GENERAL PRINCIPLES OF USING PSYCHOTROPIC DRUGS

Psychotropic drugs are immensely valuable in the treatment of mental illness. They are not, however, a substitute for psychological treatments and social care; best results are often achieved by some combination of all these approaches.

Relevant questions about psychotropic drug use include:

When is drug treatment indicated?

Severe psychiatric illness usually responds well to drugs, but medication may be less effective for milder illness, personality disorders, behaviour problems and reactions to stress. In primary care, much psychiatric symptomatology is brief and self-limiting, and medication may not be necessary- though it is often prescribed.

Do the therapeutic effects outweigh any negative aspects?

All effective drugs have side-effects, usually but not always unwanted ones. Many psychotropics react adversely with other drugs, or with alcohol, and impair driving skills.

Elderly patients, women who are pregnant or breast-feeding, and patients with medical disorders are at greatest risk of unwanted effects. Tolerance and/or dependence seldom cause problems except with benzodiazepines, but patients are often needlessly worried about ìgetting addictedî to other psychotropics, especially antidepressants.

Patients with suicidal tendencies may use psychotropic drugs for overdose if issued with large quantities. The financial cost of drug treatment is another significant factor, although likely to be considerably less than the cost of inadequately treated mental illness.

What if drug treatment seems appropriate, but has not worked?
Many patients take their drugs irregularly, or not at all. Compliance can be improved by using single-drug regimes, taken once daily. Most psychotropic drugs persist at therapeutic levels for at least 24 hours, giving little rationale for divided doses.

If drug treatment seems appropriate but has not worked, has the drug been given in adequate dosage for long enough?

Depressive illness treated with antidepressants, and schizophrenia treated with antipsychotics, may take 4ñ6 weeks to respond. With antidepressants, use of sub-therapeutic doses, for too short a time, are common errors.

How long should treatment be continued?

Benzodiazepines for anxiety and insomnia should only be given for a few weeks at a time, because of the risk of tolerance and dependence; but antidepressants, if effective, should be continued several months to prevent relapse. Lithium for prophylaxis of affective disorder, and antipsychotics for maintenance treatment of schizophrenia, are usually continued for several years and sometimes are needed for life.

With difficult or atypical cases it may be necessary to experiment with different pharmacological groups in order to find the best drug, or combination of drugs. Changes should be made one at a time, and not before each one has been given a chance to work.

Which route of administration?

Oral medication is of course the rule. Liquid rather than solid formulations are easier for some patients to swallow ñ and harder for uncooperative ones to hide in their mouths.

Intramuscular injections include ordinary short-acting ones, for example haloperidol 10 mg for severe agitation in a psychotic patient, and long-acting ìdepotî preparations where the active medication is esterified and suspended in an oily form from which it is released slowly, for example haloperidol decanoate 100 mg every four weeks to keep chronic schizophrenia in remission. Intravenous injections are rarely used, and are unsafe with some psychotropic drugs.

Proprietary or generic formulation?

Lithium is one of the few psychotropic drugs where this matters pharmacologically, as the same dose of different preparations may produce very different levels in the patient, so the prescriber must specify and stick to a particular one.

This consideration does not apply to most other drugs, so generic prescribing to reduce costs is officially encouraged. However, generic prescribing has the disadvantage that different formats (size, shape, colour, taste) of tablets containing the same dose of the same drug are available, causing patients to be alarmed if the appearance of their medication changes when a fresh supply is dispensed.

The need for explanation

Prescription of drugs should always be accompanied by clear explanation and discussion about the need for medication, why a particular compound has been chosen, the likely benefits and risks, and the effects both wanted and unwanted. Such talks take only a short time, are highly valued by patients, and have been shown to improve compliance. Written information leaflets are also helpful.

What about the new drugs?

There has been a wave of new drugs, both antipsychotics (atypicals) and antidepressants (SSRIs, etc). The manufacturers have claimed that they are as effective as older drugs, but have fewer side-effects. They do have a more favourable side-effect profile in many cases, though adverse effects are now beginning to emerge, for example, weight gain and diabetes with olanzepine.

In medicine, as in life, one does not get anything for nothing, however, and clinical experience is that the newer drugs are less powerful. Although they may be satisfactory for milder cases, they may not be as effective in more severe cases in more disadvantaged areas.

I here describe the main groups of psychotropic drugs, with reference to some commonly used examples. The British National Formulary is the standard daily reference, but it must be remembered that it is primarily written for GPs; the Maudsley Prescribing Guidelines offers more detailed guidance, specifically for mental health.

Antipsychotics (neuroleptics, major tranquillisers) specifically ameliorate psychotic symptoms (delusions and hallucinations), as well as having a general sedative action.

Chlorpromazine was first introduced in the 1950s, as an antihistamine; a French surgeon noted its marked sedative action on surgical patients, and it was then tried out on psychiatric patients, often with dramatic results. Many other compounds are now available:

ANTIPSYCHOTIC DRUGS IN COMMON USE

Generic name Proprietary name
Chlorpromazine Largactil
Clozapine Clozaril
Fluphenazine decanoate* Modecate
Flupenthixol decanoate* Depixol
Haloperidol Serenace
Haloperidol decanoate* Haldol
Olanzepine Zyprexa
Pimozide Orap
Promazine Sparine
Risperidone Risperdal
Sulpiride Dolmatil
Trifluoperazine Stelazine
Zuclopenthixol decanoate* Clopixol
Zuclopenthixol acetateÜ Acuphase
*=Long-acting intramuscular injection.
Ü=Medium-acting intramuscular injection.

Indications

• Schizophrenia.
• Mania.
• Severely agitated or violent behaviour associated with any psychiatric disorder or organic brain syndrome.
• Severe anxiety which has failed to respond to other treatments.
• In general medicine as antiemetics and to potentiate analgesics and anaesthetics.
  

Pharmacology Most antipsychotics are thought to work at least partly through blocking dopamine receptors in the brain. Serum prolactin level is a measure of this dopaminergic blockade. However, different antipsychotic drugs have different effects at the various subtypes of dopamine receptors. Most antipsychotics also have antiadrenergic, anticholinergic and antihistaminic actions.

Chlorpromazine is regarded pharmacologically as a ìdirtyî drug, that is, it has actions on several neurotransmitter systems. As indicated above, its antihistamine action produces sedation, which is often useful in acute psychiatric presentations.

By contrast, haloperidol is a ìcleanerî drug, with actions predominantly on the dopamine system. Because it does not have actions on the histamine and acetyl choline systems, it may not be strongly sedative in some patients; it may therefore need to be supplemented in clinical use by prescription of minor tranquillisers such as the benzodiazepines.

Recently, ìatypicalîantipsychotics have been introduced and have rapidly become popular. They were initially promoted as being free from side-effects, but, inevitably, after a few years, their side-effects have become apparent. Risperidone can cause extrapyramidal side-effects. Olanzepine, especially, and also other atypicals, are associated with weight gain and diabetes. They also carry a specific risk of stroke, which has caused them to be discouraged in the elderly.

Prescribers must remain alert to sudden changes in medication availability and indications. Lack of a sufficient market caused the company concerned suddenly to stop supplying droperidol. Action by the Committee on the Safety of Medicines caused the very useful and gentle drug thioridazine (Melleril) to be abruptly withdrawn as a first line treatment of schizophrenia, on the basis of reported cardiovascular problems. And more recently, as indicated above, the supposedly safe atypicals have been warned against in the elderly, where they may cause stroke.

Administration Acute psychosis may be treated with oral medication given three or four times daily. There is a calming effect from the start, but control of delusions and hallucinations may take three or four weeks, and sometimes the full benefit is not seen for six to twelve months. In schizophrenia, the positive symptoms respond better than the negative ones.

A recently introduced medium-acting intramuscular preparation, Clopixol Acuphase, which exerts its effects over two to three days, is useful in very disturbed patients.

Chronic schizophrenia is often treated by slow-release intramuscular injections (depots) every 1ñ4 weeks. Such injections may have a pharmacological advantage for some patients in whom oral medication is incompletely absorbed or undergoes rapid first-pass metabolism in the liver, but their main advantage is ensuring regular medication and follow-up for a group of patients whose compliance with treatment tends to be poor.

For some cases of schizophrenia which do not respond to conventional doses of drugs, clozapine should be considered at an early stage, as responses to this drug are seen which do not seem to occur with other agents.

High-dose regimes are much less commonly used nowadays, especially since the advent of clozapine. It is better to add a drug from another class, usually a benzodiazepine, or consider ECT.

Unwanted Effects Antipsychotic drugs have a great many potential unwanted effects. Most common and troublesome are those involving the extrapyramidal nervous system, as follows:

• Parkinsonism, with tremor, rigidity, bradykinesia and sialorrhoea
• akathisia, with mental agitation and motor restlessness
• acute dystonia, including torticollis, other abnormal postures, and oculogyric crisis.

All these extrapyramidal effects respond to anti-Parkinsonian drugs such as benzhexol or procyclidine, but these extra drugs should not be given unless required because they may cause sedation and confusion, exacerbate psychotic symptoms and anticholinergic effects, and also (especially procyclidine, because of a temporary mood-altering effect) may be abused.

Tardive dyskinesia is another syndrome of abnormal movements which develops in up to 20% of patients on long-term antipsychotic drug treatment. Elderly, female and brain-damaged patients are most likely to be affected. Involuntary movements of choreiform or athetoid type affect the orofacial muscles, and sometimes the limbs or trunk.

The cause may be proliferation or hypersensitivity of dopamine receptors after prolonged blockade by antipsychotic drugs, or imbalance between dopamine and its antagonists acetylcholine and GABA. There is no effective treatment; anti-Parkinsonian drugs help some patients. Reducing or, paradoxically, increasing the dose of the responsible antipsychotic may help. Prevention is better, in so far as this is possible, and this may be aided by using the lowest antipsychotic dose, which is effective.

Other unwanted effects of antipsychotic drugs include hypotension, cardiac arrhythmias, either dry mouth or excessive salivation (sialorrhoea), constipation, weight gain, reduced fertility, bone marrow depression, blurred vision, retention of urine, impotence, jaundice, rash, photosensitivity, and hypothermia especially in the elderly.

Neuroleptic malignant syndrome is a rare, but potentially fatal, acute complication of antipsychotic drug use. Symptoms include catatonia or extrapyramidal movements, and hyperpyrexia. Affected patients require intensive medical care.

Antipsychotics are mainly metabolised in the liver. Their main drug interaction is to potentiate the sedative effects of other psychoactive substances, most importantly alcohol, antidepressants and benzodiazepines. Liver damage is the main contraindication. Regarding use in pregnancy, no serious adverse effects on the foetus are known.

Antipsychotic drugs enter breast milk in tiny amounts, but usually, if there is clear indication for their use, the benefit of having a healthy mother outweighs any potential risk to the infant. Antipsychotic drugs lower the convulsive threshold slightly, so caution is required in patients with epilepsy. They sensitize the skin to sunburn, so advice and sunblock preparation are needed in sunny periods.

Tolerance and dependence do not occur.

Choice of Drug The newer drugs appear to offer an advance in the treatment of schizophrenia, at least in expanding the range of choice of available drugs. They are recommended by NICE to be ìconsidered in the choice of first-line treatments for individuals with newly diagnosed schizophrenia.î (1). In other words, the evidence reviewed did not allow NICE to make a recommendation that the newer drugs should generally be used as first line treatment, or that they should generally be reserved for use when a typical drug has failed.

There are those psychiatrists who still regard chlorpromazine, for example, as their first-line antipsychotic, however, they would now be in a minority. Clinical experience is that the majority of UK psychiatrists do now regard atypical antipsychotics as first-line drugs, and most will reserve the older drugs for when atypical drugs have not worked.

Overall, the advantage lies with the prescriber becoming familiar with two or three key drugs, which he can prescribe with confidence and which work in his hands.
In my own practice, I find olanzepine be a satisfactory initial treatment for acute psychotic episodes. 5 mg at night is often a suitable starting dose. There are liquid and quick dissolving tablets, which formulations are helpful if there is doubt about whether the patient can be trusted to swallow conventional pills.

It is a sedative drug, and this is helpful to patients (and nurses) in the acute stages. It does not however seem to be the most powerful drug against the core symptoms of psychosis, delusions and hallucinations. I find that a combination of olanzepine with a small dose of haloperidol (1.5 to 5 mg, for example) can be helpful if there are residual psychotic symptoms. Such doses of haloperidol are well tolerated, and the combination may be better in the long run than the alternative of persisting with maximum does of olanzepine, with the attendant risk of weight gain.

The main disadvantage of olanzepine is its association with weight gain and even with diabetes; if it is used as a maintenance treatment, therefore, the dose should be reduced to a minimum and monitoring of weight is important.

Risperidone can produce extrapyramidal effects, more so than olanzepine, but less so than with the typical antipsychotics. It is less associated with weight gain and olanzepine. There is an injectable preparation, which offers an alternative to the traditional depot antipsychotics; some patients do well on it. However, it seems not to be as strong a drug as the ìtypicalî antipsychotics for the most severely affected.

Aripiprazole and quetiapine are other atypicals available; they are felt to have benign profiles of unwanted effects, but to be of limited effectiveness in severely ill patients.

If the first drug chosen does not work, it is logical to change to one of a different chemical group. If two drugs have failed, clozapine should be considered.

Clozapine is a highly effective antipsychotic but is licensed only for use in resistant cases, which have failed to respond to first-line drugs. Because of the risk of agranulocytosis, it is only available on a named-patient basis on condition that regular blood counts are satisfactory. The full benefit of clozapine may not be seen for at least a year.

Thioridazine causes few Parkinsonian effects, and is sedative, but is more likely to cause confusion- all these because of its strong anticholinergic properties. It has been described as ìthe first atypicalî.

Haloperidol is pharmacologically ìcleanerî with fewer actions outside the dopaminergic system; it has a reputation of being prone to cause extrapyramidal effects. This may be due to its previous use in very high doses, perhaps in an effort to produce the sedation, which its mainly dopamine-focussed actions mean are inherently unlikely.

However, even small doses of haloperidol (1.5-5mg) are profoundly antipsychotic, and at this doe, haloperidol is well tolerated.. It can be supplemented with benzodiazepines (or olanzepine) if additional sedation is required. Such regimes offer an alternative, probably underused, to automatic prescription of the very much more expensive atypicals.

Amisulpiride was thought to have specific effectiveness against negative symptoms, but unfortunately, this has not been borne out in use. It appears to be a fairly gentle, though not especially strong, antipsychotic.

Three classes of antidepressants are generally distinguished, on the basis of chemical structure- tricyclics (three rings) or of their presumed pharmacological mechanism of action: the selective serotonin re-uptake inhibitors (SSRIs), and the monoamine oxidase inhibitors (MAOIs).

However, there are some antidepressants, which cannot be fitted into this somewhat arbitrary classification. Some features of these three classes are:

Tricyclics

• e.g. Trimipramine (Surmontil)
• the most effective antidepressants in severe depressive states
• anxiolytic, analgesic and hypnotic properties
• which are predictable, dose-related, and helpful
• wide dose range

MAOIs

• e.g. phenelzine (Nardil)
• underused due to fears of
  
• ìcheese reactionî
  
• & consequent dietary restriction
• effective in atypical & refractory depression
  

SSRIs

• e.g. fluoxetine (Prozac)
• widely prescribed by GPs for emotional problems
  
• probably often effectively as a placebo
• frequently but unpredictably cause
  
• agitation,
  
• GI upset
  
• sexual dysfunction
• less effective for severe cases
• limited dose range
• reports of suicidality and withdrawal symptoms

ANTIDEPRESSANTS: TRICYCLIC GROUP Tricyclics (TCAs) were for many years the standard first-line drug treatment for depressive illness, though have been supplanted by the SSRIs in this regard in general practice.

Imipramine and amitriptyline are the longest established drugs of the tricyclic group but many others exist, some having a tetracyclic or other chemical structure.

Indications

• depressive illness.
• depression associated with other psychiatric conditions.
• anxiety states and panic disorder.
• nocturnal enuresis.
• chronic pain, especially of ìneuropathicî type.

TRICYCLIC AND RELATED ANTIDEPRESSANTS IN COMMON USE

Generic name Proprietary name
Amitriptyline Tryptizol
Amoxapine Asendis
Clomipramine Anafranil
Dothiepin (now called dosulepin) Prothiaden
Doxepin Sinequan
Imipramine Tofranil
Lofepramine Gamanil
Maprotiline Ludiomil
Mianserin Bolvidon, Norval
Nortriptyline Allegron
Trazadone Molipaxin
Trimipramine Surmontil

Pharmacology One mechanism of antidepressant action is believed to be prevention of reuptake of amine neurotransmitters into neurones. Changes in the number or sensitivity of postsynaptic receptors may also be involved. Most antidepressants affect both noradrenaline and 5-HT systems but others act selectively on one or the other. They have peripheral anticholinergic effects.

Administration These drugs should be started in a small dose, increased every few days if well tolerated. The oral route is almost always used; some parenteral preparations exist but do not have any clear advantage and are now rarely used. It is often possible to give the total dose at night; this helps with sleep, and improves compliance.

Many patients in fact begin to improve within days rather than weeks, which may be due to the anxiolytic and hypnotic effects of these drugs, which are immediate. However, there may be a delay of two or more weeks before the antidepressant effect is manifest and it is essential to counsel patients about this, especially as side-effects are most prominent in the first week.

Even if a depressive episode seems to have recovered completely with drug treatment, the drug should be continued in full therapeutic dose for at least six months before dose reduction is considered.

Unwanted Effects A long list of possible unwanted effects, many of them due to tricyclicsí anticholinergic properties, are listed but in practice only a few commonly occur.

Sedation may be beneficial if the patient is anxious or sleeping badly, but can be a nuisance during the day. Affected patients must be advised not to drive or use machinery. Sedation is made worse by alcohol.

Dry mouth, blurred vision and constipation are common, and urinary retention may occur. Postural hypotension may be dose-limiting, especially in the elderly. Tricyclics can also cause confusion in elderly patients, or those with organic brain disease.

Tricyclics lower the convulsive threshold, but this effect should not stop their use in a depressed epileptic, where the benefits of effective treatment far out-weigh the risk of precipitating a fit.

Less commonly, tricyclics, especially amitriptyline, can cause cardiac arrhythmias or heart block, precipitating sudden death in some patients with cardiac disease. Other rare but potentially serious effects are precipitation of glaucoma, and hepatic and haematological reactions.

Weight gain is common, and deters some patients from taking these drugs.

Tricyclics are metabolised in the liver. They have additive interactions with monoamine oxidase inhibitors, barbiturates, phenothiazines, anticholinergics, and anticoagulants, also with alcohol.

The main contraindications are cardiac disease, glaucoma, and prostatic enlargement.

Use in pregnancy is relatively safe as no serious adverse effects on the foetus are known, and tricyclics enter breast milk in small amounts only. Tolerance and dependence are not a significant problem, and it is important to reassure patients of this; however, sudden withdrawal of a tricyclic may cause nausea, headache, sweating and insomnia.

Tricyclics- except lofepramine- are toxic in overdose, and this has been one of the reasons for SSRIs, which are generally not toxic, becoming more popular. It has not been shown that tricyclics cause an excess of suicides; on the other hand, concerns have been expressed that SSRIs can cause suicidality, linked probably to their propensity to cause agitation in some patients.

The key to seeking to minimise suicide is good overall care with risk assessment and risk management; choice of drug should be dictated by clinical effectiveness.

Choice of Drug Patients in whom depression is accompanied by agitation or insomnia are most likely to benefit from one of the more sedative tricyclics such as amitriptyline, dothiepin or trimipramine, whereas patients with psychomotor retardation may be better on a non-sedating drug such as imipramine, lofepramine or nortriptyline.

The side-effect profile may determine the choice of drug, especially in patients with co-existing medical disorders. Compounds such as amitriptyline tend to produce more unwanted effects than the newer ones, yet for some patients appear to be more effective as antidepressants.

If depression proves resistant to tricyclics, another drug may be added. Lithium augmentation is sometimes helpful. Combined therapy using a tricyclic together with an SSRI or MAOI (see below) is another option but may be hazardous, so should only be used by experienced specialists.

ANTIDEPRESSANTS: SSRI GROUP SSRIs (selective serotonin reuptake inhibitors) have been available on the UK market since 1989, and have been widely prescribed.

Their prescription to child patients; however, has become very controversial, both because of lack of evidence of effectiveness in this patient group, and also because of concerns over increased suicide risk. Recent NICE guidance is that ìAntidepressant medication should not be used for the initial treatment of children and young people with mild depressionî; even in moderate to severe depression, the place of medication is given as ìbrief psychological therapy +/ñ fluoxetineî (2).

There seems on the face of it possibly to be something of a discrepancy between this and the NICE guidance for adults. that ì..when an antidepressant is to be prescribed in routine care, it should be a selective serotonin reuptake inhibitor (SSRI)î (3).

However, NICE is really preaching to the choir on this. SSRIs have been vigorously promoted, and have been commercially successful. Many GPs use them as first-line treatment for depressive illness, on the basis of claimed therapeutic advantages which have not always stood up to critical examination.

In specialist care, there is seldom much point in initiating SSRI prescription, as most patients referred with depression will already have been tried on them in primary care. If they have had a good trial of an SSRI, then there would be no point in trying a different SSRI, as the similarities far outweigh the differences.

If there has been no response, a different drug class (TCA or MAOI) should be tried. If there has been a partial response, a second drug (for example trimipramine at night, especially if sleep remains a problem) can be added; this is a safe manoeuvre in specialist hands.

Occasionally, an SSRI may be added to the treatment regime of a patient who has made a partial response to tricyclic antidepressant medication; for example, adding fluoxetine 20 mg mane to the treatment of a patient taking trimipramine 150 mg nocte may have a modest effect in improving mood, and the alerting effects may also be useful.

SSRI ANTIDEPRESSANTS

Generic name Proprietary name
Citalopram Cipramil
Escitalopram Cipralex
Fluoxetine Prozac
Fluvoxamine Faverin
Paroxetine Seroxat
Sertraline Lustral

Points of comparison between TCAs and SSRIs include:

Efficacy: clinical trials suggest that SSRIs and tricyclics are about equal in their antidepressant properties, although some patients will respond better to one or other type of drug. However, patients included in commercial drug trials tend to be towards the milder end of the spectrum. Some trials have excluded, for example, those with suicidal risk or comorbid conditions.

Clinical experience is that severely depressed patients, especially those whose sleep is disturbed, respond better to a sedative tricyclic or other drug than to an SSRI.

Unwanted effects: SSRIs are claimed to have fewer unwanted effects than tricyclics but the picture is mixed ì ..one systematic review ..found that about twice as many people taking TCAs compared with SSRIs had dry mouth, constipation, and dizziness but that slightly more people taking SSRIs had nausea, diarrhoea, anxiety, agitation, insomnia, nervousness, and headache..î (4).

Although not physically addictive in the sense that they do not give rise to tolerance, with a constant need to increase the dose to achieve the same effect, nevertheless, some patients to find it difficult to get off them. They experience anxiety tremor and a variety of other symptoms.

There is of course a good deal in common between these symptoms, and some of the symptom for which the patient may have been prescribed the drug in the first place, so the matter is difficult to evaluate. It has been widely publicised, and legal action against the drug companies is in contemplation.

Metabolism: fluoxetine has a very long half-life; this is a disadvantage as far as drug interactions are concerned, but means the drug could theoretically be given in one dose every few days as a ìdepot antidepressantî when compliance is limited.
Safety in overdose: SSRIs are safe in overdosage.

Most tricyclics, with the exception of lofepramine, are toxic, and so SSRIs are increasingly used in suicidal patients. However, although tricyclic poisoning is a contributory factor in some suicides, it has never been shown that the total death rate is greater in patients on these potentially more poisonous drugs.

Cost: SSRIs are considerably more expensive, as most are still in patent; cheap, non-brand name (generic) preparations are available for most TCAs and MAOIs.
Dosage: SSRIs have a narrower therapeutic range, and therefore the advantage of a simple standard dose regime, especially useful in the elderly. However, the wide possible dose range of the tricyclics can also be useful, for example in permitting a very small starting dose in a patient susceptible to side-effects.

Other indications: certain SSRIs are licensed for use in eating disorders, panic disorder and obsessive-compulsive disorders, as well as for depressive illness. Fluoxetine has been widely used in the USA to ìenhanceî mood, and boost confidence, in people without formal psychiatric disorder; this practice is controversial.

ANTIDEPRESSANTS: MAOI GROUP MAOIs (monoamine oxidase inhibitors) increase brain concentrations of monoamine neurotransmitters by inhibiting the enzymes concerned in their breakdown. They are effective for depression, anxiety and phobic states, and sometimes achieve dramatic responses in patients who have failed to respond to tricyclics.

They may have a particular place in so-called atypical depression, ì..with reversed biological features, e.g. increased sleep, increased appetite, mood reactivity, and rejection sensitivityî (5). The BNF recommends that ìMAOIs should be tried in any patients who are refractory to treatment with other antidepressants as there is occasionally a dramatic responseî, (6), though this advice is, sadly, seldom followed in practice.


MAOI ANTIDEPRESSANTS

Generic name Proprietary name
Isocarboxazid Marplan
Moclobemide Mannerix
Phenelzine Nardil
Tranylcypromine Parnate

In addition to their anticholinergic side-effects (similar to those described above for the tricyclics), MAOIs may cause potentially dangerous interactions with sympathomimetic drugs (including common cold remedies) and tyramine-containing foods.

Such interactions produce headache and palpitations and, rarely, a hypertensive crisis leading to a stroke or sudden death.

Patients on MAOIs should be given a card listing the items to avoid. It is probable that the risks have been overestimated, and that these effective drugs have been underused as a result.

The most recently introduced MAOI, moclobemide, is less prone to cause food and drug interactions because it is selective for the MAO-A isoform, which is found in the liver as opposed to the gut. It can be used on a trial basis: patients who respond somewhat to it can then be tried on a ìproperî, full-strength MAOI.

INTERACTIONS WITH MAOIs

Foods

• Cheese (strong)
• Red wine (espec. Chianti)
• Beer (strong)
• Game Yeast
• Smoked fish
• ìMarmiteî
• ìBovrilî

Drugs

• SSRIs
• Amphetamines
• L-Dopa
• Fenfluramine
• Local anaesthetics
• Ephedrine

OTHER ANTIDEPRESSANT DRUGS

When the last edition of this book was coming out, antidepressants new to the market included Venlafaxine (see below) and Nefazadone.

However, nefazodone had to be withdrawn after a few years, because of liver toxicity. This should stand as a further warning, as if any were needed, against hasty prescription of new medications. (The wise psychiatrist will wait a few years whilst other doctors try out new drugs on their patients.)

Nevertheless, the field of antidepressant prescribing seems notwithstanding to continue to be a ìdedicated follower of fashionî; the latest SSRI or other compound being likely to be widely adopted if it is innocuous and skillfully marketed.

Flupenthixol, which has somewhat confusingly been renamed flupentixol, is mainly used as an antipsychotic drug- most frequently as the long acting depot injection Modecate. However, low doses (1 to 3 mg daily) are given by mouth as an antidepressant medication. It can also be a useful adjunct when there has been a partial response to other forms of antidepressant treatment.

Tryptophan is a precursor of the amines thought to be low in depression. It was a popular adjuvant treatment in depression some years ago, but had to be withdrawn because of eosinophilia-myalgia syndrome. This was probably due to contamination of supplies with yeast. It is now available again; it should be initiated under specialist supervision.

Venlafaxine has been successfully marketed as ìa serotonin noradrenaline reuptake inhibitor or SNRIî, though of course it shares this characteristic with many other existing drugs. However, it has fewer sedative and antimuscarinic effects than the TCAs. The CSM recommends that venlafaxine should be initiated and maintained by specialists only, and avoided in patients with heart disease, electrolyte imbalance and hypertension.

Mirtazapine, is a presynaptic α2-antagonist, and increases brain NA and serotonin functionality. It is markedly sedative; it is useful in anxiety for that reason, but it also seems to be an effective antidepressant. Other drugs include reboxetine and duloxetine.


Benzodiazepines were widely prescribed in the 1960s and 1970s as anxiolytics and hypnotics. For a while they were perceived as ìwonder drugsî against neurosis, with no side-effects or addiction potential, in contrast to their predecessors the barbiturates.

In the 1980s, however, because of concern about their inappropriate use for people with social and interpersonal problems rather than true psychiatric disorder, and because of the emerging risk of dependence, prescription of benzodiazepines was discouraged, with psychological techniques of anxiety management being recommended as an alternative.

Current CSM advice is that:

1. Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness.

2. The use of benzodiazepines to treat short-term ëmildí anxiety is inappropriate and unsuitable.

3. Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress.


BENZODIAZEPINES IN COMMON USE

Generic name
Alprazolam
Chlordiazepoxide
Diazepam
Flurazepam
nitrazepam
Lorazepam
Temazepam

It is important to realise that the CSMís sensible and cautious advice does not constitute a ban on benzodiazepines. The pendulum has however swung perhaps a little too far, and at present, benzodiazepines as effective remedies for short-term anxiety are probably underused. Excessive prescription should certainly be avoided, but some authorities consider these drugs remain a reasonable long-term treatment for a small minority of chronically anxious patients. Intensive effort to wean all long-term users off benzodiazepines is not automatically justified.

Further concern about benzodiazepines stems from their popularity with drug misusers. Intravenous injection of the gel from temazepam capsules has recently become prevalent and may cause gangrene of the limbs; these capsules have therefore been withdrawn.

Indications

• Short-term treatment of pathological anxiety.
• Short-term treatment of insomnia.
• Adjunctive treatment of psychosis and acute behavioural disturbance in inpatient settings
• Alcohol withdrawal states. (e.g. DTs) and detoxification
• Status epilepticus.
• Muscle spasticity.
• Anaesthetic premedication.
• Sedation in terminal illness.
  

Pharmacology

Benzodiazepines probably act through modification of the GABA and glycine neurotransmitter systems in the limbic system and spinal cord.

Administration

Benzodiazepines for anxiety or insomnia are most effective if taken only when required, rather than on a fixed dose regime, and only for a few weeks at a time. Intramuscular, intravenous and rectal preparations are available for emergency use.

Unwanted Effects

Benzodiazepines, even in overdose, are not toxic. Apart from drowsiness, they may have few unwanted effects in the young healthy person, but the elderly may experience marked side-effects of which neurological and psychiatric ones are most important.

These include confusion, depression, drowsiness, amnesia, impaired psychomotor performance including an effect on driving, ataxia, dysarthria and headache. Some subjects experience ìparadoxicalî effects of excitement, aggression or insomnia. Benzodiazepines potentiate the effects of alcohol and other cerebral depressants.

Use in pregnancy should be avoided. In late pregnancy, benzodiazepines can cause the ìfloppy infant syndromeî of hypotonia, respiratory embarrassment and hypothermia, and the baby may develop withdrawal symptoms after delivery. Benzodiazepines readily enter breast milk.

Tolerance and dependence may develop with regular use. Psychological dependence is common. Physical dependence develops in around 20% of those who take benzodiazepines long-term. Suddenly stopping the drugs in such patients causes a withdrawal syndrome of insomnia, tremor, fits, anorexia, vomiting, sweating and cramps.

This syndrome, which is most often seen after the withdrawal of a short-acting drug such as alprazolam, lorazepam or temazepam, may be mistaken for recurrence of the original anxiety for which the drug was prescribed. Withdrawal symptoms can be avoided by tapering the drug gradually, while introducing psychological anxiety management techniques. Some authorities recommend converting the benzodiazepine-dependent patient to the equivalent dose of diazepam, which can then be reduced by 1 mg per week over a period of 1ñ12 months.

Choice of Drug

Many benzodiazepines are available. They vary in potency and duration of action but many are metabolised to the same compound, oxazepam, and are to some extent interchangeable. The same compound can often be used in low dose to treat anxiety and in higher dose to induce sleep.

Longer-acting ones can be given in a single nighttime dose to provide an immediate hypnotic effect followed by an anxiolytic effect next day. The shorter-acting ones are suitable for insomnia, which is not accompanied by daytime anxiety, or for phobic anxiety related to specific situations.

Other Drugs for Anxiety and Insomnia

Various alternatives to the benzodiazepines are available as hypnotics and/or anxiolytics, though all have unwanted effects of their own.

Antidepressants are often used to treat chronic anxiety, or anxiety mixed with depression. Trimpramine, trazodone and mirtazepine are suitable. Some immediate benefit may occur due to the sedative action, and gradual further improvement should follow over several weeks.

Other options include beta-blockers such as propranolol, effective mainly for the physical symptoms of anxiety; antipsychotics such as chlorpromazine in low dose; antihistamines such as promethazine, and newer preparations such as buspirone.

For insomnia, long-established remedies include chloral hydrate and promethazine; newer drugs include zolpidem and zopiclone. Hypnotics are recommended for occasional use only; dealing with the cause of the insomnia is a better alternative to drugs. Causes include noise, discomfort, a restless partner, worry, shift-work, travel, excess alcohol or caffeine intake, or unrealistic expectations about the amount of sleep required.

Barbiturates, once widely used as hypnotics and anxiolytics before benzodiazepines became available, are now obsolete as psychotropic drugs because of the high risk of dependence and high toxicity in overdose.


These drugs are used as prophylactic medication in bipolar affective disorder. That is, they are given long-term in order to reduce the frequency duration and severity of further episodes of affective disorder, whether manic or depressive.

The drugs do have slight effectiveness in the acute episode, and are usually started during it; however, they are not strong enough to be relied on by themselves for treatment of acute episodes, needing to be supplemented by major tranquillisers and/or benzodiazepines.

The main drugs in use in the UK are lithium, and certain drugs which were originally marketed as anticonvulsants but which have been found to have effectiveness in this area; these include sodium valproate, carbamazepine, and to some extent, lamotrigine and other drugs.

LITHIUM is the lightest of the alkali metals. It was the first drug found to be effective as a mood stabiliser. It remains the standard treatment in the UK for probably the majority of psychiatrists. In the US, under medicolegal pressure, it is less frequently used as a first line treatment because of concerns about renal and other long-term effects (see below).

Indications

• Prophylaxis of recurrent episodes of affective disorder, when these are sufficiently frequent or disabling to justify long-term continuous drug treatment. In the past, lithium has been used mainly in bipolar disorder, being effective in reducing both frequency and severity of episodes. Lithium is now increasingly used in prophylaxis of recurrent unipolar depression also.
• Adjunctive treatment of episodes of mania and depression.
• Schizophrenia, especially of schizoaffective type.
  

Administration

Although any one of lithiumís soluble salts could potentially be used, only the carbonate (tablets) and citrate (liquid) are marketed.

The most practical formulations are modified release tablets, allowing once daily dosage. Because bioavailability varies greatly between different brands, the prescriber should specify the brand.

Therapeutic effect is related to serum lithium level. The therapeutic range is between 0.4 ñ 1.0 mmol/litre. Levels of 0.8ñ1.0 mmol/litre were traditionally recommended for prophylaxis, but these would now be regarded as higher than necessary for satisfactory maintenance of the majority of patients.

The aim is to keep patients well on the minimum dose, which is achieved by frequent monitoring of the clinical state, and by regular blood tests.

Lithium has a narrow therapeutic margin, and there is individual variation in the dosage needed to produce a given serum level, so regular measurements are required. Blood for serum lithium should be taken eight hours after the last dose. This usually means first thing in the morning after the regular nighttime dose.

Blood tests may be weekly for say the first four weeks of therapy, but eventually patients can be maintained satisfactorily on a blood test every year. The blood test should include thyroid function tests and urea and electrolytes, to make sure that the thyroid and kidneys are not being affected.

Patients should carry a lithium card and be advised to maintain good fluid intake, without huge fluctuations in the amount of salt they consume. If they become unwell, they should seek medical advice and informed the doctor that they are taking lithium.

Extra tests should be performed in the event of a change in the preparation or in dosage; if symptoms suggesting lithium toxicity develop; intercurrent illness; or prescription of additional drugs, which may interact, especially diuretics.

If a patient has remained free of depression or mania for some years, it is reasonable to try gradual withdrawal of lithium, as the illness may have undergone a natural remission.

Unwanted Effects

• Relatively harmless: nausea, mild diarrhoea, fine tremor (which can be treated by a beta-blocker), weight gain, oedema, and exacerbation of psoriasis.
• Acute symptoms suggesting lithium intoxication: vomiting, diarrhoea, coarse tremor, drowsiness, vertigo, dysarthria and cardiac arrhythmias. This condition is serious and, if such symptoms develop, lithium should be stopped immediately and blood taken for estimation of the serum level.
• Long-term effects of gradual onset: hypothyroidism (affecting 3% of patients per year, usually reversible when the drug is stopped, and treatable with thyroxine if lithium is continued); rarely, thyrotoxicosis; histological and functional changes in the kidney, of uncertain significance.
  

Case Example

A postgraduate student, 23 years old, presented with an episode of psychotic depression which responded well to inpatient treatment, but he developed a manic illness some months later. He was started on lithium, but stopped taking it after a few days, complaining of tremor; he had also, through a doctor relative, found out about its unwanted effects, and felt that these had not been properly discussed with him.

He declined other mood stabilisers, as he had become distrustful.

He recovered, but had a further severe manic episode one year later. This time, he responded only slowly to antipsychotic medication, and valproate was added with gradual success.

He then took valproate for several years; he continued to have affective episodes approximately annually, though they were less severe and able to be managed without inpatient admission. He came to accept the medication as the price of his mental stability.

Lithium should only be used in low dose, and under frequent supervision, in patients with cardiac or renal impairment, thyroid disease, diabetes insipidus, Addisonís disease, obesity, or on diuretic therapy. Neurological impairment after combined dosage with lithium and haloperidol in high dose has been reported.

Use in early pregnancy is teratogenic, the most common foetal malformation affecting the tricuspid valve of the heart. This and other deformities can be detected by ultrasound. After the first trimester, lithium is believed to be safe, and may need to be continued in women with severe manic-depressive illness although the drug should be stopped for a few days at the time of delivery because of the risk of toxicity. Lithium enters breast milk.

CARBAMAZEPINE is widely used as an anticonvulsant and for other indications such as atypical facial pain. It is an alternative for prophylaxis of affective disorder, being more effective or better tolerated than lithium in some patients. As with lithium, regular measurements of serum levels are necessary to make sure they are within the therapeutic range. In resistant cases, lithium and carbamazepine can be used together. It can cause or exacerbate blood (e.g. leucopenia), liver and skin conditions; monitoring of a full blood count, liver and renal function tests, as well as blood level of the drug, is necessary.

VALPROATE is also used. This can be either the sodium salt, or semi-sodium. Again monitoring of blood levels is required.

Lithium, carbamazepine, and valproate, are all supported by evidence of effectiveness in prevention of relapse (7); olanzepine has recently been licensed for this indication also.


Specialised drugs used, for example in dementia, and in substance misuse, are discussed in the chapters concerned.


British National Formulary. Published in frequently updated editions by British Medical Association and Royal Pharmaceutical Society of Great Britain.

Maudsley Prescribing Guidelines, London Dunitz: 2005