Whilst a classical anti-psychotic drug should provide adequate treatment of positive symptoms including hallucinations and delusions in at least 60% of cases, patients are often left wi
Trang 1The reality is more complex since the receptor
binding profile of clozapine and the newer atypical
antipsychotic agents suggests that D2-receptor
blockade is not essential for antipsychotic effect
The atypical drugs act on numerous receptors and
modulate several interacting transmitter systems
Clozapine is a highly effective antipsychotic It has
little affinity for the D2-receptor compared with
classical drugs but binds more avidly to other
dopamine subtypes (e.g D1, D3 and D4) It blocks
muscarinic acetylcholine receptors, as do certain
classical agents (e.g thioridazine), a property which
may reduce the experience of extrapyramidal effects
Clozapine binds more readily as an antagonist at
a2-adrenoceptors than the classical drugs and also
blocks histamine and serotonin receptors (5HT2 and
others)
The newer atypical psychotropics vary widely
in their receptor binding profiles Olanzapine and
quetiapine bear resemblance to the profile of
cloza-pine in that their therapeutic effects appear to derive
from action on different receptors and transmitter
systems All atypicals (except amisulpride) exhibit
greater antagonism of 5HT2-receptors than D2
-receptors compared with the classical agents
Atypical drugs that do antagonise dopamine D2
-receptors appear to have affinity for those in the
Fig 19.3 Sagittal brain section illustrating dopaminergic pathways.
I Mesolimbic pathway (overactive in psychotic illness according to
the dopamine hypothesis of schizophrenia).VTA= ventrotegmental
area 2 Nigrostriatal pathway (involved in motor control,
underactive in Parkinson's Disease and associated with
extrapyramidal motor symptoms) 3 Tuberoinfundibular pathway
(inhibits prolactin release from the hypothalamus).
mesolimbic system (producing antipsychotic effect) rather than the nigrostriatal system (associated with unwanted motor effects) In contrast to classical antipsychotics, risperidone shares with clozapine
an ability antagonise a2-adrenoceptors, a property which may have utility in the treatment of schizo-phrenia and is seen as an area of interest for developing new drugs
PHARMACOKINETICS
Like antidepressants, antipsychotics are well absorbed and distributed after oral administration
In situations where very rapid relief of symptoms
or disturbed behaviour is required, faster uptake into plasma can be achieved through the intramus-cular route Again in common with antidepressants, antipsychotics are mainly metabolised by cyto-chrome P450 isoenzymes in the liver, e.g CYP 2D6 (zuclopenthixol, risperidone [Table 19.2a]), CYP 3A4 (sertindole [Table 19.2b]), CYP 1A2 (olanzapine, clozapine) Metabolism of some compounds is parti-cularly complex (e.g chlorpromazine, haloperidol), involving more than one main pathway, utilising several P450 enzymes or resulting in the production
of many inactive metabolites Antipsychotic plasma levels can be increased or decreased by co-prescription of drugs which are inhibitors, inducers
or substrates of the same isozyme Amisulpride is
an exception to the general rule as it is eliminated
by the kidneys without hepatic metabolism
Examples of plasma half-lives for antipsychotics include quetiapine 7 h, clozapine 12 h, haloperidol
18 h and olazapine 33 h Depot intramuscular injec-tions are available from which drug is released over 2-4 weeks
EFFICACY
Symptoms in schizophrenia are defined as positive and negative (Table 19.4) Whilst a classical
anti-psychotic drug should provide adequate treatment
of positive symptoms including hallucinations and delusions in at least 60% of cases, patients are often left with unresolved negative symptoms such as apathy, flattening of affect and alogia Evidence suggests that clozapine and the newer atypicals have a significant advantage over classical drugs against negative symptoms Clozapine has a
Trang 2A N T I P S Y C H O T I C S
further advantage over all other antipsychotics,
whether classical or atypical, in that it may be
effective when other antipsychotics prescribed at
adequate doses have failed or are not tolerated
Schizophrenia often runs a chronic relapsing and
remitting course Less than one-quarter of patients
who experience a psychotic episode and are
diag-nosed as having schizophrenia succeed in avoiding
further episodes Nevertheless, taking antipsychotics
as prophylaxis significantly reduces the likelihood
of relapse
MODE OF USE
Since the potency (therapeutic efficacy in relation
to weight) of antipsychotic agents varies markedly
between compounds, it is useful to think of the
effective antipsychotic dose of classical agents in
terms of ''chlorpromazine equivalents' (see Table 19.5).
For example, haloperidol has a relatively high
anti-psychotic potency, such that 2-3 mg is equivalent to
chlorpromazine 100 mg, whereas sulpiride 200 mg
(low potency) is required for the same antipsychotic
effect
Patients who are 'neuroleptic naive' (i.e have
never previously taken any antipsychotic agent)
should start at the lowest available dosage, such as
haloperidol 0.5 mg/day or chlorpromazine 25 mg/
day, in case the patient is particularly susceptible
to adverse effects, especially extrapyramidal motor
symptoms Conservative starting doses are also recommended in the elderly and for patients with learning disabilities who may require antipsychotics for psychosis or severe behavioural disturbance The dose can be titrated up at intervals, until the desired effect in treating psychotic symptoms, calming disturbed behaviour or effecting sedation
is achieved The interval depends on the context, with the urgency of the situation and previous use of antipsychotics being factors which would accelerate the upward titration An important issue
is that the longer a psychosis is left untreated the less favourable is the outcome; thus drug treatment should be instigated as soon as an adequate period
of assessment has allowed a provisional diagnosis
to be established
For each antipsychotic agent there is a licensed maximum dose; for example up to 1000 mg of chlorpromazine/day may be given under the United Kingdom licence Prescribing beyond the licensed maximum dose requires specialist consent When two antipsychotics are co-prescribed, the maximum antipsychotic dose should not exceed
1000 mg of chlorpromazine equivalents/day except under specialist supervision For some antipsycho-tics the licenced maximum dose is considerably less than 1000 mg of chlorpromazine equivalents/day For instance, the licenced maximum dose of
thioridazine was reduced to 600 mg/day following
concerns about its cardiovascular toxicity Note
TABLE 19.4 Symptoms of schizophrenia
Positive symptoms Negative symptoms
Hallucinations, most commonly auditory (i.e voices) in the 3rd person,
which patients may find threatening.The voices may also give
commands.Visual hallucinations are rare.
Delusions, most commonly persecutory.'Passivity phenomena'
include delusions of thought broadcasting, thought insertion
or thought withdrawal, made actions, impulses or feelings.
Bizarre behaviours including agitation, sexual disinhibition,
repetitive behaviour, wearing of striking but inappropriate
clothing.
Thought disorder manifest by failure in the organisation of speech
such that it drifts away from the point (tangentiality), never
reaches the point (circumstantiality), moves from one topic to
the next illogically (loosened associations, knight's move thinking),
breaks off abruptly only to continue on an unrelated topic (derailment)
or moves from one topic to the next on the basis of a pun or words
which sound similar (clang association).
Affective flattening manifest by unchanging facial expression
with lack of communication through expression, poor eye contact, lack of responsiveness, psychomotor slowing
Alogia (literally'absence of words' manifesting clinically as a
lack of spontaneous speech (poverty of speech).
Anhedonia (inability to derive pleasure from any activity)
and Associality (narrowing of repertoire of interests and
impaired relationships)
Apathy IAvolution involving lack of energy, lack of motivation
to work, participate in activities or initiate any goal-directed behaviour, and poor personal hygiene.
Attention problems involving an inability to focus on any
one issue or engage fully with communication.
Trang 3that plasma electrolytes and an ECG should be
checked on introducing or increasing the dose of
thioridazine and that an ECG should be seen before
prescribing pimozide and sertindole
Prescription of atypical antipsychotics follows
similar rules to those for classical drugs, starting at
low doses in neuroleptic naive patients Whereas
there is a wide range of effective doses for many
classical agents (e.g chlorpromazine 25-1000 mg/
day), much narrower ranges have been defined for
atypical agents (Table 19.5) While classical
anti-psychotics are licenced for the management of
acutely disturbed behaviour as well as for
schizo-phrenia, atypical agents are generally licenced only
for the latter indication, although that for
risperi-done is broader For most atypical agents used in
schizophrenia, a brief period of dose titration by
protocol up to a stated lowest therapeutic dose is
usual, e.g risperidone 4 mg/day, quetiapine
300 mg/day Dose increases are indicated where
there is no response after 2 weeks and these may be
repeated until the maximum licenced dose is achieved
Clozapine may be initiated only under specialist
supervision and only after two other antipsychotic
agents have failed through lack of efficacy or
adverse effects Additionally, leucocyte count
moni-toring is mandatory (danger of agranulocytosis)
and blood pressure checking is required (for
hypo-tensive effect) Patients are most vulnerable to
agranulocytosis on initiation of therapy with 75% of
cases occurring in the first 18 weeks The dose
titration schedule must be followed strictly, starting
with clozapine 12.5 mg nocte and working up over
a period of four weeks to a target therapeutic dose
of 450 mg/day
Alternative administration strategies in
acute use of antipsychotics
Some of the antipsychotics are available as
intra-muscular injections for patients who are unable or
unwilling to swallow tablets (as is common in
psychosis or severe behavioural disturbance)
Halo-peridol is most often used for these indications on
psychiatric inpatient wards (chlorpromazine i.m
being restricted due to hypotension and skin
nodule formation) Olanzapine may be given i.m
for acute behavioural disturbance in schizophrenia This drug is also presented as a Velotab' which dissolves rapidly on contact with the tongue allow-ing drug to be absorbed despite lack of cooperation from a disturbed patient
Long-acting (depot) injections
Haloperidol, zudopenthixol, fluphenazine, flupentixol
and pipothiazine are available as depot intramuscular
injections for maintenance treatment of patients with schizophrenia and other chronic psychotic disorders Provided the patient is willing to agree to have depot injections, usually by a community
psychiatric nurse at intervals of 2-4 weeks, the need
to take tablets two or three times a day is removed Poor compliance with oral medication is the most common cause of admission to hospital with a relapse of schizophrenia A reduced initial dose of the depot medication should be given, with a review for unwanted effects after 5-10 days
Rapid tranquillisation
Rapid tranquillisation protocols have been devised for patients who are severely disturbed and violent
or potentially violent and have not responded to nonpharmacological approaches The risks from administering psychotropic drugs (e.g cardiac arrhythmia with high-dose antipsychotics) may greatly outweigh the risk of leaving the patient untreated, including physical trauma and the consequences of over-stressing the cardiovascular system
A benzodiazepine, e.g lomzepam 1-2 mg i.v (into
a large vein) failing which i.m (dilute with an equal volume of water or physiological saline) is the first option if the patient is not already receiving an antipsychotic drug Patients requiring rapid tranquillisation are commonly taking antipsycho-tics for established illness and an additional anti-psychotic may then be used if the patient has not received an adequate dose; otherwise a
benzo-diazepine should given Haloperidol 2-10 mg i.m is
currently preferred for rapid tranquillisation, but new protocols may evolve with the development of atypical antipsychotics that can be given i.m When i.m antipsychotic or benzodiazepine tranquilliser is given as an emergency, pulse, blood pressure,
Trang 4A N T I P S Y C H O T I C S
temperature and respiration should be monitored,
and pulse oximetry (oxygen saturation) if
con-sciousness is lost
When at least two doses of haloperidol i.m
fail to produce the desired result, zuclopenthixol
acetate i.m is an alternative This heavily sedating
drug usually produces a calming effect within
2 h, persisting for 2-3 days if used at appropriate
dose Zuclopenthixol acetate should never be
prescribed to the neuroleptic naive Patients must
be observed with the utmost care following
admin-istration Some will require a second dose within
1-2 days
Amylobarbitone and paraldehyde have a role in
emergencies when antipsychotic and benzodiazepine
options have been exhausted
ADVERSE EFFECTS (see Table 19.5)
Active psychotic illnesses often cause patients to
have poor insight into their condition; unwanted
drug effects can compromise already fragile
com-pliance and lead to avoidable relapse
Classical antipsychotics
It is rare for any patient taking classical
anti-psychotic agents completely to escape their adverse
effects Thus it is essential to discuss with patients
the possibility of unwanted effects and regularly to
review this aspect of their care
Extrapyramidal symptoms All classical
anti-psychotics are capable of producing these effects
because they act by blocking dopamine receptors in
the nigrostriatal pathway The result is that some
75% of patients experience extrapyramidal symptoms
which may appear shortly after starting the drug or
increasing its dose (acute effects), or some time after
a particular dose level has been established (tardive
effects, see p 387)
Acute extrapyramidal symptoms Dystonias are
manifest as abnormal movements of the tongue
and facial muscles with fixed postures and spasm,
including torticollis and bizarre eye movements
('oculogyric crisis') Parkinsonian symptoms result
in the classical triad of bradykinesia, rigidity and
tremor Both dystonias and parkinsonian symptoms
are believed to result from a shift in favour of cholinergic rather than dopaminergic neurotrans-mission in the nigrostriatal pathway (see p 422) Anticholinergic agents, e.g procyclidine, orphe-nadrine or benztropine, restore the balance in fav-our of dopaminergic transmission but are liable to provoke antimuscarinic effects (dry mouth, urine retention, constipation, exacerbation of glaucoma and confusion) and they offer no relief for tardive dyskinesia, which may even worsen They should
be used only in response to clear dystonic or parkinsonian symptoms rather than for prophyl-axis Benzodiazepines, with their general inhibitory
effects, are an alternative Thioridazine and related
Type 2 phenothiazines are less likely to provoke extrapyramidal effects as they also block cholinergic transmission (but patients may suffer antimusca-rinic effects) Note that confusion from anticholiner-gic effects may mimic or complicate schizophrenic thought disorder
Akathisia is a state of motor and psychological
restlessness, in which patients exhibit persistent foot tapping, moving of legs repetitively and being unable to settle or relax A strong association has been noted between its presence in treated schizo-phrenics and subsequent suicide A (3-adrenoceptor blocker is the best treatment, although anticholiner-gic agents may be effective where akathisia coexists with dystonias and parkinsonian symptoms Differ-entiating symptoms of psychotic illness from adverse drug effects is often difficult: drug-induced akathisia may be mistaken for agitation induced by psychosis
Tardive dyskinesia affects about 25% of patients
taking classical antipsychotic drugs, the risk increasing with length of exposure It was formerly thought to be a consequence of up-regulation or supersensitivity of dopamine receptors A preferred explanation is that tardive dyskinesia is a conse-quence of oxidative damage after neuroleptic-induced increases in glutamate transmission Patients display a spectrum of abnormal movements from minor tongue protusion, lip-smacking, rotational tongue movements and facial grimacing, choreo-athetoid movements of the head and neck and even
to twisting and gyrating of the whole body It is less likely to remit on stopping the causative agent than
Trang 5TABLE 19.5 Relative frequency of selected adverse effects of antipsychotic drugs
Drug
Classical
Chlorpromazine
Thioridazine
Trifluoperazine
Haloperidol
Sulpiride
Zuclopenthixol
Atypical
Clozapine**
Olanzapine
Quetiapine
Risperidone
Amisulpride
CPZ Equiv Dose
100mg
50 mg 5mg
3 mg
200 mg
25 mg Min eff.
dose (/day)
300 mg 5-1 0 mg
300 mg 4mg
800 mg
Max dose (/day)
1 000 mg
300 mg*
50 mg
30 mg
2400 mg 150mg
Max dose (/day)
900 mg
20 mg
750 mg I6mg
1 200 mg
Structure
Type 1 Phenothiazine Type 2 Phenothiazine Type 3 Phenothiazine Butyrophenone Substituted benzamide Thioxanthene
Dibenzodiazepine Theinobenzodiazepine Dibenzothiazepine Benzisoxazole Substituted benzamide
++
+
+++
+++
+
++
++
+++
+ + +
++
+++
+++
+++
+++
+++
+++
++
+++
++
++
+
++
+
+++
+ + +
+ + + + + +
+++ +++
+ +
++
+ +
+++
++
+ + +
++
++
+++
+++
+ + +
+ + + +
+++ ++ +++
+
Key: CPZ equiv dose = Chlorpromazine equivalent dose.This concept is of value in comparing the potency of classical antipsychotics Dose ranges are not specified as they are extremely wide and drugs are normally titrated up from low starting doses (e.g Chlorpromazine 25 mg
or equivalent) until an adequate antipsychotic effect is achieved or the maximum dose reached.The Chlorpromazine equivalent dose concept is of less value for atypical antipsychotics since minimum effective doses (Min eff dose) and narrower therapeutic ranges have been defined Maximum dose (Max dose) can be exceeded only under specialist supervision.
* The maximum recommended dose of thioradazine was reduced to 300 mg/day (or 600 mg/day in hospitalised patients) following concerns about QT prolongation and risk of fatal cardiac arrhythmias at higher doses.
** A dose of clozapine 50 mg is considered equivalent to Chlorpromazine 100 mg.
1f Lower doses of amisulpride (e.g 100 mg/day) are indicated for patients with negative symptoms of schizophrenia only.
are simple dystonias and parkinsonian symptoms
Any anticholinergic agent should be withdrawn
immediately Reduction of the dose of classical
anti-psychotic is often advised but anti-psychotic symptoms
may then worsen or be 'unmasked' Alternatively,
an atypical antipsychotic can provide rapid
improvement whilst retaining control of psychotic
symptoms
Atypical drugs, particularly at high doses, can
yet cause extrapyramidal effects and this strategy
is not always helpful If the classical antipsychotic
is simply continued, tardive dyskinesia remits
spontaneously in around 30% of patients within a
year but since the condition is difficult to tolerate,
patients may be keen to try other medications, even
where evidence suggests that the success rates for
remission are limited These include vitamin E,
benzodiazepines, (3-blockers, bromocriptine and
tetrabenazine Clozapine, which does not appear to cause tardive dyskinesia, may be used in severe cases where continuing antipsychotic treatment is required and symptoms have not responded to other medication strategies
Cardiovascular effects Postural hypotension may result from blockade of oc-adrenoceptors; it is dose-related Prolongation of the QT interval in the cardiac cycle may rarely lead to ventricular arrhyth-mias and sudden death (but particular warnings and constraints apply to the use of thioridazine and pimozide)
Prolactin elevation Classical antipsychotics raise plasma prolactin concentrations by their blocking action on dopamine receptors in the tuberoinfundi-bular pathway (Fig 19.3 and p 711) and can cause
Trang 6A N T I P S Y C H O T I C S
gynaecomastia and galactorrhoea in both sexes, and
menstrual disturbances A change to an atypical
agent such as quetiapine or olanzapine (but not
risperidone or amisulpride) should minimise these
effects If continuation of the existing classical
antipsychotic is obligatory, a dopamine agonist
such as bromocriptine or amantadine may be
beneficial
Sedation In the acute treatment of psychotic
illness this may be a highly desirable property but it
may be unwelcome as the patient seeks to resume
work, study or relationships
Classical antipsychotics may also be associated
with:
• weight gain (a problem with almost all classical
antipsychotics with the exception of loxapine,
most pronounced with fluphenazine and
flupentixol)
• seizures (chlorpromazine and thioridazine are
especially likely to lower the convulsion threshold)
• interference with temperature regulation
(hypothermia or hyperthermia, especially in the
elderly)
• skin problems (phenothiazines, particularly
chlorpromazine, may provoke photosensitivity
necessitating advice about limiting exposure to
sunlight Rashes and urticaria may also occur)
• sexual dysfunction (ejaculatory problems through
a-adrenoceptor blockade)
• retinal pigmentation (chlorpromazine, thioridazine,
vision is affected if dose is prolonged and high)
• corneal and lens opacities
• blood dyscmsias (agranulocytosis and leucopenia)
• osteoporosis (associated with prolactin elevation)
• jaundice (including cholestatic).
Atypical antipsychotics
Atypical drugs can provoke a range of adverse
effects that is similar to that of the classical
anti-psychotics but is generally lesser in degree (with
exceptions) The following are the main differences
Atypical antpipsychotics provoke fewer
extra-pyramidal effects (less blockade of dopamine D2
-receptors in the nigrostriatal pathway)
Neverthe-less, extrapyramidal effects are seen, notably with
high dose of risperidone (8-12 mg per day) and
olanzapine (> 20 mg/day)
Clozapine and olanzapine are the most likely of
the atypical agents to cause anticholinergic
(anti-muscarinic) effects They are more likely than other
atypicals to cause weight gain (glucose tolerance
may be impaired and should be monitored in susceptible individuals) and are second only to
quetiapine in their sedative effects Sexual dysfunction
and skin problems are rare with atypical anti-psychotics Risperidone and amisulpride are as likely as classical antipsychotics to raise prolactin
concentrations and cause galactorrhoea.
Clozapine warrants further mention, given its
value for patients with treatment-resistant schizo-phrenia or severe treatment-related extrapyramidal symptoms It may cause postural hypotension and tachycardia, and provoke seizures in 3-5% of patients at doses above 600 mg/day Most important
is the risk of agranulocytosis in up to 2% of patients
(compared with 0.2% in classical antipsychotics) When clozapine was first licenced without require-ments for regular white count monitoring, the haematological problems caused appreciable morta-lity Thanks to strict monitoring, there have been no recorded deaths from agranulocytosis since clozapine was reintroduced in the United Kingdom, and internationally the death rate among the small minority who develop agranulocytosis is now less than 1 in 1000
Neuroleptic malignant syndrome
The syndrome may develop in up to 1% of patients using antipsychotics and is more prevalent at high doses The elderly, and those with organic brain disease, hyperthyroidism or dehydration are thought to be most susceptible Clinical features include:
• fever
• confusion or fluctuating consciousness
• rigidity of muscles which may become severe
• autonomic instability manifest by labile blood pressure
• tachycardia
• urinary incontinence or retention
Raised plasma creatine kinase concentration and white cell count are suggestive (but not conclusive)
of neuroleptic malignant syndrome There is some clinical overlap with the 'serotonin syndrome' (see
Trang 7p 376) and concomitant use of SSRI antidepressants
(or possibly TCAs) with antipsychotics may increase
risk
It is essential to discontinue the antipsychotic
when the syndrome is suspected and to be ready to
transfer the patient to a medical ward for
rehydra-tion Benzodiazepines are indicated for sedation
and their transquillising effect may be useful where
active psychosis has to be left untreated Dopamine
agonists (bromocriptine, dantrolene) are beneficial
in some cases There is also evidence to support
a role for electroconvulsive therapy in treatment
of neuroleptic malignant syndrome Even when
recognised and treated, the condition carries a
mortality of 12-15%, through cardiac arrhythmia,
rhabdomyolysis or respiratory failure The condition
usually lasts for 5-7 days after the antipsychotic
is stopped but may continue longer when a depot
preparation has been used Fortunately those who
survive tend to have no long lasting physical effects
from their ordeal
CLASSICAL VERSUS ATYPICAL
ANTIPSYCHOTICS
As atypical antipsychotics have become established
as alternatives to classical agents, clinicians are
presented with the dilemma as to which should be
their first choice in patients with schizophrenia and
psychotic illnesses, and indeed whether there is
sufficient justification to transfer a patient stabilised
on a classical agent over to an atypical
Atypical antipsychotics may have advantages in
three areas First, they appear to be better tolerated,2
in particular being less likely than classical agents
to induce extrapyramidal effects and
hyperprolac-2 Whilst the advantages of atypicals over classical
antipsychotics may seem clear cut, one analysis using only
trials where doses of classical antipsychotics were at or
below a dose of haloperidol 12 mg/day or equivalent (now
regarded as the upper limit for optimised use of these
agents) produced rather different results Although the
atypicals retained their advantage in causing extrapyramidal
side effects less frequently, overall tolerability and efficacy
appeared to be similar Geddes J et al 2000 Atypical
antipsychotics in the treatment of schizophrenia: systematic
overview and meta-regression analysis British Medical
Journal 321: 1371-1376.
tinaemia (with gynaecomastia and galactorrhoea), although these latter remain common with risperi-done and amisulpride Improved tolerance is reflected
in better compliance with taking atypical agents, so lessening the chance of psychosis being untreated with the likelihood of relapse once remission has been achieved Secondly, atypical antipsychotics are more efficacious against the negative symptoms of schizophrenia which are particularly debilitating in chronic illness
Thirdly, clozapine (but not the newer atypicals)
is more effective than classical agents for resistant schizophrenia
Atypical antipsychotics are significantly more expensive than classical drugs In some countries this will be the overriding argument for retaining classical agents as first choice drugs in schizoph-renia Additionally, if a patient is successfully main-tained on a classical antipsychotic, transfer to an atypical agent is difficult to justify Where a classical antipsychotic is not achieving optimal results or causes unwanted effects, a more persuasive case for change to an atypical can be made
But economic analysis must take into account factors beyond the crude cost of drugs If atypical antipsychotics truly cause fewer distressing extra-pyramidal symptoms and improve compliance, they may prevent relapse of psychotic illness and protect patients against lasting damage from periods of untreated psychosis Greater effective-ness in treating negative symptoms would afford patients with schizophrenia more opportunity of re-integrating into the community and to make positive contributions to society rather than the alternative of long-term institutionalisation Such factors alleviate the cost burden of psychotic illness
on society, and must form part of the overall accounting between classical and atypical drugs as first line treatment
Mood stabilisers
In bipolar affective disorder patients suffer episodes
of mania, hypomania and depression, classically
with periods of normal mood in between Manic
episodes involve greatly elevated mood, often
interspersed with periods of irritability or undue
Trang 8M O O D S T A B I L I S E R S
11
excitement, accompanied by biological symptoms
(increased energy, restlessness, decreased need for
sleep, increased sex drive), loss of social inhibitions,
irresponsible behaviour and grandiosity Psychotic
features may be present, particularly disordered
thinking manifested by grandiose delusions and
'flight of ideas' (acceleration of the pattern of
thought with rapid speech) Hypomania is a less
dramatic and dangerous presentation but retains
the features of elation or irritability and the
biolo-gical symptoms, abnormalities in speech being
limited to increased talkativeness and in social
conduct to overfamiliarity and mild recklessness
Depressive episodes may include any of the
depres-sive symptoms described before and may include
psychotic features
Lithium salts were known anecdotally to have
beneficial psychotropic effects as long ago as the
middle of the 19th century but scientific evidence
of their efficacy followed a serendipitous discovery
In 1949, during a search for biologically active
substances in mania, urine from manic patients was
injected into guinea pigs The animals appeared to
be affected by the accompanying large amounts of
urea and it was postulated that administration
of urate would exacerbate manic effects Lithium
urate, which is highly soluble, was selected to
conduct investigations into urate toxicity It was
found to be sedative and to protect against manic
urine toxicity Lithium carbonate was tried in manic
patients, was found to be effective in the acute state
and, later, to prevent recurrent attacks.3
Lithium salts are ineffective for prophylaxis of
bipolar affective disorder in around 35% of patients
and cause several unwanted effects The search
for alternatives has produced drugs that are more
familiar as anticonvulsants, notably carbamazepine
and sodium valproate, and possibly lamotrigine
LITHIUM
The mode of action is not fully understood The
main effect of lithium is probably to inhibit
hydro-lysis of inositol phosphate, so reducing the recycling
of free inositol for synthesis of
phosphatidylino-3 Cade J F 1970 The story of lithium In: Ayd F J, Blackwell B
(eds) Biological psychiatry Lippincott, Philadelphia.
sitides These intracellular molecules are part of the transmembrane signalling system that is important
in regulating intracellullar calcium ion concentra-tion, which subsequently affects neurotransmitter release Other putative mechanisms involve the cyclic AMP 'second messenger' system and mono-aminergic and cholinergic neurotransmitters
Pharmacokinetics Knowledge of pharmacokinetics
of lithium is important for successful use since the therapeutic plasma concentration is close to the toxic concentration (low therapeutic index) Lithium
is a small ion that, given orally, is rapidly absorbed throughout the gut High peak plasma concentra-tions are avoided by using sustained-release formu-lations which deliver the peak plasma lithium concentrations in about 5 h At first lithium is distributed throughout the extracellular water but with continued administration it enters the cells and is eventually distributed throughout the total body water with a somewhat higher concentration
in brain, bones and thyroid gland The apparent volume of distribution is about 50 1 in a 70 kg person (whose total body water is about 40 1) which
is compatible with the above Lithium is easily dialysable from the blood but the concentration gradient from cell to blood is not great and the intracellular concentration (which determines toxi-city) falls slowly Lithium enters cells about as readily as does sodium but does not leave as readily (mechanism uncertain) Being a metallic ion it is not metabolised, nor is it bound to plasma proteins Only the kidneys eliminate lithium Like sodium,
it is filtered by the glomerulus and 80% is reabsorbed
by the proximal tubule but it is not reabsorbed by the distal tubule Intake of sodium and water are the principal determinants of its elimination In sodium deficiency lithium is retained in the body, thus concomitant use of a diuretic can reduce lithium clearance by as much as 50% and precipitate toxi-city Sodium chloride and water are used to treat lithium toxicity
With chronic use the plasma t l / 2 of lithium is 15-30 h Lithium is usually given 12-hourly to avoid unnecessary fluctuation (peak and trough concentrations) and maintain a plasma concentra-tion just below the toxic level A steady-state plasma concentration will be attained after about
5-6 days (i.e 5 x t l / 2 ) in patients with normal renal
389
Trang 9function Old people and patients with impaired
renal function will have a longer tl / 2 so that steady
state will be reached later and dose increments
must be adjusted accordingly
Indications and use Lithium carbonate is effective
treatment in > 75% of episodes of acute mania or
hypomania Because its therapeutic action takes 2-3
weeks to develop, lithium is generally used in
com-bination with a benzodiazepine such as lorazepam
or diazepam (or with an antipsychotic agent where
there are also psychotic features)
For prophylaxis, lithium is indicated when there
have been two episodes of mood disturbance in
two years, although in some cases it is advisable
to continue with prophylactic use after one severe
episode When an adequate dose of lithium is
taken consistently, around 65% of patients achieve
improved control of their illness
Patients who start lithium only to discontinue
it within two years have a significantly poorer
outcome than matched patients who are not given
any pharmacological prophylaxis The existence of
this 'rebound effect' dictates that persistence with
long-term treatment is of great importance
Lithium is also used to augment the action of
antidepressants in treatment-resistant depression
(see p 375)
Pharmaceutics It is important for any patient to
adhere to the same pharmaceutical brand, as the dose
of lithium ion (Li+) delivered by each tablet depends
on the pharmaceutical preparation For example,
each Camcolit 250 mg tablet contains 6.8 mmol, each
Liskonium 450 mg tablet contains 12.2 mmol and
each Priadel 200 mg tablet contains 5.4 mmol of Li+
Thus the proprietary name must be stated on the
prescription Some patients cannot tolerate
slow-release preparations because slow-release of lithium ions
distally in the intestine causes diarrhoea; they may
be better served by the liquid preparation, lithium
citrate, which is absorbed proximally Patients who
are naive to lithium should be started at the lowest
dose of the preparation selected Any change in
preparation demands the same precautions as does
initiation of therapy
Monitoring The difference between therapeutic
and toxic doses is narrow and therapy must be
guided by monitoring of the plasma concentration once a steady state is reached Increments are made at weekly intervals until the concentration lies within the required range of 0.4-1 mmol/1 (maintenance at the lower level is preferred for elderly patients) The timing of blood sampling is important By convention a blood sample is taken prior to the morning dose, as close as possible to
12 h after the evening dose When the therapeutic range is reached, the plasma concentration should
be checked every three months Likewise, for toxicity monitoring, thyroid function (especially in women) and renal function (plasma creatinine and electrolytes) should be measured before initiation and every 3 months during therapy
Patient education about the role of lithium in
the prophylaxis of bipolar affective disorder and discussion of the pros and cons of taking the drug are particularly important to encourage compliance with therapy; treatment cards, information leaflets and where appropriate, video material are used
Adverse effects Lithium is associated with three categories of adverse effects
• Those experienced at plasma concentrations
within the therapeutic range (see above) include
fine tremor (especially involving the fingers; if this is difficult to tolerate a (3-blocker may benefit), constipation, polyuria and polydipsia (due to loss of concentrating ability by the distal renal tubules), metallic taste in the mouth, weight gain, oedema, goitre, hypothyroidism, acne, rash, diabetes insipidus and cardiac arrhythmias There can also be mild cognitive and memory impairment
• Signs of intoxication, associated with plasma
concentrations greater than 1.5 mmol/1 are mainly gastrointestinal (diarrhoea, anorexia, vomiting) and neurological (blurred vision, muscle weakness, drowsiness, sluggishness and coarse tremor, leading on to giddiness, ataxia and dysarthria)
• Frank toxicity, due to severe overdosage or rapid
reduction in renal clearance, usually associated with plasma concentration greater than
2 mmol/1, constitutes an acute medical emergency Hyperreflexia, hyperextension of
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Trang 10limbs, convulsions, toxic psychoses, syncope,
oliguria, coma and even death may result if
treatment is not instigated urgently
Overdose is treated by use of i.v fluid to maintain
a good urine output guided by frequent
measure-ment of plasma electrolytes and osmolality
Hyper-natraemia indicates probable diabetes insipidus
and isotonic dextrose should then be used until
plasma sodium concentration and osmolality become
normal Isotonic saline forms part of the fluid
regimen (but overuse may result in
hypernatrae-mia) and potassium supplement will be required
Haemodialysis is effective but may have to be
repeated frequently as plasma concentration rises
after acute reduction (due to equilibration as lithium
leaves cells and also by continued absorption from
sustained-release formulations)
Interactions Several types of drug interfere with
lithium excretion by the renal tubules, causing
the plasma concentration to rise These include
diuretics (thiazides more than loop type), ACE
inhibitors and angiotensin-11 antagonists, and
non-steroidal anti-inflammatory analgesics Theophylline
and sodium-containing antacids reduce plasma
lithium concentration The effects can be important
because lithium has such a low therapeutic ratio
Diltiazem, verapamil, carbamazepine and
pheny-toin may cause neurotoxicity without affecting the
plasma lithium Concomitant use of thioridazine
should be avoided as ventricular arrhythmias may
result
Carbamazepine
Carbamazepine is licenced as an alternative to
lithium for prophylaxis of bipolar affective
dis-order, although clinical trial evidence is actually
stronger to support its use in the treatment of acute
mania Carbamazepine appears to be more effective
than lithium for rapidly cycling bipolar disorders,
i.e with recurrent swift transitions from mania to
depression It is also effective in combination with
lithium Its mode of action is thought to involve
agonism of inhibitory GABA transmission at the
GABA-benzodiazepine receptor complex (see also
Epilepsy, p 417)
M O O D S T A B I L I S E R S
Valproic acid
Valproic acid is the drug of first choice for prophylaxis of bipolar affective disorder in the United States, despite the lack of robust clinical trial evidence in support of this indication But treat-ment with valproic acid is easy to initiate (especially compared to lithium), it is well tolerated and its use appears likely to extend if the evidence-base
expands As the semisodium salt, valproic acid is
licenced for use in the treatment of acute mania
unresponsive to lithium (Note: sodium valproate, see
p 420, is unlicenced for this indication.) Treatment with carbamazepine or valproic acid appears not to be associated with the 'rebound effect' of relapse into manic symptoms that may accompany early withdrawal of lithium therapy
Other drugs
Evidence is emerging regarding the efficacy of lamotrigine in prophylaxis of bipolar affective disorder and treatment of bipolar depression Other drugs which have been used in augmentation of existing agents include the anticonvulsant gaba-pentin, the benzodiazepine clonazepam, and the calcium channel blocking agents verapamil and nimodipine
Drugs used in anxiety and sleep disorders
The disability and health costs caused by anxiety disorders are comparable to those of other common medical conditions such as diabetes, arthritis or hypertension People with anxiety disorders expe-rience impaired physical and role functioning, more work days lost due to illness, increased impairment
at work and high use of health services Our under-standing of the nature of anxiety has increased greatly from advances in research in psychology and neuroscience It is now possible to distinguish different types of anxiety with distinct biological and cognitive symptoms Clear criteria have been accepted for the diagnosis of various anxiety disorders The last decade has seen developments
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