Aripiprazole
is a safe drug particularly in switching patients from other antipsychotic
monotherapy. It would appear the aripiprazole should be a very competitive
with the dominant atypical of the day which is olanzopine. Only major
limitation of olanzopine is weight gain.
Ziprasidone is the drug of first choice if weight gain is a problem.
Quetiapine is a safe drug particularly useful in patients with a first
episode of schizophrenia and is the drug of first choice in those
patients susceptible to extrapyramidal side effects including parkinsonism.
Risperidone is more effective in depression and an ideal drug as a
first line treatment for psychotic patients until worrisome adverse
effects begin to occur.
Clozapine was the first effective drug against resistant schizophrenia
and still would have been a drug of first choice but for incidence
of agranulocytosis requiring regular blood monitoring at least during
the first 4 months. Weight gain is another reservation.
Introduction
Schizophrenia is the most chronic and debilitating of all mental illnesses,
with a lifetime prevalence of nearly 1% worldwide and an annual incidences
of about 10-15 per 100,000 population. It is one of the most complex
and challenging of psychiatric disorders, which interferes with a
person’s ability to think clearly, manage emotions, and make
decisions and relate to others.1-4
This illness tends to manifest itself in early adulthood and is characterized
by positive symptoms, negative symptoms, and cognitive deficits. It
is a lifelong disorder with enormous medical, social and economic
consequences if left untreated. While there is no cure of schizophrenia,
it is a treatable illness.3
Since their discovery in 1950s conventional antipsychotics (dopamine
antagonists) formed the mainstay of drug treatment for schizophrenia
and other psychotic disorders.4-6 Classical antipsychotics
unspecifically block both mesolimbic A10 dopamine pathways,
resulting in antipsychotic efficacy, and nigrostrial A9
pathways resulting in unwanted extrapyramidal side effects (EPS),
tardiv dyskinesia and neurocognitive deficit.7 The blockade of receptors
in the tubero infundibular dopamine system result in prolactin elevations
and sexual dysfunction, inadequate efficacy, resistance to treatment,
significant interpatient variation ranging from complete remission
to absolute refractoriness, and having little effect on negative symptoms
are the problems encountered with their usage.8-10
Newer antipsychotics (atypical) were developed in response to limitations
associated with conventional agents. These possess a lower EPS liability,
and show a better efficacy in the treatment of negative and depressive
symptoms, and cognitive disorders associated with schizophrenia owing
to a higher affinity to serotonin receptors, or to a differential
blockage of A10 vs A9 pathways, respectively.
However, atypical antipsychotics were associated with other side effects
like substantial wait gain, hyperglycaemia, cholesterol level elevation,
and QT interval prolongation. Thus, there was still an unmet need
for novel antipsychotics that are better tolerated than currently
available atypical drugs.
Atypical antipsychotics block Dopamine D2 receptors, mainly
those in the mesolimbic dopamine pathways. Since the dopamine receptor
blockage is non-specific, D2 receptors in the nigrotriatal pathway
are also blocked, leading to motor side effects. To overcome these
side effects, dopamine system stabilizer (DSS) were developed. It
acts both as agonist and antagonist at different situations and thus
as a dopamine system stabilizer. It acts as dopaminergic antagonist,
when there is a high dopamine activity, and as an agonist when there
is a low dopamine activity.11
Atypical antipsychotics
Clozapine
Clozapine was the first effective drug against resistant schizophrenia
with significant improvement in both positive and negative psychotic
symptoms. Low incidence of extrapyramidal symptoms and still lower
incidence of tardiv dyskinesia and neuroleptic malignant syndrome
would have made it a drug of first choice but for incidence of agranulocytosis
(about 0.7%) requiring regular blood monitoring in order to limit
the risk of mortality associated with undetected agranulocytosis.6
The drug does have problems and dangers, it does not work for every
one and patients who are helped substantially may still be far from
well. However, it is thus far the only antipsychotic drug that has
been shown in controlled studies to be clearly more effective than
older standard neuroleptics.12 It is also thus far the only antipsychotic
drug that causes essentially no pseudoparkinsonim or dystonia and
that is apparently unlikely to cause tardiv dyskinesia.8
Clozapine was withdrawn from general use after deaths from agranulocytosis
were reported from Finland in the mid 1970s. But over the intervening
years, no other antipsychotic with similar properties was found, perhaps
because clozapine has an odd mix of pharmacological effects more dopamine
(D1) than D2 effects, more effect on cortical
limbic dopaminergic (5HT2), histaminic, and a-adrenergic
blocking activity than other available neuroleptics.12
However, the drug was reintroduced after clozapine’s efficacy
in treating patients with demonstrably treatment resistant schizophrenia
was published by Kane et al in 1988.12
Side effect and dosage schedule
Major side effects were weight gain, sedation, akathisia, orthostatic
hypotension and agranulocytosis. However, agranulocytosis associated
with clozapine use is believed to be an autoimmune reaction, not a
direct toxic effect on the bone marrow. It is not dose related. Most
cases occur in the second through fourth months of treatment, but
some reactions have occurred as late as 18 months after the drug was
begun. Patients developing agranulocytosis once will rapidly develop
it again if the drug is restarted.12
Clozapine is available in both 25 mg and 100 mg scored tablets. The
starting dose should remain preferably low (12.5 mg) at bed time.
Initial dose may produce alarming symptoms of drowsiness lasting for
many hours. The dosage should be increased slowly and cautiously from
12.5 mg/day to 200 mg/day over the first 2-3 weeks, then stabilized
at that dosage for a few weeks, with further increase as tolerated.
According to our assessment most of our subjects do not require more
than two to three tabs per day. Some patients respond to a dose as
low 25 mg per day preferably given in the evening even without the
knowledge of the patient if not cooperative. Sedation is one major
side effect limiting dosage increase. Many patients develop tolerance
to this effect but some do not. Cardiovascular side effects, both
orthostatic hypotension and tachycardia can occur early in clozapine
treatment. With long term treatment with clozapine, the majority of
patients gain weight. There is controversy about whether clozapine
is likely to cause diabetes and ketoacidosis. Multiple cases have
been reported; however, it is not entirely clear whether these incidences
reflect an effect of the drug.
Drug interaction
Although it is ideal to withdraw other neuroleptics before clozapine
began, low dosage of clozapine to on going antipsychotic therapy are
allowed, followed by tapering of other antipsychotics before clozapine
dosage of 200 mg/day is reached. Clozapine can be combined with benzodiazepines,
lithium, valproic acid, TCAs, trazodone and fluoxetine and even ECT.12
However, concurrent use of lithium along with clozapine may precipitate
neuroleptic malignant syndrome. But drugs, that are known to induce
agranulocytosis, such as carbamazepine should be avoided.
It has been suggested that clozapine is useful in treating all patients
requiring antipsychotics who have failed to respond to several other
antipsychotics, in those with tardiv dyskinesia, and in those who
have severe uncontrolled EPS, specially akathisia.
Risperidone
Risperidone was the first atypical antipsychotic agent introduced
after clozapine to have become available for general prescription
use. The drug exerts relatively more D2 and D1
antagonism. It also has antagonist effect at 5HT2 and possibly
5HT1 receptors. Several multiple collaborative double-blind
studies have documented resperidone’s apparent effectiveness
in treating patients with schizophrenia and its unusual dose - response
relationship : 6 mg/day is more effective and associated with fewer
side effects than larger dosages, whereas 2 mg/day has been shown
to be more safe but less effective. The 6 mg (3 mg bid) dosage has
been shown as effective as 20 mg of haloperidol. However, first assessment
shows that 1 mg bid is the ideal dose of risperidone in stabilizing
the patients which could be raised to 2 mg bid in selected cases but
more slowly. It seems to be an ideal drug as a first line treatment
for psychotic patients until worrisome adverse effects began to occur
: EPS, orthostatic hypotension, agitation and over sedation. Orthostatic
has been particularly problematic in some patients and occasionally
results in syncope and fall.12 Some of these adverse effects
can be avoided if the dose had been raised more slowly and keeping
in mind pharmacokinetic interactions with other drugs, especially
SSRIs which may enhance the orthostatic side effects. Risperidone
appears more likely to raise prolactin levels than does olanzapine.
Clozapine has always seemed much better than older neuroleptics, risperidone
seems more like a some what improved haloperidol, it is as effective
as haloperidol but has fewer side effects typically associated with
latter drug. However, attempt to switch patient from clozapine to
risperidone are often disappointing in the outcome. Still, at least
one study has suggested that over a 1-year period, risperidone was
equal in efficacy to clozapine and better tolerated.13
In affective psychotic patients risperidone may be more effective
for depression and may be more likely to cause mania whereas clozapine
is more effective for mania - like state and may be effective for
depression. However, compared to clozapine risperidone does not cause
agranulocytosis and has better cognitive function but causes increased
incidence of malignant syndrome in addition to extra pyramidal activity.14,10
Olanzapine
Olanzapine was introduced to the US market in 1996. Like other atypical
antipsychotics, it has a high binding ratio of 5HT2 to
D2 receptors. The receptor binding affinities of olanzapine
appear to lie some where between the very broad receptor effects of
clozapine and the more narrow receptor binding risperidone. Like clozapine,
olanzapine is an antagonist of dopamine receptors (D1-D4)
and the 5HT2 receptor. In addition, it is antihistaminic,
is anticholinergic, and blocks a1-adernergic receptors. Olanzapine
appears to be at least as effective as haloperidol in short-term treatment
of schizophrenia. It may be better than haloperidol in improving negative
symptoms, concurrent depression and suicidality and cognition in addition
to positive symptoms, including delusions, hallucinations, and thought
disorders.15,16 Olanzapine is valuable in the treatment
of mood disorders and has been approved by FOA for the treatment of
acute mania.12,15 Recently it has been demonstrated that
intramuscular olanzapine is a safe and effective treatment for acutely
agitated patients with bipolar mania17 which provides an
alternative to oral formulations for controlling agitation when rapid
action or compliance are significant concern.
Several case reports suggest that olanzapine may be effective as a
monotherapy for psychotic depression. There is growing evidence that
olanzapine may offer distinct advantages over traditional agents in
the treatment of schizoaffective disorder. The mood - stabilizing
and enhancing effects of olanzapine may render it a simpler and less
toxic approach to treating schizoaffective disorder than combining
a standard antipsychotic with a mood stabilizer or anti depressant.
There is growing evidence that olanzapine may have a role to play
as an adjunctive or augmenting agent in the treatment of unipolar
depression.12,18 Available data suggest that olanzapine
may be considered a first line treatment for the patient in an acute
episode of schizophrenia.16
It remains to be seen whether olanzapine is as useful as clozapine
in the treatment of refractory schizophrenia. Head to head trials
of olanzapine and risperidone suggest that the drugs are probably
equally effective but differ in side - effect profiles. Olanzapine
is associated with more weight gain and sedation whereas risperidone
is more likely to increase prolactin levels and produce EPS.
Like risperidone and clozapine, olanzapine produces a-adrenergic blockade,
resulting in a dose - related increase in orthostasis and dizziness.
We suggest monitoring orthostatic blood pressure, particularly with
older patients and those with a history of postural hypotension. Support
stockings help orthostasis in older patients. However, these orthostatic
effects are not nearly as dramatic as the effects that can occur with
clozapine.
The most problematic side-effects with long-term maintenance use of
olanzapine are weight gain and sedation. Weight gain is terribly distressing
for many patients, large weight gain has been associated with a negative
impact on blood sugar and triglyceride levels and add to the necessity
of monitoring controlling weight gain in patients treated with olanzapine.
The weight gain associated with olanzapine appears to be from an increased
appetite, and desire to eat more.
Olanzapine is very sedating for many patients and should be taken
at bed time if possible. About 40% of patients will report day time
somnolence at a dosage of 15 mg/day. Talking the olanzapine on an
empty stomach about an hour before bed time may increase the night
time sedation and reduce the day time somnolence. NMS appears to be
uncommon and there are no reported cases of agranulocytosis. Minor
elevation of hepatic transaminase may occur but no serious hepatic
problems associated with olanzapine has been reported.
Olanzapine appears to be fairly safe in over dose. Olanzapine is usually
started at 1.25 - 2.5 mg/day and increased upto 5 mg in the first
week, which could be raised upto 10 mg/day. According to our assessment
further rise in the dose upto 20 mg/day are not required in our subjects.
Quetiapine
Quetiapine (seroquel) was released in United States in 1998. Like
clozapine, the drug appears to have low affinity for D1
and D2 receptors, but relatively high affinity for D4
receptors.12 Clozapine, olanzapine, and quetiapine all
seem to have more pronounced affects on mesolimbic dopamine activity
than on nigrostriatal pathways, a phenomenon that accounts for their
low tendency to produce EPS. Like other atypical agents, quetiapine
appears to have high affinity for 5HT2 receptors. Quetiapine
does not appear to have very significant anticholinergic or antihistaminic
effects, but it does block a1-adrenergic receptors to some extent.
One potential drawback of the current preparation of quetiapine is
its very short half-life - the average half-life is about 2-3 hours
- and quetiapine therefore needs to be given at least two times day.
For chronically psychotic patients this multiple dosing is less than
ideal and might result in compliance problems. Fortunately, a sustained
release preparation is under development.
Quetiapine is a novel antipsychotic with proven efficacy in schizophrenia
across all domains, positive, negative as well as cognitive function.19
It has been shown to be effective and well tolerated in patients particularly
vulnerable to the extrapyramidal side effects including those with
Alzheimer’s disease associated with conventional antipsychotic,
making it well suited for use as first-line therapy.
It has been reported that quetiapine is an effective antipsychotic
in patients with a first episode of schizophrenia and that its efficacy
is probably due to its significant but only transiently high blockade
of dopamine D2 receptors.20 However, weight
gain associated with quetiapine though less than olanzapine and clozapine
is more than that seen with ziprasidone and risperidone but risk of
complications from overdose is small.12
Ziprasidone
Ziprasidone another atypical antipsychotic, was released to US market
in the year 2000. Like other antipsychotics it was a complex pharmacology.
It appears to be an agonist at the 5HT1A receptor and an antagonist
at 5HT1D and 5HT2C receptors. It has been shown
to enhance the release of dopamine in the dorsolateral prefrontal
cortex and block the reuptake of both norepinephrine and serotonin.
These attributes make ziprasidone a good antidepressant and anxiolytic
as well as an effective antipsychotic. The drug appears to show relative
weak affinity for muscarinic and a-adrenergic receptors. The pharmacology
of ziprasidone suggests that it should have antidepressant and anxiolytic
effects of nonpsychotic patients as well.12
Ziprasidone appeared to be as effective as 15 mg of haloperidol in
improving positive psychotic symptoms and superior to haloperidol
in its effects on negative symptoms and depression. It has been shown
to substantially reduce depressive symptoms.12
Ziprasidone appears to be well tolerated. Most notable is that it
is unique among the atypical agents in not being associated with significant
weight gain.21 This feature alone should make ziprasidone
extremely popular, since clozapine and olanzapine have been so problematic
in this regard. As with other atypical antipsychotics, ziprasidone
is associated with low incidence of EPS, much like with olanzapine
and probably better than with risperidone, although head to head trial
have not been completed.
The most common side effects observed in clinical trials with ziprasidone
are drowsiness, dyspepsia, dizziness, constipation and nausea. However,
it has a short half-life (5 hours) that necessitates twice a day dosing.
The dosage range that appears most effective in clinical studies is
60-80 mg bid which may be doubled but rarely required. Another major
advantage that ziprasidone has over other atypicals is the intramuscular
formulation.
Aripiprazole
Aripiprazole is an atypical antipsychotic with a some what unique
pharmacological profile. It is a partial agonist at the D2
and 5HT1A receptors and also has 5-HT2 properties
found with other atypical antipsychotics. Among the other pharmacological
properties of aripiprazole is its affinity as a presynaptic D2 auto
receptor agonist. Thus it can enhance as well as inhibit dopamine
release in specific regions of the brain. Aripiprazole’s pharmacological
profile indicate that it has antipsychotic, antimanic, and antidepressant
properties.12 It has a long half-life about 50-80 hours
and steady state therefore is not achieved for about 2 weeks.
Aripiprazole a quinoline derivative is extolled as the first dopamine
system stabilizer among atypical antipsychotic drugs developed to
over come side effects associated with atypical antipsychotics. It
has shown efficacy in the treatment of positive and negative symptoms
of psychosis as well as mood symptoms, a low rate of neurological
side effects and significant adverse effect on serum prolactin concentration.22,23
In addition, aripiprazole was not associated with significant weight
gain or QT prolongation in both acute and long term trials.24,25
In the treatment of acute mania, the effects of aripiprazole were
superior to those of placebo, and the effects were seen within 4 day.26
Aripiprazole appeared to significantly reduce the irritability, lability,
and aggressiveness associated with acute mania. Switching patients
to aripiprazole from other antipsychotic mnonotherapy was safe.27
Further more, patient's symptoms may continue to improve after switching
to aripiprazole.
On the surface, it would appear that aripiprazole should be very competitive
with dominant atypical of the day, which is olanzapine.
The effective dose range of aripiprazole is 10-30 mg administered
as a once daily oral tablet with or without food. The recommended
starting dose of 15 mg daily enables physicians to initiate therapy
at an effective dose without the need for titration.28
Dosage can be subsequently adjusted to optimize individual patient
response and that total daily dose can be divided into bid.
Collectively, aripiprazole is an important atypical antipsychotic
candidate with a favourable safety profile. More over, the mechanism
of action of aripiprazole differentiates it from both typical and
atypical antipsychotics and hence, may provide important leads for
pharmacotherapy of schizophrenia and other psychotic disorders.29
References
1. Turner T. ABC of mental health ; Schizophrenia. BMJ 1997;315:108-11.
2. Shur E. The epidemiology of schizophrenia. Br Hosp Med 1988; 40
(1) : 38-40.
3. Liberman J, Carson WH, Shah AR, et al. Meta-analysis of the efficacy
aripiprazole in schizophrenia. N Engl J Med 2002; 5 (1) : S186.
4. Kane JM. Schizophrenia. N Engl J Med 1996; 334 : 34-41.
5. Kane JM. Management strategies for the treatment of schizophrenia.
J Clin Psychiatry 1999; 60 (13) : 13-17.
6. Dhar HL, Dave KP. Current concepts of treatment of schizophrenia.
Ind J Clin Pharmacol Therapeutics 1999; 19 (3) : 48-53.
7. Carlson A. The current status of the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology 1998; 1 (3) : 179-86.
8. Love RC. Novel versus conventional antipsychotic drug. Pharmacotherapy
1996; 16 : 6S-10S.
9. Emsley RA. Partial response to antipsychotic treatment; the patient
with enduring symptoms. J Clin Psychiatry 1999; 60 (23) : 10-13.
10. Dhar HL,Dave KP. Newer Antipsychotic drugs and refractory schizophrenia.
Current Medical Trends 2000; 4/3 : 770-78.
11. Keltner NL, Johnson V. Biological perspectives - Aripiprazole
: a third generation of antipsychotics begins. Perspect Psychiatry
Care 2002; 38 (4) : 157-59.
12. Alan F, Schatz ERG, Jonathan O Cole, Charles De Bathistaeds. Manual
of clinical psychopharmacology 2003, American Psychiatric publishing
Inc, 4th edition. 187-93.
13. Azorin JM, Spiegel R, Remington G, et al. A double-blind comparative
study of clozapine and risperidone in the management of severe chronic
schizophrenia. Am J Psychiatry 2001; 158 : 1305-13.
14. Gerlach J, Peacock L. New antipsychotics; the present status.
Int Clin Pharmacol 1995; 3 (suppl) : 39-48.
15. John M Davis, Nancy Chen. The effects of Olanzapine on 5 Dimensions
of schizophrenia derived by Factor Analysis : combined results of
the North American and International trail. J Clin Psychiatry 2001;
62 (10) : 757-75.
16. Bruce J Kinon; Suraja M Roychowdhary, Denai R Milton, et al. Effective
resolution with olanzapine of acute presentation of Behavioral agitation
and positive Psychotic symptoms in schizophrenia. J Clin Psychiatry
2001; 62 (suppl) : 17-21.
17. Karena Meethan, Fan Zhang, Stacy David, et al. A double-blind,
randomized comparison of the efficacy and safety of Intramuscular
injections of olanzapine, lorazepam, or placebo in treating acute
agitated patients diagnosed with Bipolar mania. J Clin Psychopharmacology
2001; 21 : 389-97.
18. Anthony J Rothschild, Kimberly S Bales, Kelly L Boehringer, et
al. Olanzapine response in psychotic depression. J Clin Psychiatry
1999; 60 (2) : 116-18.
19. Tonmoy Sharma. Quetiapine - efficacy in different domains. European
Neuropsychopharmacology 2001; 11 (suppl 4) : S385-S390.
20. Sitra Tauscher - Wisnjewski, Shitij Kapur, Johannes Tauscher,
et al. Quetiapine : an effective antipsychotic in first-episode schizsophrenia
despite only transient high dopamine-z receptor blockade. J Clin Psychiatry
2002; 63 (11) : 992-97.
21. Alison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight
gain : a comprehensive research synthesis. Am J Psychiatry 1999; 156
: 1686-96.
22. John M Kane, William H Carson, Anutosh R Saha. Efficacy and safety
of aripiprazole and haloperidol versus placebo in patients with schizophrenia
and schizoaffective disorder. J Clin Psychiatry 2002; 63 : 763-71.
23. Goodnick PJ, Jerry JM. Aripiprazole : profile on efficacy and
safety. Expert Opin Pharmacother 2002; 3 (12) : 1773-81.
24. Burris KD, Moloki TF, Xuc, et al. Aripiprazole : a novel antipsychotic,
is a high-affinity partial agonist at human dopamine D2 receptors.
J Pharmacol Exp Ther 2002; 302 (1) : 381-89.
25. Keck Jr PE, Mc Elroy SL. Aripiprazole : a partial dopamine D2
receptor agonist antipsychotic. Expert Opin Investig Drugs 2003; 12
(4) : 655-62.
26. Jody D, Marcus R, Keck P, et al. Aripiprazole versus placebo in
acute mania. Poster presented at XXIIIrd Collegium International.
Neuropsychopharmacologium Congress, Montreat Canada 2002; 23-27.
27. Daniel E Casey, William H Carson, Anutosh R Saha, et al. Switching
patients to aripiprazole from other antipsychotic agents: a multicentre
randomized study. Psychopharmacology 2003; 166 : 391-99.
28. Daniel DG, Shah A, Ingenito G, et al. Aripiprazole a novel antipsychotic
overview of a phase 2 study. Int J Neuropsychopharmacol 2000; 3 (1)
: 157.
29. Ozdemir V, Fouie J, Ozdener F, et al. Aripiprazole. Curr Opin
Investig. Drugs 2002; 3 (1) : 1130-20.
EPILEPSY
: A PREDICTOR OF STROKE?
‘Onset of seizures in late life is associated with a striking
increase in the risk of stroke’.
Cerebrovascular disease is thought to be a major cause of epilepsy
in late life. Paul Cleary and colleagues investigated the hypothesis
that the onset of seizures after the age of 60 years in people
with no history of overt stroke might be association with heightened
risk of subsequent stroke. They found that seizures in elderly
people are the initial manifestation of otherwise occult cerebrovascular
disease. The investigators suggest that further research is warranted
to assess the benefit of specific interventions against stroke
in elderly patients with epilepsy.
BHJ, 2004; 3 : 1175, 1184. |
*Director,
Medical Research Centre, Bombay Hospital Trust, Mumbai 400 020. **Ex.
Hon. Professor and Head, Department of Psychiatry, LTM Medical College,
Sion, Mumbai 400 022.
