Pharmacogenomics: can we predict response to antipsychotics?
Using a genomic approach to prescribing is advantageous
for economic and clinical reasons. If it were possible to predict a potential
response to treatment there would be fewer clinic visits and less switching
between different agents.
Severe adverse effects and low compliance complicate
drug treatment of psychiatric disorders: furthermore, up to 30 per cent
of patients fail to respond to antipsychotic treatment. Pharmacogenomic
research in psychiatry aims to elucidate the reasons for treatment failure
and adverse reactions that may occur. Based on a genetic test, treatments
could potentially be individualised for particular patients. Professor
Robert Kerwin, Institute of Psychiatry, told the conference: "We could
predict which patients would respond to a particular drug, and identify
treatment resistance much earlier."
Clozapine, the only effective drug for treatment-resistant
schizophrenia, has a response rate of around 60 per cent. We already have
data for the binding affinities of clozapine for a range of different
receptors, including dopamine (D) and serotonin (5-HT). By considering
the genetic variations at each receptor, ie, which allele (gene variant)
is present, and variations in response in those patients, we can identify
genetic factors necessary for successful treatment with clozapine. Results
from blood tests on 300 clozapine patients indicate that response can
be predicted by the combination of polymorphisms in four genes within
key receptors such as 5-HT2a and 5-HT2c. This method
would be successful in 78 per cent of cases — particularly females.
Similar results have been obtained with olanzapine
with broadly similar genes predicting clinical response, although differences
do exist. As with many antipsychotics, the most important receptors here
are the dopamine D3 and 5-HT receptors.
The technique already represents a useful drug discovery
tool, allowing follow-up drugs to be designed more effectively. The next
step will be prospective patient testing — with exciting implications
for the commercial sector.
Other studies have investigated whether genetic
variations in cytochrome P (CYP) 450 metabolising enzymes can influence
the therapeutic efficacy and tolerability of antipsychotic and antidepressant
drugs. Results indicate that polymorphisms here cannot fully account for
differences in patient response, but might contribute to explaining why
adverse drug reactions occur. For example, CYP2D6 and CYP1A2 are associated
with tardive dyskinesia and other drug-induced movement disorders, although
the effect is small. Genetic variations in metabolising enzymes may therefore
be important for dose adjustments and in the prevention of side effects,
thus providing another step towards the individualisation of psychotropic
treatment.
Glutamate in schizophrenia
A considerable body of evidence indicates that glutamic
acid is involved in schizophrenia, Professor Peter Redfern, Bath University,
told the conference. Glutamic acid is an excitatory amino acid synthesised
from glucose or glutamine, with all the characteristics of a classical
neurotransmitter. It acts on two main types of receptor: those linked
to ion channels (ionotropic) and second messenger cascades (metabotropic).
Stimulation of a key ionotropic receptor, NMDA, leads to long-term potentiation,
an essential element in the process of laying down memories, with over-stimulation
leading to cell death.
Evidence for the involvement of glutamic acid in
schizophrenia used to depend on observations of drug pharmacology. Ketamine
and phencyclidine are psychotomimetic, capable of inducing hallucinations,
cognitive disturbances, agitation and paranoia, as well as negative symptoms.
They are non-competitive antagonists at NMDA receptors. There is also
evidence from brain imaging studies and post-mortem neurochemistry to
suggest that glutamate function is decreased in schizophrenia, eg, decreased
levels of glutamine and NMDA receptors. However, it is unclear whether
the observed changes are causative or secondary to disease or drug treatment.
This evidence adds to, rather than replaces, the
dopamine hypothesis of schizophrenia. Schizophrenia can be seen as an
imbalance between dopamine hyperactivity and glutamate hypoactivity. Complex
interactions exist between the two, with glutamate stimulating the release
of dopamine from nerve terminals and dopamine inhibiting glutamate release.
One version of this hypothesis is that this imbalance affects the "thalamic
filter". Sensory input is normally filtered at the thalamic level, with
only a fraction of it passed on to the cerebral cortex. If the filter
becomes less efficient, via increased dopamine inhibition or reduced glutamate
excitation, the cerebral cortex becomes overloaded with sensory information,
resulting in hallucinations and possible cognitive impairment.
Symptoms of schizophrenia should theoretically be
reduced by activating the glutamate NMDA receptors. Their direct stimulation
is not viable due to their wide distribution in the central nervous system
and the dangers of excitotoxicity. However, NMDA activity could be modified
by increasing the availability of necessary co-factors such as glycine.
Although not the case with clozapine, negative symptoms in refractory
schizophrenia have been improved by the addition of glycine to existing
medication.
More recently, attention has turned to the prefrontal
cortex, an area in which blockade of NMDA receptors with phencyclidine
leads to increased glutamate release. According to this hypothesis, schizophrenia
is still seen as an imbalance between dopamine and glutamine, but one
which occurs between neurones innervating pyramidal cells in the cortex.
Pharmacological strategies to decrease glutamate release or block post-synaptic
non-NMDA receptors could prove useful as antipsychotics. In addition,
upward modulation of NMDA receptors might improve the response to conventional
antipsychotic medication.
Early interventions
Schizophrenia often progresses to a chronic form
of the illness, involving "deficit" features such as affective flattening,
anhedonia and cognitive impairment, with around 25 per cent of patients
becoming treatment-resistant. It has been shown that the long-term chronic
form of the illness becomes more likely as the duration of untreated psychosis
increases. The perception is that the earlier the treatment, the shorter
the duration of untreated psychosis and the better the prognosis, said
Dr Mike Launer (Burnley NHS Trust). But how early can patients actually
be treated in practice?
First-episode patients have been shown to have already
been symptomatic for around three years before presenting for treatment.
It has been suggested that the three years immediately preceding a psychotic
episode are important, providing a period of time in which psychological
interventions could be particularly effective. The possibility therefore
exists for prophylactic treatment to begin even before the first psychotic
episode occurs if vulnerable individuals could be identified.
Evidence exists for an early prodromal phase of
the illness, which may be identified before symptoms have progressed to
a diagnosable psychotic illness. Studies have shown that childhood traits
such as gloomy, timid or isolative behaviour could serve as markers for
the illness. Rating scales have been devised that attempt to identify
pre-emptive psychotic symptoms and lead to early psychiatric referral.
Others have used tools such as magnetic resonance imaging together with
studies of childhood development and psychopathology to predict and treat
potentially psychotic patients using risperidone or cognitive behavioural
therapy. Although some cases could be prevented in this way, a significant
proportion could not. Furthermore, this type of approach would inevitably
result in significant numbers being treated unnecessarily — particularly
controversial in the case of a drug intervention.
The whole concept of the prodrome is still highly
under-researched but could provide the key to effective early intervention
in psychosis. Currently, however, the best approach to prevent chronic
forms of the illness is aggressive treatment of first-episodes of psychosis
and recognising treatment-resistance as early as possible, so that agents
such as clozapine can be used to their best advantage.
Child and adolescent psychiatry
Paediatric psychopharmacology promises to offer
exciting developments in the treatment of child mental health problems
over the next decade, said Professor Chris Hollis, University of Nottingham.
Yet many disagree with the use of psychotropics in children, raising arguments
such as the lack of evidence in children, potential risks to the developing
brain and the inhibition of normal psychological development.
Methylphenidate, a CNS stimulant, is the most commonly
prescribed medication in child and adolescent psychiatric practice, licensed
for the treatment of attention deficit hyperactivity disorder (ADHD).
Other drugs routinely prescribed include dexamphetamine, also licensed
for the treatment of ADHD. Trial evidence exists for the use of imipramine,
clonidine and amfebutamone (bupropion) with less evidence for moclobemide,
venlafaxine, fluoxetine and risperidone. Other drugs of importance in
child psychiatry include clonidine in Tourette's syndrome, selective serotonin
reuptake inhibitors in depression, obsessive-compulsive disorder and anxiety
disorders, and atypical antipsychotics for early-onset psychosis.
Methylphenidate is a highly effective treatment
in around 70 per cent of patients with ADHD, with three times daily dosing
more effective than twice daily. The rigorous MTA trial of 600 patients
in the United States confirmed that the medicine is more effective than
behavioural treatments. Stimulants were first shown to be effective for
hyperactivity in the 1930s and there are now over 70 positive randomised
controlled trials (RCTs) for their use. Prescriptions for methylphenidate
(Ritalin) have increased from 14,700 in 1995 to 158,000 in 1999. Despite
this, the National Institute of Clinical Excellence (NICE) suggests that
the drug is vastly underused. Two-thirds of the 73,000 six- to 16-year-olds
with severe hyperactivity in England and Wales still do not receive methylphenidate.
NICE recommends that methylphenidate should be used as part of a comprehensive
treatment programme for ADHD patients. Although treatment should be initiated
by an ADHD specialist, prescribing and monitoring can be continued by
the GP under a shared care protocol.
Professor Hollis predicted that drug use in child
psychiatry will increase dramatically, with benefits vastly outweighing
the risks of treatment. The evidence base needs to be strengthened, as
many drugs still have to be prescribed off-licence, some on anecdotal
evidence only. Better training is needed for clinicians and pharmacists
in this specialist area and specialist pharmacists can make vital contributions
to informed decision making in this area.
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