Biological treatments

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CHAPTER 13 Biological treatments

Darryl Bassett, David J. Castle

Psychopharmacology

Medications in psychiatry are used not only to reduce symptoms and modify maladaptive behaviour, but also to facilitate psychological therapies of various kinds. Many patients with mental disorders are significantly more vigilant and more anxious about changes in bodily sensations than other people. Thus, ‘side effects’ tend to be more often identified and more often found to be poorly tolerable. However, tolerance usually improves with persistence and patients should be advised of this. It is essential that patients are made aware of common side effects as well as the risk of less common ones (particularly when potentially very serious or life-threatening). The majority of patients find being aware of potential problems and their management reassuring.

This chapter outlines medications which may be prescribed or encountered in clinical practice. Clinical tips are included and common uses of medications are summarised. Less commonly used medications are included as a resource, should they be encountered in clinical practice.

Drug interactions

Most medications are metabolised, at least to some extent, in the liver by the cytochrome P450 enzyme group (CYP enzymes) and this includes most psychotropic medications. A number of psychotropic medications inhibit or induce isoenzymes of this enzyme group creating potentially significant changes in the blood levels of other medications. Inhibition will promote increased levels and induction will promote decreased levels. These effects need to be considered in the prescribing of medication combinations and must be considered before prescribing. CYP polymorphisms and levels vary from person to person, and also over different racial groups. Genetic testing is now available to determine the profile of these polymorphisms if there are specific clinical indications (see Tables 13.1, 13.2 and 13.3).

TABLE 13.1 CYP isoenzyme inhibition by antidepressants

TABLE 13.2 Drugs metabolised by cytochrome P450 (CYP) isoenzymes

TABLE 13.3 Inducers or inhibitors of the cytochrome P450 isoenzymes

Some specific examples are noted below. Pharmacists can be very helpful with advice, computerised prescribing programs include warnings about potential interactions, and the internet site ‘MedWatch’ is very useful.

Cigarette smoking induces CYP1A2 and therefore blood levels of some medications (e.g. clozapine) may be lower in smokers than expected.

ABC membrane transport proteins (ATP-bound cassette membrane proteins) are heavily involved in the regulation of transport of multiple substances across cell membranes, including the gut, blood-brain barrier, placenta, kidneys and other organs. P-glycoprotein (Pgp) is one such membrane transport protein which has a significant role in the regulation of transport of medications and other substances and therefore pharmacokinetics (including drug interactions). Most psychotropic medications cross the blood-brain barrier by passive diffusion through their lipophilic characteristics, but Pgp can modify transfer against concentration gradients. A number of medications inhibit Pgp and therefore have interactive effects on the action of other medications. Examples of such inhibitors include most selective serotonin reuptake inhibitors (SSRIs) and serotonergic and noradrenergic reuptake inhibitors (SNRIs) (with the currently known exception of desmethylvenlafaxine), atypical antipsychotics such as risperidone and olanzapine (less so paliperidone) and a variety of other medications. The tendency of Pgp to have common substrates with the CYP3A group of enzymes can also cause alterations in the bioavailability of several medications. Finally, various neurological diseases alter Pgp activity at the blood-brain barrier.

The combination of medications is a common and often necessary element of clinical practice in medicine. However, it always requires attention to possible interactions, which can be complex and very significant. At the same time, not all combinations are problematic and many interactions are trivial in effect.

The combination of antidepressants in the treatment of depressive disorders is an area of some controversy and any combinations should be approached cautiously and with attention to relative effects on CYP enzymes and Pgp. Most medications are carried in the blood bound to proteins. As many share the same carrier proteins, competition alters the level of ‘free’ drug and therefore effect. Alterations in the levels of warfarin, for example, are commonly important (Box 13.1).

BOX 13.1 Serotonin syndrome

When medications which markedly increase the level of serotonin at nerve synapses are combined with other medications or substances with similar effects, the increase in serotonin levels can produce the symptoms of a serotonin syndrome.

Common examples include an SSRI with a monoamine oxidase inhibitor (MAOI), an SSRI with lithium (often safe), an SSRI with clomipramine and an SSRI with a ‘triptan’ (e.g. sumatriptan) used to treat migraine. This is characterised by three potential groups of clinical phenomena:

1. cardiovascular: flushing of the skin, increased sweating, tachycardia, and increased or decreased blood pressure

2. neurological: tremor, hyperreflexia, myoclonus, delirium and seizures, and

3. gastrointestinal: nausea, vomiting, diarrhoea and abdominal pains.

The severity of the syndrome may vary from mild to life-threatening.

Absorption

Medication absorption and therefore bioavailability is affected by:

the pharmaceutical preparation of the medication (e.g. wafer, enteric coated or controlled release)

the timing in relation to food (which can also affect tolerance)

the concurrent use of other substances (e.g. antacids), and

gastrointestinal function (e.g. diarrhoea).

Hepatic and renal dysfunction

Hepatic and/or renal diseases may interfere with medication metabolism and/or excretion.

Age

The very young and the aged exhibit differences in fat/lean body ratios, medication absorption from the gut, hepatic and renal function, and tolerance of side effects from medications (see Chs 16 and 17).

BOX 13.2 Practical notes

The use of herbal remedies, other ‘over-the-counter’ medicines and illicit substances may promote significant interactions with prescribed medications.

Hypericum perforatum (St John’s Wort) has weak antidepressant properties and contains a group of substances which have antidepressant properties. Combination with serotonergic antidepressants can provoke a serotonin syndrome (Box 13.1). Several medicinal herbs either induce or inhibit CYP enzymes. Combination of these with psychotropic medications requires specific enquiry for each case.

Many ‘recreational’ substances may interact seriously with medications and include alcohol, amphetamines (various forms), cocaine and opiates.

Adherence with medication regimes is improved with education about the medications, taking the medications when patients follow other habits (e.g. brushing teeth, after meals or upon retiring to bed), dosette boxes and bubble-packs filled by pharmacists.

Common side effects can be managed as suggested below:

• sedation: take shortly before retiring to bed

• weight gain: a planned, healthy diet with frequent small meals and regular exercise

• dry mouth: frequent sips of water with lemon juice; chewing sugar-free gum; selected types of toothpaste (detergent free); and a variety of artificial saliva substitutes

• orthostatic hypotension: stand gradually in stages, and

• nausea: take medications after food; use antiemetic medications concurrently.

Specific medications

The categories used to classify medications are chosen by the manufacturer when first applying for registration with regulatory authorities. This means that medications may have multiple applications but be ‘known’ by their initial categorisation. Dose ranges given are daily and are suggested for ‘routine’ applications, but exceptions may arise. Side effects listed are those encountered commonly in clinical practice and those which are of particular seriousness. More detailed and comprehensive lists of side effects can be obtained from the ‘References and further reading’ and various printed and electronic prescribing guides.

Most psychotropic medications reduce the seizure threshold, but some have more potent effects than others and will be highlighted in the text.

Anxiolytics

Indications

Anxiolytics are:

indicated in anxiety of any form

best used for acute treatment of distressing anxiety and ceased as soon as possible, and

useful in the first week when introducing antidepressant medications for anxiety or anxious depression.

Mode of action

Benzodiazepines act through activation of GABA receptors (the brain’s ‘braking system’), reducing neuronal arousal generally. Buspirone is a serotonin receptor-1A partial agonist, providing optimal serotonergic activity. Clinical notes on anxiolytics are provided in Box 13.3.

BOX 13.3 Clinical notes on anxiolytics

Diazepam is used frequently in presentations of acute anxiety and is useful for patients to keep for ‘crisis’ situations. Its rapid absorption by mouth, and duration of action lasting several hours, makes diazepam a flexible anxiolytic for all forms of anxiety disorder for short-term relief. Encourage patients to use this sparingly to minimise tolerance, dependence and adverse effects on the process of capacity to learn. Just knowing that the patient has ready access if in crisis can provide the confidence to manage without.

Alprazolam is preferred by many patients for short-term relief of panic attacks, but should not be seen as a substitute for cognitive and behavioural interventions. Clear education about the management of panic attacks is essential, in any event.

Benzodiazepines

These include alprazolam, clonazepam, diazepam, flunitrazepam, lorazepam and oxazepam (see Table 13.4).

TABLE 13.4 Dose ranges, equivalent doses to diazepam, and half-lives of anxiolytics

General comments

Benzodiazepines have anticonvulsant and muscle-relaxing properties in addition to anxiolytic properties, which can be very useful at times.

Safety in oral overdose is very good.

Adverse effects

Sedation is the most common side effect.

Benzodiazepines can interfere with cognition, including memory, balance and reaction times, and may be addictive over time.

When combined with alcohol or other sedative medications, benzodiazepines amplify sedation and increase the adverse effect upon reaction times, reflexes and cognitive functions generally.

Use should be intermittent if at all possible, as tolerance develops rapidly and there is significant dependence over time.

Benzodiazepines suppress respiration in very high concentrations (e.g. with bolus intravenous administration).

Spirodecanediones (buspirone)

General comments

Start at 5 mg and increase slowly because of dizziness, which usually resolves with time.

Spirodecanediones are not addictive, are well tolerated over time, do not affect cognition and are easily withdrawn. They are not sedating.

Antidepressants

General comments

All antidepressants relieve core symptoms and signs of depressive disorders with biological features (see Ch 6).

They are also very effective in the treatment of all forms of anxiety disorders and particularly useful in treatment-resistant panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder.

Response in depressive disorders usually takes at least 1 week to be evident and 2 or more weeks to become significant. Optimal response will take several months.

Response in anxiety disorders is slower than for depressive disorders (3–4 weeks) and usually requires relatively higher doses. Start with a low dose to minimise aggravation of anxiety early and increase gradually. Concurrent use of a benzodiazepine may be useful early in this treatment.

Choice of antidepressant is usually initially based upon prominent symptoms (e.g. prominent anxiety might suggest a sedating antidepressant first), response, side effect profile and prescriber preference.

Inappropriate secretion of antidiuretic hormone (SIADH) may occur and result in hyponatraemia (most commonly with SSRIs and SNRIs). Symptoms may include lethargy, muscle weakness, impaired concentration, and potentially hypotension and cardiac arrhythmias. The effect is usually temporary. It is most common in elderly patients. Fluid restriction for a week or more may be required or the medication may need to be changed.

The metabolism and therefore pharmacokinetics of most antidepressants are affected by polymorphisms of CYP enzymes (e.g. as found in racial variations). Desmethylvenlafaxine is not.

The dose ranges, half-lives and common side effects of SSRIs are summarised in Table 13.5.

Suicide and the use of antidepressant medications has been the subject of intense discussion and research. The current findings of this research are summarised in Box 13.4.

Clinical notes on the use of antidepressants are summarised in Box 13.5.

TABLE 13.5 Dose ranges, half-lives and common side effects of SSRIs

BOX 13.4 Antidepressants and the risk of suicide

• The risk of suicide increases around the time of presentation for treatment and in the early stages of treatment for depression or psychosis with any treatment.

• The highest risk of suicide occurs in the week before treatment.

• Some antidepressants may increase the risk of suicidal behaviour by enhancing impulsivity and aggression in the first 2 weeks of treatment, particularly in children and adolescents (notably males). However, care should be exercised with patients under the age of 25 as a sensible precaution.

• There is no evidence that antidepressants increase the risk of suicide in adults, but there is evidence that using antidepressants may reduce the risk of suicide in adults.

• The increased risk of self-injury and suicidal thinking may be reduced by concurrent use of anxiolytic and antipsychotic medications, and may be less with certain antidepressants (e.g. mirtazapine).

BOX 13.5 Clinical notes on antidepressants

Below are suggestions for the choice of antidepressants in common clinical situations, based upon research and personal experience/preference. The list is not exhaustive and clinical judgment must be used in each case, particularly when there is a past history of antidepressant use. When treating depressive disorders, begin with the lowest manufactured dose and increase after 2 weeks if the response is inadequate. When treating anxiety disorders, begin with half the lowest manufactured dose (where practicable) and combine with an anxiolytic for the first week (except NASAs and TCAs). Anxiety disorders will usually require an increase in dose after 2 weeks to achieve an adequate response. Suggestions are:

• depression (uncomplicated): SSRIs

• depression (anxious): usually SSRIs (particularly citalopram, escitalopram, fluvoxamine and paroxetine); if severe, NASAs and TCAs can be useful

• depression (retarded): fluoxetine, SNRIs, reboxetine and nortriptyline

• depression (premenstrual): SSRIs

• depression (severe): SNRIs, mirtazapine and TCAs

• depression (failing to respond to or intolerant of SSRIs): SNRIs, NASAs and TCAs

• depression (treatment-resistant): higher than usual doses of any antidepressants used; TCAs, MAOIs and bupropion

• depression (psychotic): any antidepressant, but particularly SNRIs or TCAs; always combine with an antipsychotic medication

• generalised anxiety disorder: SSRIs; use SNRIs, NASAs or TCAs if failing to respond to SSRIs

• panic disorder: SSRIs combined with an anxiolytic for the first week to avoid provoking panic attacks; SNRIs, NASAs or TCAs if failing to respond to SSRIs

• post-traumatic stress disorder: SSRIs; use SNRIs, NASAs or TCAs if failing to respond to SSRIs

• obsessive-compulsive disorder: SSRIs; use TCAs (particularly clomipramine) if failing to respond to SSRIs; relatively high doses may be required, and

• social anxiety disorder, agoraphobia: SSRIs; use SNRIs, NASAs or TCAs if failing to respond to SSRIs.

Selective serotonin reuptake inhibitors (SSRIs)

These include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline (see Table 13.5).

General comments

Consumption after food reduces the intensity of nausea and reduces the risk of gastric erosion.

There is some evidence of greater efficacy and greater efficiency with an increased dose of escitalopram than with citalopram.

They are safe in overdose.

Indications

SSRIs are indicated in depressive and anxiety disorders with significant somatic/melancholic symptoms.

Mode of action

By reducing the reuptake of serotonin and sometimes noradrenaline after release from pre-synaptic terminals, these medications improve the capacity of the brain to recover optimal function during depressive disorders or severe anxiety. Neurotrophic factor release is strongly enhanced.

Adverse effects

Nausea is common in the first few days, but it usually improves with time.

There may be disturbed sleep with initial and/or middle insomnia (unpleasant wakefulness after a period of sleep, followed by further sleep).

There may be sexual dysfunction, including orgasmic delay and suppression of libido; it improves with time and sexual activity; it is particularly significant for females.

SSRIs do not interfere with cognition.

Movement disorders such as restless legs syndrome, periodic limb movement disorder and bruxism may be aggravated.

Platelet adhesion and function is mildly impaired and may result in bruising, an increase in bleeding time and increased risk of gastric bleeding (clotting factors are not affected).

Gastro-oesophageal reflux may be aggravated.

Hyponatraemia may occur (see ‘General comments’ on antidepressants, above).

Withdrawal should be gradual as discontinuation can be very uncomfortable (e.g. dizziness, light-headedness, insomnia, agitation and irritability); it is worst with paroxetine.

There may be reduced male fertility.

Serotonergic and noradrenergic reuptake inhibitors (SNRIs)

These include desvenlafaxine, duloxetine and venlafaxine. Details of dose range, half-lives and adverse effects can be found in Table 13.6.

TABLE 13.6 Dose ranges, half-lives and common side effects of other antidepressants

Indications

SNRIs are indicated in depressive and anxiety disorders with significant vegetative symptoms.

SNRIs are popular in more severe disorders or when response to SSRIs is inadequate.

Duloxetine can be very helpful in the management of chronic pain; other members of this group can also be of benefit in this regard.

Mode of action

It is similar to SSRIs but with greater effect upon noradrenaline; duloxetine and desvenlafaxine have significant dual serotonergic/noradrenergic effect at usual doses; venlafaxine requires a relatively high dose (more than 225 mg daily) to achieve a significant noradrenergic effect.

Adverse effects

There may be similar unwanted effects to SSRIs; side effects with venlafaxine appear clinically more severe than duloxetine and desvenlafaxine.

Withdrawal should be very gradual, as discontinuation can be very uncomfortable (dizziness, light-headedness, insomnia, agitation and irritability); it appears to be most severe for venlafaxine and less severe for duloxetine and desvenlafaxine.

Duloxetine may be mildly sedating at first or may be activating.

Diastolic hypertension may rise; the increase is proportional to the dose; the effects of duloxetine and desvenlafaxine appear less severe than for venlafaxine.

Hyponatraemia may occur (see ‘General comments’ on antidepressants, above).

Selective noradrenergic reuptake inhibitors (NRIs)

These include reboxetine (see Table 13.6).

General comment

Use of reboxetine is not accompanied by weight gain.

Indications

NRIs are indicated in depressive and anxiety disorders with significant somatic/melancholic symptoms.

NRIs are activating and energising.

Mode of action

By reducing the reuptake of noradrenaline after release from pre-synaptic terminals, these medications improve the capacity of the brain to recover optimal function during depressive disorders or severe anxiety. Neurotrophic factor release is significantly enhanced.

Adverse effects

Initial insomnia may occur.

NRIs may provoke abnormal ejaculation and urinary retention in males; rarely, there is heightened genital arousal in females.

They can amplify anxiety markedly, particularly early in treatment.

Withdrawal is best achieved slowly, but is usually not uncomfortable.

Movement disorders such as restless legs syndrome, periodic limb movement disorder and bruxism may be aggravated.

Platelet adhesion and function is mildly impaired and may result in bruising and an increase in bleeding time and increased gastric bleeding.

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