoms, patients tended to receive TCAs below the minimum therapeutic dose, and sometimes received St John’s wort in doses above the maximum recommended in commercially available preparations. Use of St John’s wort is further complicated by the lack of standardisation of the ingredients. A large multi-centre trial found only limited evidence of benefit for St John’s wort over placebo in significant major depression.2


Despite these reservations, there is certainly a small proportion of patients who, when presented with all the available facts, express a strong desire to take only St John’s wort, perhaps from a preference for herbally derived compounds over conventional medicine. For patients with mild depression, it seems reasonable on existing evidence to accede to this preference rather than impair the therapeutic alliance and risk prescribing a conventional antidepressant that will not be taken.






Adverse effects


Those who wish to take St John’s wort should be made aware that it may cause dry mouth, dizziness, sedation, gastrointestinal disturbance and confusion. Importantly also, it induces hepatic P450 enzymes (CYP 1A2 and CYP 3A4) with the result that the plasma concentration and therapeutic efficacy of warfarin, oral contraceptives, some anticonvulsants, antipsychotics and HIV protease/reverse transcriptase inhibitors are reduced. Concomitant use of tryptophan and St John’s wort may cause serotonergic effects including nausea and agitation.



Electroconvulsive therapy


ECT involves the passage of a small electrical charge across the brain by electrodes applied to the frontotemporal aspects of the scalp with the aim of inducing a tonic–clonic seizure. Reference to it is made here principally to indicate its place in therapy.


ECT requires the patient to be under a general anaesthetic, so carrying the small risks associated with general anaesthesia in minor surgical operations. It may cause memory problems, although these are generally transient. For these reasons, as well as the relative ease of use of antidepressant drugs, ECT is usually reserved for psychiatric illness where pharmacological treatments have been unsuccessful or where the potential for rapid improvement characteristic of ECT treatment is important. This may arise where patients are in acute danger from their mental state, for instance the severely depressed patient who has stopped eating or drinking, or those with florid psychotic symptoms. Modern-day ECT is a safe and effective alternative to antidepressant treatment and remains a first-line option in clinical circumstances where a rapid response is desired, when it can be life saving.



Antipsychotics




Classification


Originally tested as an antihistamine, chlorpromazine serendipitously emerged as an effective treatment for psychotic illness in the 1950s. Chlorpromazine-like drugs were originally termed ‘neuroleptics’ or ‘major tranquillisers’, but the preferred usage now is ‘antipsychotics’. Classification is by chemical structure, e.g. phenothiazines, butyrophenones. Within the large phenothiazine group, compounds are divided into three types on the basis of the side-chain, as this tends to predict adverse effect profiles (Table 20.3). The continuing search for greater efficacy and better tolerability led researchers and clinicians to reinvestigate clozapine, a drug that was originally licensed in the 1960s but subsequently withdrawn because of toxic haematological effects. Clozapine appeared to offer greater effectiveness in treatment-resistant schizophrenia, to have efficacy against ‘negative’ in addition to ‘positive’ psychiatric symptoms (see Table 20.4), and to be less likely to cause extrapyramidal motor symptoms. It regained its licence in the early 1990s with strict requirements on dose titration and haematological monitoring. The renewed interest in clozapine and its unusual efficacy and tolerability stimulated researchers to examine other ‘atypical’ antipsychotic drugs.


Table 20.3 Antipsychotic drugs



































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Jun 18, 2016 | Posted by in PHARMACY | Comments Off on Psychotropic drugs

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Atypical antipsychoticsa Classical antipsychotics  
Clozapine Phenothiazines  
Olanzapine Type 1 Chlorpromazine
Quetiapine   Promazine
Risperidone Type 2 Pericyazine
Ziprasidone Type 3 Trifluoperazine
Amisulprideb   Prochlorperazine
Zotepine   Fluphenazine