Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 21A) pptx

Antidepressant drugs Antidepressants can be broadly divided into four main classes Table 19.1, tricydics TCA, named after their three ring structure, selective serotonin reuptake inhibit

Psychotropic drugs

SYNOPSIS

Advances in drug treatment have

revolutionised the practice of psychiatry over

the past six decades Drugs provide a degree of

stability and control in the lives of those

suffering from schizophrenia, a chronic

debilitating illness with impact so profound that

it accounts for 2-3% of UK national health

spending Similarly, the impact of medication in

alleviating the burden on individuals, their

families and society of depression, which has a

lifetime prevalence of up to I in 6 of the

population, is substantial Psychotropic drugs

greatly improve the prognosis of other

common conditions such as anxiety disorders,

attention deficit/hyperactivity disorder and

bipolar affective disorder.

In this chapter the following drug groups are

considered

Antidepressants

Antipsychotics ('neuroleptics')

Mood stabilisers

Drugs for anxiety and sleep disorders

Drugs for Alzheimer's dementia

Drugs for attention deficit/hyperactivity

disorder

Writing prescriptions is easy, understanding people is

hard (Franz Kafka, 1883-1924)

In 1940 psychotropic medication was limited to

chloral hydrate, barbiturates and amphetamine By

contrast, the modern-day formulary lists almost 100 psychotropic drugs, with efficacious treatment avail-able for the vast majority of psychiatric diagnoses and in all phases of life Psychotropic medication has been a key factor in accelerating the closure of Victorian 'asylums' such that the psychiatric inpatient population is now a tiny fraction of its 1954 peak of 148,000 in England and Wales

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 the presence of hallucinations, delusions or extreme abnormalities of behaviour including marked overactivity, retardation and catatonia, usually accompanied by a lack of insight Psychotic disorders therefore include schizophrenia, severe forms of depression and mania Psychosis may also be due to illicit substances or organic con-ditions Clinical features of schizophrenia may be 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 that would formerly have been grouped under 'neuroses' include depression in the absence

of psychotic symptoms, 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) and sleep disorders

367

Also falling within the scope of modern

psychia-tric 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 Chapter 10), 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

PSYCHOLOGICALTREATMENT

No account of drug treatment strategies for

psy-chiatric illness would be complete without

consi-deration of psychological therapies Psychotherapy

is broad in content, ranging from simple counselling

and 'supportive psychotherapy' sessions through

ongoing formal psychoanalysis to newer techniques

such as cognitive behavioural therapy

As a general rule, psychotic illnesses (e.g

schizo-phrenia, mania and depressive psychosis) require

drugs as first-line treatment, with

psychothera-peutic approaches limited to an adjunctive role, for

instance in promoting drug compliance, improving

family relationships and helping individuals cope

with distressing symptoms By contrast, for

non-psychotic depression and anxiety disorders such as

panic disorder and obsessive-compulsive disorder,

forms of psychotherapy are available which 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 to use 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

(in which individuals identify faulty views and

negative automatic thoughts and attempt to replace

them with ways of thinking less likely to lead to

depression), interpersonal therapy (which focuses

on relationships, roles and losses), brief dynamic

psychotherapy (a time-limited version of traditional

psychoanalysis) and cognitive analytical therapy

(another well structured time-limited therapy which

combines the best points of cognitive therapy and

traditional analysis)

Finally, it must be stressed that all doctors who prescribe psychotropic drugs engage in a 'thera-peutic 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 both to take the medica-tion and to adopt a mindset that might actually make him or her feel better 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 'therapeutic 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 19.1), tricydics (TCA, named after their three ring structure), selective serotonin

reuptake inhibitors (SSRIs), monoamine oxidase inhibi-tors (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 differences between individual TCAs and of the distinct characteristics of the novel compounds Since antidepressants are largely similar

in their therapeutic efficacy, awareness of profiles of unwanted effects is of particular importance

An alternative categorisation of antidepressants is based solely on mechanism of action (Fig 19.1) The majority of antidepressants, including TCAs, SSRIs

and related compounds are reuptake inhibitors Certain

novel agents including trazodone and mirtazapine are

receptor blockers while MAOIs are enzyme inhibitors.

The first TCAs (imipramine and amitriptyline) and MAOIs appeared between 1957 and 1961 (Fig 19.1) The MAOIs were developed from anti-tuberculosis agents which had been noted to elevate mood Independently, imipramine was synthesised from the antipsychotic drug chlorpro-mazine and found to have antidepressant rather than antipsychotic properties Over the next 25

A N Tl D E P RE SS AN T D R U G S

19

TABLE 19.1 Classification of antidepressants

Tricyclics Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors

Dothiepin (dosulepin)

Amitriptyline

Lofepramine

Clomipramine

Imipramine

Trimipramine

Doxepin

Nortriptyline

Protriptyline

Desipramine

Fluoxetine Paroxetine Sertraline Citalopram*

Fluvoxamine

Phenelzine Isocarboxazid Tranylcypromine Moclobemide (RIMA)

Novel compounds

Mainly noradrenergic Mainly serotonergic

Reboxetine (NaRI) Trazodone

Nefazodone

Mixed

Venlafaxine (SNRI)

Mirtazapine (NaSSA)

Milnacipran (SNRI)

Within each class or subclass drugs are listed in order of frequency of prescription in the United Kingdom (1997 data) Abbreviations; RIMA—reversible inhibitor of monoamine oxidase; NaRI—noradrenaline reuptake inhibitor; SNRI—serotonin and noradrenaline reuptake inhibitor; NaSSA—noradrenaline and specific serotonergic antidepressant.

* Citalopram is a racemic mixture of S and R isomers.The antidepressant activity of citalopram appears to reside in the S-isomer.

Escitalopram the pure S-isomer, may offer clinical benefits over existing preparations.

Trazodone, nefazodone and mirtazapine have been classed as 'receptor blocking' antidepressants based on their antagonism of

postsynaptic serotonin receptors (trazodone, nefazodone) and presynaptic 2 -receptors (trazodone, mirtazapine) Nefazodone has additional weak SSRI activity.

fl Not available in the United Kingdom.

years the TCA class enlarged to more than 10 agents

with heterogeneous pharmacological profiles and

further modifications of the original three ring

structure gave rise to the related (but

pharmaco-logically distinct) antidepressant trazodone

In the 1980s an entirely new class of

antidepres-sant arrived with the SSRIs, firstly fluvoxamine

immediately followed by fluoxetine (Prozac) Within

10 years, the SSRI class accounted for half of

anti-depressant prescriptions in the United Kingdom

Further developments in the evolution of the

anti-depressants have been novel compounds such as

venlafaxine, reboxetine, nefazodone and

mirtaza-pine, and a reversible monoamine oxidase inhibitor,

moclobemide

Mechanism of action

The monoamine hypothesis proposes that, in

depres-sion, there is deficiency of the neurotransmitters

noradrenaline and serotonin in the brain which can

be altered by antidepressants Drugs that affect

depression can modify amine storage, release, or

uptake (Fig 19.2) Thus the concentration of amines

in nerve endings and/or at postsynaptic receptors

is enhanced In support of the monoamine hypo-thesis are the findings that amfetamines, which release presynaptic noradrenaline and dopamine from stores and prevent their reuptake, have a weak antidepressant effect, whilst the antihypertensive agent reserpine, which prevents normal noradrena-line storage, causes depression, as does experimental depletion of the serotonin precursor tryptophan The importance of serotonin is further illustrated by the finding that depressed patients may exhibit down-regulation of some postsynaptic serotonin receptors

Specific serotonin reuptake inhibitors, as the class name implies, act predominantly by prevent-ing serotonin reuptake and have more limited effects

on noradrenaline reuptake Tricyclic antidepressants

in general inhibit noradrenaline reuptake, but effects on serotonin reuptake vary widely; desipra-mine and protriptyline have minimal potential for raising serotonin concentrations, whereas clomi-pramine possesses a greater propensity for blocking serotonin reuptake than for noradrenaline The

Reuptake inhibitors

1950s

1960s

1970s

1980s

1990s

Tricyclics

Amitriptyline Imipramine

Predominantly

noradrenergic TCAs

Desipramine

Predominantly seratonergic TCAs Clomipramine

SSRIs

Fluoxetine Paroxetine

SNRIs

Venlafaxine NaRls

Reboxetine

Receptor blockers

Mianserin

Trazodone

Nefazodone

Mirtazapine

Enzyme inhibitors

Monoamine Oxidase Inhibitors

Phenelzine

RIMAs

Moclobemide

Key-Drugs classes in boxed, shaded fields represent the three major antidepressants groups, tricyclics (TCAs), selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors.

Novel compounds are left unboxed.

NaRI-noradrenaline reuptake inhibitor

SNRI-serotonin and noradrenaline reuptake inhibitor

RIMA-reversible inhibitor of monoamine oxidase

*-Mianserin is rarely used due to associations with aplastic anaemia

t-Nefazodone is both a reuptake inhibitor and receptor blocker

Fig 19.1 Flow chart of the evolution of antidepressant drugs and classification by mechanism of action.

novel compound venlafaxine is capable of exerting

powerful inhibition of reuptake of both

trans-mitters, noradrenergic activity appearing at doses

greater than 200 mg/day Mirtazapine also achieves

an increase in noradrenergic and serotonergic

neuro-transmission, but through antagonism of

presynap-tic a2-autoreceptors (receptors that mediate negative

feedback for transmitter release, i.e an

autoinhibi-tory feedback system) Nefazodone has properties

of weak serotonin reuptake inhibition but

addi-tionally has complex but principally antagonist

effects on postsynaptic serotonin receptors, a property

it shares with trazodone

MAOIs increase the availability of noradrenaline

and serotonin by preventing their destruction by

the monoamine oxidase type A enzyme in the

presynaptic terminal The older MAOIs, phenelzine,

tranylcypromine and isocarboxazid, bind irreversibly

to monamine oxidase enzyme 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 MAOI are thus

called hit and run drugs as their effects greatly

outlast their detectable presence in the body 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

A N T I D E P R E S S A N T D R U G S 19

Physiological processes at the synapse:

1 When an electrical signal reaches the presynaptic terminal, presynaptic amine vesicles

fuse with the neuronal membrane and release their contents into the synaptic cleft.

2 Amines in the synaptic cleft bind to postsynaptic receptors to produce a post synaptic

response.

3 Amines may be removed from the synaptic cleft by reuptake into the presynaptic

neuron.

4 The monoamine oxidase enzyme breaks down presynaptic amines.

Effects of antidepressants:

A Tricyclics prevent presynaptic reuptake of the amines nonadrenaline and serotonin

B SSRIs predominantly block reuptake of serotonin.

C MAOIs reduce the activity of monoamine oxidase in breaking down presynaptic

amines (leaving more available for release into the presynaptic cleft).

D Some antidepressants (e.g nefazodone) block postsynaptic receptors directly.

Fig 19.2 Mechanism of action of antidepressant drugs at the synapse.

regulating the transcription of genes that influence

survival of other proteins including brain derived

neurotrophic factor (BDNF) which exerts effects on

neuronal growth The role of BDNF in depression

is supported by the observation that stress both

reduces its expression and impairs neurogenesis

While the monoamine hypothesis of depression

is conceptually straightforward, it is in reality it

is 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

hypothalamopituitary-thyroid axis and the hypothalamopituitary-adrenal

axis (HPA) The finding that 50% of depressed

patients have elevated plasma cortisol

concentra-tions constitutes evidence that depression may be

associated with increased HPA drive

Drugs with similar modes of action to

antidepres-sants find other uses in medicine Amfebutamone/

buproprion inhibits reuptake of both dopamine and noradrenaline and was originally developed and used as an antidepressant; it is now used to assist smoking cessation (see p 178) Sibutramine, licenced

as an anorectic agent, is a serotonin and noradrenaline reuptake inhibitor (see p 697) Despite its similarity

of action to venlafaxine and evidence of an anti-depressant effect from animal studies, sibutramine has yet to be recognised as effective for depression

PHARMACOKINETICS

The antidepressants listed in Table 19.1 are generally well absorbed after oral administration Steady-state plasma concentrations of TCAs show great individual variation but correlate with thera-peutic effect Measurement of plasma concentration can be useful especially where there is apparent failure of response (though it is often not available)

Antidepressants in general are inactivated

princi-pally by metabolism by hepatic cytochrome P450

enzymes (see p 112) Of the many isoenzymes

iden-tified, the most important in antidepressant

metabolism are Cytochrome P450 (CYP) 2D6 (Table

19.2a) and CYP 3A4 (Table 19.2b) Other important

P450 enzymes are CYP 1A2 (inhibited by the SSRI

fluvoxamine, induced by cigarette smoking,

sub-strates include caffeine and the atypical antipsychotics

clozapine and olanzapine) and the CYP 2C group

(inhibition by fluvoxamine and fluoxetine, involved

in breakdown of moclobemide) Sometimes several

CYP enzymes are capable of mediating the same

metabolic step For example at least six isoenzymes,

including CYP 2D6, 3A4 and 2C9 can mediate the

desmethylation of the SSRI sertraline to its major

metabolite

Several of these drugs produce active

meta-bolites which prolong their action (e.g fluoxetine is

TABLE 1 9.2A Psychotropic (and selected other) drugs

known to be CYP 2D6 substrates and inhibitors

CYP 2D6 inhibitors

Antidepressants

Paroxetine

Fluoxetine

CYP 2D6 substrates

Antidepressants

Paroxetine

Fluoxetine

Citalopram

Sertraline

Venlafaxine*

Amitriptyline

Clomipramine

Desipramine

Imipramine

Nortriptyline

Antipsychotics

Chlorpromazine Haloperidol Thioridazine Zuclopenthixol Perphenazine Risperidone

Miscellaneous Dexfenfluramine Opioids Codeine Hydrocodeine Dihydrocodeine Tramadolol Ethyl Morphine Tenamfetamine ('Ecstasy') Bupropion -blockers Propanolol Metoprolol Timolol Bufaralol

A substrate is a substance that is acted upon and changed by an

enzyme An enzyme inducer accelerates metabolism of

co-prescribed drugs which are substrates of the same enzyme,

reducing their effect An enzyme inhibitor retards metabolism of

co-prescribed drugs, increasing their effects (see Chapter 7,

Metabolism) Competition between drugs that are substrates for

the same enzyme may retard their metabolism, increase plasma

concentration and lead to enhanced therapeutic or adverse

effects.

*CYP 2D6 is involved only in the breakdown of venlafaxine to its

active metabolite and implications of 2D6 interactions are of

limited significance.

metabolised to norfluoxetine, t1/2 200 h) The meta-bolic products of certain TCAs are antidepressants

in their own right, e.g nortriptyline (from ami-triptyline), desipramine (from lofepramine) and imipramine (from clomipramine)

Half-lives of TCAs lie generally in the range of

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 tricyclic antidepressants intolerable and it is often worth starting at a very low dose If the drug is then tolerated, plasma concentration assay may to confirm the suspicion that the patient is a poor metaboliser

TABLE I9.2B Psychotropic (and selected other) drugs

known to be CYP 3A4 substrates, inhibitors and inducers

CYP 3A4 inhibitors

Antidepressants

Nefazodone Fluoxetine

CYP 3A4 substrates

Antidepressants Anxiolytics, hypnotics

and antipsychotics

Fluoxetine Sertraline Amitriptyline Imipramine Nortriptyline Trazodone*

Alprazolam Buspirone Diazepam Midazolam Triazolam Zopiclone Haloperidol Quetiapine Sertindole

CYP 3A4 inducers

Antidepressant

St John's Wort

Other drugs Cimetidine Erythromycin Ketoconazole (and grapefruit juice)

Miscellaneous Buprenorphine Carbamazepine Cortisol Dexamethasone Methadone Testosterone Calcium channel blockers Diltiazem

Nifedipine Amlodipine Other drugs Amiodarone Omeprazole Oral contraceptives Simvastatin

Miscellaneous Carbamazepine Phenobarbital Phenytoin

* mCPP, 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.

THERAPEUTIC EFFICACY

Provided antidepressant drugs are prescribed at

an adequate dose and taken regularly, 60-70% of

patients with moderate or severe depression should

respond within 3-4 weeks Meta-analyses have

shown little evidence that any particular drug or

class of antidepressant is more efficacious than

others, but there are four possible exceptions to this

general statement

• Small trials have suggested that the SNRI agent

venlafaxine, in high dose (> 150 mg/day) may

have greater efficacy than other antidepressants

• Amitriptyline appears to be slightly more

effective than other TCAs and also SSRIs but this

advantage is compromised by its poor

tolerability 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

• Evidence suggests that in patients hospitalised

with severe depression, TCAs as a class (also

venlafaxine) may be slightly more effective than

either SSRIs or MAOIs

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

tolerability, safety in overdose and likelihood of an

effective dose being reached SSRIs, lofepramine,

mirtazapine, nefazodone, reboxetine and venlafaxine are

highlighted as best fulfilling these needs

MODE OF USE

The action of TCAs in ameliorating mood is usually

absent in the first 2 weeks of therapy and at least 4

weeks must elapse to constitute an adequate trial

Where a minimal response is noted in this period, it

is reasonable to extend the trial to 6 weeks to see

A N T I D E P R E S S A N T D R U G S

if further benefit is achieved By contrast, patients may experience unwanted drug effects imme-diately on starting treatment (and they should be warned), but such symptoms often diminish with time Titrating from a generally tolerable starting dose, e.g amitriptyline 30-75 mg/day (25-50 mg/ day for imipramine), with weekly increments to

a recognised 'minimum therapeutic' dose, usually around 125 mg/day (140 mg/day for lofepramine) lessens the impact of adverse symptoms before

a degree of tolerance (and therapeutic benefit) develops 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 the test of response or nonresponse be considered adequate Some patients do achieve response or remission

at subtherapeutic doses, for reasons of drug kinetics and individual metabolism, 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)

TCAs are given either in divided doses or, for the more sedative compounds, as a single evening dose

SSRIs have advantages over tricyclics in simplicity

of introduction and use Dose titration is often unnecessary since the minimum therapeutic dose can usually be tolerated as a starting dose Divided doses are not 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

The novel compounds nefazodone and trazodone usually require 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 de-pression by gradual titration from 75 to 375 mg/day There is some need for dose titration when using MAOIs although recommended starting doses (e.g phenelzine 15 mg t.d.s.) may be effective Unlike other drug classes, reduction to a lower maintenance dose

is recommended after a response is achieved

CHANGING AND STOPPING

ANTIDEPRESSANTS

When an antidepressant fails through lack of efficacy

despite an adequate trial or due to unacceptable side

effects, it is generally advisable to change to a drug of

a different class For a patient who does not respond to

an SSRI it is logical to try a TCA or a novel compound

such as venlafaxine, reboxetine or mirtazapine Any

of these options may offer a greater increase in

synaptic noradrenaline than the ineffective SSRI

There is also evidence to suggest that patients failing

on one SSRI may respond to a different drug within

the class, an approach which is particularly useful

where other antidepressant classes have been

un-successful previously, are contraindicated, or have

characteristics which the patient or doctor feel are

undesirable For example, a patient who is keen to

avoid putting on weight may prefer to try a second

SSRI after an initial failure than to switch to a TCA or

MAOI since both of these classes commonly cause

weight gain Awareness of differences between drugs

within a class may also be helpful, e.g the greater

serotonergic enhancing effects of clomipramine

compared to other tricyclics may be advantageous in

a patient who cannot tolerate any other drug class

When changing between SSRIs and/or TCAs doses

should be reduced progressively over 2-4 weeks

Where a new drug is to be introduced it should be

'cross-tapered' i.e the dose gradually increased as

that of the substituted drug is reduced Changes to

or from MAOIs must be handled with great caution

due to the dangers of interactions between

anti-depressant classes (see below) Therefore MAOIs

cannot safely be introduced within 2 weeks of

stop-ping paroxetine, sertraline or tricyclics (3 weeks

for imipramine and clomipramine; combination

of the latter with tranylcypramine is particularly

dangerous), and not until 5 weeks after stopping

fluoxetine, the active metabolite of which has a very

long t l / 2 (9 days) Similarly, TCAs and SSRIs should

not be introduced until 2-3 weeks have elapsed from

discontinuation of MAOI (as these are irreversible

inhibitors, see p 370) No washout period is required

when using the reversible monoamine oxidase

inhibitor moclobemide

When a patient achieves remission, the

antidepres-sant should be continued for at least 9 months at the

dose which 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 anti-depressant offers protection, as further relapse is almost inevitable in the next three years

When ceasing use of an antidepressant, the dose should be reduced over at least 6 weeks to avoid

a discontinuation syndrome (symptoms include anxiety, agitation, nausea and mood swings) Dis-continuation of SSRIs and venlafaxine are asso-ciated additionally with dizziness, electric shock-like sensations and paraesthesia Short-acting drugs that do not produce active metabolites are most likely

to cause such problems Paroxetine in particular

is associated with severe withdrawal symptoms including bad dreams, paraesthesia and dizziness (which can be misdiagnosed as labyrinthitis)

AUGMENTATION

Augmentation, i.e the addition of another drug, is used to enhance the effects of standard antidepres-sants when two or more have successively failed to alleviate depressive symptoms despite treatment

at an adequate dose for an adequate time The therapeutic efficacy of new agents, e.g venlafaxine, has provided clinicians with further options which now tend to be employed before augmentation but the following may be used

The most common is augmentation is with the

mood stabiliser lithium carbonate Indeed, lithium may

be effective as monotherapy for depression but is not preferred because of its adverse effect profile and need for plasma concentration monitoring Its prescription

in combination with antidepressants that have failed

to produce remission is more usual and evidence suggests that up to 50% of patients who have not: responded to standard antidepressants can respond after lithium augmentation 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 389) Thyroid hormones also aid antidepressant action

Guidance points to the combination of

tri-iodotyronine (T3) and TCAs as being most effective

(but effects of lofepramine may be augmented by

levothyroxine to the extent that co-administration

should be avoided) The amino acid isomer

L-tryptophan, a precursor of serotonin, may also

augment but such use is restricted to hospital

specialists who must monitor haematological

function (it is associated with an eosinophilia/

myalgia syndrome though this may have been due

to an impurity rather than the L-tryptophan itself)

The (3-adrenoceptor blocker pindolol can augment

the action of SSRIs Pindolol may act by binding to

a serotonin autoreceptor and thus interfere with a

homeostatic mechanism which acts to reduce

sero-tonin concentrations after the initial elevation by

SSRI action

None of these augmentation strategies is ideal,

since they either require plasma monitoring (lithium,

tryptophan, tri-iodothyronine), expose the patient

to potential toxicity (lithium, tryptophan) or have

only a moderate evidence base for efficacy

(tri-iodothyronine, pindolol)

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 393)

SSRIs are effective in milder cases of the eating

disorder bulimia nervosa, particularly fluoxetine (in

higher doses than are required for depression) This

effect is independent of that on depression (which

may co-exist) and may therefore involve action on

transmitter systems other than those involved in

modulating depression Antidepressants appear to

be ineffective in anorexia nervosa

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

Tricyclic antidepressants

The commonest unwanted effects are those of the

antimuscarinic action, i.e dry mouth (predisposing

A N T I D E P R E S S A N T D R U G S

to tooth decay), blurred vision and difficulty with accommodation, raised intraocular pressure (glaucoma may be precipitated), bladder neck obstruction (may lead to urinary retention in older males)

Patients may also experience: postural hypo-tension (through inhibition of a-adrenoceptors) which is often a limiting factor in their utility in the elderly, interference with sexual function, weight gain (through blockade of histamine H1 receptors), prolongation of the QT interval of the ECG which predisposes to cardiac arrhythmias especially in overdose (use of TCAs after myocardial infarction

is contraindicated)

Some TCAs (especially trimipramine and ami-triptyline) are heavily sedating through a combination

of antihistaminergic and a-adrenergic blocking actions 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

It is essential to remember that 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)

Overdose Depression is a risk factor for both

parasuicide and completed suicide, and TCAs are commonly taken by those who deliberately

self-harm Dothiepin (dosulepin) and amitriptyline are

particularly toxic in overdose, being responsible for

up to 300 deaths per year in the UK despite the many alternative antidepressants that are available 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

pharma-cology of TCAs Antimuscarinic effects result in warm, dry skin from vasodilatation and inhibition

of sweating, blurred vision from paralysis of accom-modation, pupillary dilatation and urinary retention Consciousness is commonly dulled and respira-tion depression and hypothermia may develop Neurological signs include hyperreflexia, myo-clonus and divergent strabismus Extensor plantar responses may accompany lesser degrees of impaired

consciousness and provide scope for diagnostic

confusion, e.g with structural brain damage

Con-vulsions occur in a proportion of patients

Halluci-nations and delirium occur during recovery of

consciousness, often accompanied by a

character-istic plucking at bedclothes

Sinus tachycardia (due to vagal blockade) is a

common feature but abnormalities of cardiac

conduction accompany moderate to severe

intoxi-cation and may proceed to dangerous tachy- 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 preceed cardiac

arrhythmias and arrest, and their suppression with

diazepam is important The temptation to treat

cardiac arrhythmias ought to be resisted if cardiac

output and tissue perfusion are adequate

Correc-tion of hypoxia with oxygen and acidosis by i.v

infusion of sodium bicarbonate are reasonable first

measures and usually suffice

Reboxetine is not structurally related to tricyclic

agents and acts predominantly by noradrenergic

reuptake inhibition Antimuscarinic effects trouble

only a minority of patients, postural hypotension

may occur and impotence in males It is relatively

safe in overdose

Selective serotonin reuptake inhibitors

SSRIs have a range of unwanted effects including

nausea, anorexia, dizziness, gastrointestinal

disturb-ance, agitation, akathisia (motor restlessness) and

anorgasmia (failure to experience an orgasm) They

lack direct sedative effect, an advantage in patients

who need to drive vehicles SSRIs can disrupt

the pattern of sleep with increased awakenings,

transient reduction in the amount of REM and

in-creased REM latency but eventually sleep improves

due to elevation of mood This class of

antidepres-sant does not cause the problems of postural

hypo-tension, antimuscarinic or antihistaminergic effects seen with TCAs Their use is not associated with weight gain and conversely they may induce weight loss through their anorectic effects SSRIs are relatively safe in overdose

The serotonin syndrome is a rare but dangerous complication of SSRIs and features restlessness, tremor, shivering and myoclonus possibly leading

on to convulsions, coma and death Risk is increased

by co-administration with drugs that enhance serotonin transmission, especially MAOIs, the anti-migraine drug sumatriptan and St John's Wort

Note When SSRIs are compared with TCAs for patients who discontinue therapy (a surrogate end-point for tolerability), most meta-analyses show a slight benefit in favour of SSRIs Comparisons which exclude TCAs with the most prominent anti-muscarinic effects (amitriptyline and imipramine) show either marginal benefits in favour of SSRIs or

no difference between the groups It is noteworthy that despite their pronounced adverse effects, amitriptyline and imipramine tend to be selected as 'standard' TCAs against which SSRIs are compared Lofepramine, the second most prescribed TCA

in the UK and the one TCA which causes little sedation, has few antimuscarinic effects and is

as safe as SSRIs in overdose is; it under-represented

in meta-analyses

Novel compounds

Venlafaxine produces some unwanted effects that resemble those of SSRIs with a higher incidence of nausea Sustained hypertension (due to blockade

of noradrenaline reuptake) is a problem in a small percentage of patients at high dose and blood pressure should be monitored when > 200 mg/day

is taken

Nefazodone lacks antimuscarinic effects but may cause postural hypotension and abdominal discom-fort It appears to improve sleep quality and seems not to interfere with sexual function

Mirtazapine also has benefits in rarely being asso-ciated with sexual dysfunction and in improving