By Robert W. Buchanan, MD
[Fall 2007; Vol. 34, No. 1; Pg 4, 10-11]
Over
the past decade, the recovery movement has generated a growing appreciation of
the need to improve the treatment of people with schizophrenia.
It emphasized that we need to move the focus of therapeutic interventions
beyond the treatment of positive symptoms,
to enhance social and vocational functional role performance and
outcomes.
There are multiple definitions of “recovery”.
They range from an emphasis on symptom amelioration and normative
adaptation and functioning in the community to a focus on the “process” of
recovery.
Its interventions impact upon not only external indicators of recovery,
such as occupational functioning, but also enhance the sense of hope,
autonomy/empowerment, and adaptation to the illness of the person with
schizophrenia.
There
are a number of roadblocks to the path of recovery. One is the lack of effective
interventions for many of the primary and secondary problems that afflict people
with schizophrenia.
Over the past 50 years, the major emphasis of drug development has been
on “positive” psychotic symptoms, which has led to the development of a
number of antipsychotic drugs with largely overlapping efficacy profiles.
They tend to be moderately effective for positive symptoms, but have
limited effects on negative symptoms and cognitive impairments.
These limitations are critically important, because positive symptoms
have little long-term impact on functional outcomes.
The Maryland Psychiatric Research Center has spent the last 30 years
dedicated to the development of novel pharmacological treatments for not only
positive psychotic symptoms, but also for the primary determinants of poor
functional outcome: persistent negative symptoms and cognitive impairments, (as
well as
co-occurring medical and psychiatric conditions).
The
following is a brief summary of some of our recent efforts to help develop
better treatments..
Although conventional antipsychotics (e.g. fluphenazine , haloperidol
and perphenazine)
and second generation antipsychotics (e.g. risperidone , olanzapine ,quetiapine
, ziprasidone , and aripiprazole)
are equally effective in the treatment of positive symptoms in
treatment-responsive people, there are few options for those who fail to
respond.
In fact, only clozapine has been shown to be effective in people with
treatment-resistant positive symptoms, an observation that was recently
replicated in the CATIE study.
The question that arises is,”What about the 40 – 60% of people who
fail to adequately respond to clozapine?”
The most common practice is to add a second antipsychotic-- a practice
for which there is little evidence.
We are currently in the last year of the largest study ever designed to
evaluate the efficacy and safety of adding risperidone to clozapine in those
people who have not had an adequate response to clozapine alone.
The study will be the largest one yet.
Many
studies have demonstrated the critical relationship between persistent (or
enduring) negative symptoms and cognitive impairments, and poor social and
vocational role outcome and performance.
We designed a series of investigations to evaluate various
pharmacological approaches for the treatment of persistent negative symptoms. A
number of studies in inpatients and outpatients with schizophrenia have shown
that neither clozapine nor olanzapine is effective for these symptoms.
Rather, we believe the benefit of these drugs for negative symptoms is
limited to their beneficial effect on depressive or extrapyramidal signs. We
examined the efficacy of two drugs, D-cycloserine and glycine, which enhance
glutamatergic function and have been shown in small pilot studies to improve
negative symptoms when added to antipsychotics.
In the largest study to date, we found that these agents had limited
effectiveness for persistent negative symptoms.
The
results of these and other studies have clearly demonstrated the limitations of
currently available treatments, including second generation antipsychotics, and
have led to ongoing NIMH
support for an
investigation of alternative approaches to the treatment of negative
symptoms.
Although we continue to be interested in glutamatergic mechanisms, we are
currently assessing the efficacy of rasagiline, a selective MAO-B inhibitor.
It is hypothesized that decreased dopamine in the prefrontal cortex plays
a role in the pathophysiology of negative symptoms. The central role that the
MAO-B enzyme plays in the deactivation of the dopamine signal in the prefrontal
cortex may be important, too.
Cognitive
impairments play a major role in determining functional outcome.
People with schizophrenia often have a broad range of cognitive
impairments, including abnormalities of attention/information processing,
problem-solving, processing speed, verbal and visual learning and memory, and
working memory. Despite appropriate treatment, many people with schizophrenia
continue to exhibit pronounced cognitive impairments, which has led to the
investigation of adjunctive co-therapy of these impairments.
In particular, we have been interested in the potential benefit of drugs
that act through the cholinergic system.
We have conducted a series of studies that have demonstrated that acute
nicotine is effective in reversing eye-tracking, sensory gating and visual
memory impairments in people with schizophrenia.
We have recently completed a large randomized clinical trial of
adjunctive galantamine, an acetylcholinesterase inhibitor and allosteric
modulator of nicotinic receptors.
We found that it had selective benefits for processing speed and verbal
memory-- both cognitive processes linked to functional outcome.
We have also been involved in NIMH- sponsored efforts to facilitate the
development of new treatments.
The Measurement and Treatment Research to Improve Cognition in
Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and
Schizophrenia (TURNS) initiatives have stimulated efforts to develop new
targets.
The TURNS project, a consortium of seven academic sites, is charged with
the selection and evaluation of new pharmacological agents, which may help in
the treatment of cognitive impairments.
We are currently conducting three “proof of concept” studies to
evaluate novel GABAergic, nicotinic, and serotonergic mechanisms.
People
with schizophrenia are also often afflicted with multiple co-occurring
disorders.
These include medical disorders secondary to the drugs that are used to
treat their condition, and also substance abuse disorders.
These further complicate their treatment
and their efforts to recover.
The advent of second-generation antipsychotics and the increased
incidence of weight gain, metabolic abnormalities and concern about cardiac
complications, combined with the recent documentation of the poor quality of
medical care provided to people with schizophrenia, has led to an increased
awareness. We need: 1) more effective strategies for ensuring sufficient medical
monitoring and 2) interventions for the treatment of co-occurring medical
conditions.
Should we encourage people with schizophrenia who have gained weight or
have developed hyperlipidemias or glucose dysregulation
to switch to a different antipsychotic, or treat the secondary medical
condition?
We are currently conducting a study on the efficacy of adjunctive
rimonabant, a cannabinoid (CB)1 antagonist, for weight gain and metabolic
abnormalities.
The primary
focus of our efforts to develop treatments for co-occurring substance use
disorders has been on nicotine dependence.
We have conducted a pilot study and clinical trial examining the efficacy
of combining bupropion and group therapy.
We have documented the efficacy of the group therapy component and have
also shown that bupropion (compared to placebo) provides additional benefit in
helping people with schizophrenia to stop smoking cigarettes.
However, only 22% of subjects did quit smoking by the end of the 14-week
study.
This cessation rate is considerably lower than what is seen in smoking
cessation studies with controls. The results suggest that a different approach
may be required in people with schizophrenia.
Therefore, we have designed a study to examine the efficacy of
varenicline, which is a partial agonist of the "4$2
nicotinic receptor, which may be abnormal in schizophrenia. Thus, it may serve
to reverse an underlying pathophysiological impairment as well as treat nicotine
dependence.
Although
alcohol abuse is a major problem, pharmacological interventions that benefit
primary alcohol abusers have not been widely studied in schizophrenia.
There are three FDA-approved medications for treatment of alcohol use
disorders: disulfiram, naltrexone, and acamprosate.
There is reason to believe that acamprosate may provide a unique benefit
to people with schizophrenia and co-occurring alcohol use disorders. It may
enhance glutamatergic functioning when the system is under-stimulated and
decrease glutamatergic functioning when
it is over-stimulated.
We plan to assess its safety and tolerability
in people who have schizophrenia.
In
conclusion, we hope to enter a new era of pharmacological treatment of
schizophrenia.
Recent advances in molecular biology have markedly increased our
understanding of how the brain works and what may be wrong with it in people who
suffer from schizophrenia.
If these recent advances can be translated into novel drugs with
mechanisms that extend beyond simple dopamine receptor blockade,
we should be able to offer our patients more effective treatments that
target those aspects of their illness that
most importantly determine whether they will really recover.