ADVANCED PSYCHOPHARMACOLOGY
Psychology 572 Spring, 2005
Dr. John M. Morgan Tuesday & Thursday, 8am to 9:20
Natural Resources 201
Eric Dick
Eillen Klima
Heather French
Jean E. Horn
A Literary Review of Atypical Antipsychotics, their Medical
Benefits as well as their Side Effects.
ATYPICAL NEUROLEPTICS: ARIPIPRAZOLE, OLANZAPINE, AND
RISPERIDONE
Extrapyramidal side effects commonly associated with first generation
antischizophrenic drugs range from parkinsonism (signified by rigidity and
tremors), akathisia (compulsive restlessness), dystonias (sudden jerky
movements that occur during the beginning of psychopharmacological
treatment), and tardive dyskinesia (characterized by lip smacking, protrusions
of the tongue, and puffing of the cheeks) (Palfai, & Jankiewicz, 2001). While
some side effects must always be tolerated, a newer class of drugs called
atypical antischizophrenics is known for the ability to decrease both positive
and negative symptoms of schizophrenia without causing extrapyramidal side
effects (Feldman, Meyer, & Quenzer, 1997). In this paper, we will focus on
three specific atypical antischizophrenic drugs: Risperidone (Risperdal),
Aripiprazole (Abilify), and Olanzapine (Zyprexa).
CASE SAMPLES
C.O is my neighbor, and she lives down the street from me. I knocked on C.O?s
Eureka apartment front door. I hear the familiar words, ?Come in.? from
somewhere inside. I think to myself I could just be anybody, but C.O. never
seems concerned about that. I walk in and the foul odor of the cat litter
boxes, trash, soiled laundry, her unwashed body and long oily hair are
repulsive. I try not to breathe too deeply, but I can still taste the air in her tiny
apartment. Several cats are on the couch, chairs and floor. The windows are
closed and covered with heavy drapery. It is hard for me to see in a room so
dark. I tell C.O. who I am and I know to head for her bedroom where she will
be laying on her bed hardly moving or acknowledging my presence. She will
usually tell me what the spirits are unhappy about with her today. She says
the spirits and the devil argue over her thoughts and control her behavior.
They tell not to take the medication from her doctor, because she will
ultimately be punished for doing so. I tell her I came by because I needed one
of her hugs. That usually makes her smile, and she wraps her arms around me.
I hug her back and remind her how much the neighborhood cares about her.
Sometimes she shares her latest poetry that she has composed or artwork
that seems to only make sense to her. Her poetry is written all over the living
and dining room walls and is fascinating to read, it is usually about Jesus, but
it doesn?t make any sense to me. Her drawings are too confusing for me to
understand. Other times, she stares blankly and doesn?t say anything at all. I
remind her to take her medicine (Abilify), because it will stop the voices, and
then I let her know that I will come back on another day for one of her amazing
hugs. When C.O. takes her neuroleptic medication, she is clean, often happy,
she is appropriately dressed and her apartment is not so dark and dirty.
Mr.G disguised in his son?s clothing followed his children to school one
morning, because he knew his children were going to be kidnapped. He said
that they had been kidnapped before by strangers who keep surveillance on
him. He says that his kids have been brainwashed to conspire against him.
Mr.G also mentioned that a family member had put a contract out on his life.
He said he has been to the police many times about this matter and that they
are not helping to protect him or his children, and he must take matters into
his own hands. He has disconnected his telephone and the computer, because
the neighbors who are also involved in the conspiracy have infiltrated both.
He says that he does not want to take his Zyprexa (olanzapine), because it
makes him sleep for two days at a time. He hasn?t been able to sleep much
lately and must protect his and his children?s lives, even if it means that
somebody could get hurt. After a brief hospitalization, Mr.G is back on his
medication and is capable of caring for his family.
Justanothermoron (2002) reported his experience in 2001...
Dose: T+ 0:00 (2:00am) Ingested 4 (1 mg each) Risperidol (Risperidone) tablets
while sitting in front of the computer.
Dose: T+ 9:00 (11:00am) HOLY HELL WHAT?S WRONG WITH ME? I FEEL
COMPLETELY STRANGE. Very groggy, almost like I have been sedated with a
tranquilizer. I?m not happy or sad, I feel just in existence, all off of 4 mg?
Dose: T+ 13:00 (3:00am) Effects at peak sedation, I can feel why this is such
an effective treatment for psychotic episodes. I can?t sleep, I just sit there,
almost feeling like I?m having brief hallucinations, but nothing I can verify. I
just don?t feel like myself at all. Trying not to think about it and go on with my
day, but I?m also pondering another attempt at sleep.
Dose: T+ 18:00 (8:00pm): Finally got some sleep, awoke feeling normal finally.
That was almost a scary experience, and I?m still a little dull on the emotional
side of things. Wow, never again will I do that.
Final Notes: Antipsychotics may have tons of uses in the medical world, but
have zero recreational value whatsoever. Feeling like a total zombie is a
horrible state to be in. I?d recommend that anyone trying this out think, again.
It was really bad making the mistake of reading the side effects AFTER
ingesting the substance; the mental stress building up to this experience was
hell in itself; almost like when you think you might have just taken a little too
much acid at one time. Let me reiterate once more, NEVER AGAIN unless in
an emergency such as a psychotic reaction to another psychedelic, but then it
might be wise to seek medical care instead. (Justananothermoron, 2002, p.1,
2)
BEHAVIORAL FEATURES
Atypical neuroleptics are also known as the second generation antipsychotics
or the new antipsychotics. The primary use for this category of drugs are
mental and mood disorders, specifically schizophrenia (psychotic disorders),
bipolar mania and for hallucinogen persisting perceptual disorder. These
drugs contain serotonergic and dopaminergic blocking effects in the central
nervous system. Recreational uses of these drugs are unlikely, because of the
negative impact on behavior (as described previously by Justanothermoron).
The essential features of schizophrenia are a mixture of cognitive and
emotional dysfunctions that include perception, inferential thinking, language
and communication, behavioral monitoring, affect, fluency and productivity of
thought and speech, hedonic capacity, volition and drive, and attention
(DSMIVTR, 2000). Characteristic symptoms may be conceptualized as falling
into two categories: positive and negative. The positive symptoms appear to
reflect an excess or distortion of normal functions, whereas the negative
symptoms appear to reflect a diminution or loss of normal functions. The
positive symptoms include distortions in thought content (delusions),
perception (hallucinations), language and thought process (disorganized
speech), self monitoring of behavior (grossly disorganized or catatonic
behavior). These positive symptoms may comprise two distinct dimensions,
which may in turn be related to different underlying neural mechanisms and
clinical correlates. The psychotic dimension includes delusions and
hallucinations, whereas the disorganization dimension includes disorganized
speech and behavior. Negative symptoms include restrictions in the range and
intensity of emotional expression (affective flattening), in the fluency and
productivity of thought and speech (alogia), and in the initiating of goal
directed behavior (avolition). Delusions are erroneous beliefs that involve
misinterpretations of perceptions or experiences. Their content may include a
variety of themes (e.g., persecutory, referential, somatic, religious, or
grandiose). Persecutory delusions are the most common; the person believes
he or she is being tormented, followed, tricked, spied on, or ridiculed.
Referential delusions are also common; the person believes that certain
gestures, comments, passages from books, newspapers, song lyrics, or other
environmental cues are specifically directed at him or her. The distinction
between a delusion and a strongly held idea is sometimes difficult to make and
depends in part on the degree of conviction with which the belief is held
despite clear contradictory evidence regarding its veracity.
A manic episode is experienced in Bipolar I Disorders and is defined by a
distinct period during which there is an abnormally and persistently elevated,
expansive, or irritable mood (DSMIVTR, 2000). The mood disturbance must be
accompanied by at least additional symptoms that include inflated self esteem
or grandiosity, decreased need for sleep, pressure of speech, flight of ideas,
and increased involvement in goal directed activities or psychomotor
agitation, an excessive involvement with pleasurable activities with a high
potential for painful consequences and can exhibit psychotic features.
Hallucinogen Persisting Perception Disorder (HPPD) (flashbacks) is the
transient recurrence of disturbances in perception that are reminiscent of
those experienced during one or more earlier Hallucinogen Intoxication. The
person must have had no recent Hallucinogen Intoxication and must show no
current drug toxicity (DSMIVTR, 2000). The perceptual disturbances may
include geometric forms, peripheral field images, and flashes of color,
intensified colors, trailing images, perceptions of entire objects, afterimages,
and halos around objects, macropsia, and micropsia.
PHYSIOLOGICAL EFFECTS
Some evidence suggests that at least some of the symptoms of schizophrenia,
bipolar, and other psychotic disorders involve a biochemical imbalance
(Carlson, 1986). Dopamine (DA) and Serotonin (5HT) have been implicated as
transmitter substances that might be involved in these disorders. Currently,
the most encouraging explanation is in the Dysregulation Hypothesis (Palfai &
Jankiewicz, 2001). This hypothesis suggests that the neuroleptic drugs affect
the DA and 5HT neurotransmitters. DA and 5HT are both nitrogen containing
compounds descended from amino acids and are referred to as bioamines.
DA neurons are only found in the CNS and originate from two areas of the
brain; the substantia nigra and the ventral tegmental area. There are four
major pathways of the human brain: 1) Nigrostriatal tract: Connects the
substantia nigra with areas of the basal ganglia. Associated with movement
and its degeneration is linked to Parkinson?s disease. 2) Mesolimbic tract:
Connects the midbrain to various limbic structures. The pathway involving the
ventral tegmentum, the medical forebrain bundle, and the nucleus accumbens
is associated with pleasure, reward, and the reinforcing effects of drugs. 3)
Mesocortical tract: Connects areas of the midbrain to the prefrontal cortex.
4) Tuberoinfundibular tract: Originates in the ventral tegmentum area.
Connects the hypothalamus with the pituitary and is involved in the release of
hormones (Palfai and Jankiewicz, 2001, p. 144)
Ninety eight percent of 5HT in the body is found in the blood and smooth
muscles of the gastrointestinal tract. Most brain 5HT is concentrated in the
pineal gland and most of the serotonergic somae lie in the raphe nuclei, part of
the brain stem between the pons and medulla near the midline of the upper
brain stem. 5HT may be involved with arousal and slow wave sleep. The
fibers of the 5HT neurons diffuse through the brain. An ascending pathway
from the raphe nuclei to the medial forebrain bundle (pleasure), hypothalamus
(temperature control, basal ganglia (movement), amygdala (mood), lateral
geniculate body (vision), cortex (sensory perception). 5HT neurons spread to
almost every area of the neo cortex. Stimulation of the 5HT pathways usually
causes inhibition. 5HT has been associated with the hypothalamic control of
hormone release, appetite, and feeding behaviors in addition to sleep and
arousal. Serotonergic pathways throughout the brain may be responsible for
the regulation of biorhythms and synchronization of functions.
EMPIRICAL RESEARCH
RISPERIDONE/RISPERDAL
Risperidone (Risperdal) underwent premarketing trials in North America that
included (in overlapping categories) short term (6 to 8 weeks) and longer term
exposure, open label and blind studies, uncontrolled and controlled studies
(with placebo), and inpatient and outpatient studies. Two thousand six
hundred and seven (2607) patients with schizophrenia and acute bipolar mania
were assessed separately on risperidone monotherapy and as adjunctive
therapy to mood stabilizers. Adverse effects ranging from extrapyramidal
symptoms, gastrointestinal symptoms, and psychiatric symptoms occurred at
an incidence rate of 1 to 2 percent or more among Risperidone patients.
Risperidone has not been systematically studied in humans or animals for the
risk of physical and psychological dependence
(http://rxlist.com/cgi/generic/risperid_ad.htm).
Risperidone demonstrated good activity against various symptoms and signs
associated with schizophrenia (Green, 2005). Marder et al. (1997) study looked
at 513 schizophrenic patients and found significant improvement in positive
and negative symptoms, including disorganized thought, uncontrolled
hostility/excitement, and anxiety /depression. There is some evidence that
Risperidone is also effective in treating bipolar affective disorder, obsessive
compulsive disorder and related disorders e.g. Tourette?s syndrome.
Risperidone is effective in treating autistic/pervasive developmental disorders
and adolescent schizophrenia. There has been interest in the drug?s use to
treat aggression in severe dementia in the elderly population.
Marder, & Meibach, (1995) conducted a study on risperidone in the treatment
of schizophrenia. The intention was to investigate the safety and efficacy of
risperidone in the treatment of schizophrenia, and to determine its optimal
dose. In this double blind study, 388 schizophrenic patients from twenty sites
across the United States were randomly assigned to 8 week treatments.
Treatment assignments were either to a placebo, one of four doses of
risperidone (2, 6, 10, or 16 mg), or 20 mg of haloperidol daily. The results
showed that 6 mg of risperidone was optimal, as it was as effective as 16 mg.
Additionally, extrapyramidal side effects were greater in patients treated with
16 mg of risperidone or 20 mg of haloperidol, yet the incidence of
extrapyramidal side effects was no greater in patients receiving 6 mg of
risperidone than in patients receiving placebo. Therefore, risperidone was
found to be a safe antischizophrenic drug that was effective against both
positive and negative symptoms and had considerably less side effects than
other drugs.
In the (Chouinard, et al. 1993) study, 135 inpatients with diagnoses of chronic
schizophrenia were randomly assigned to 8 week treatments in a double blind
study. Treatment group assignments were to either risperidone (2, 6, 10, or 16
mg per day), haloperidol 20 mg per day, or placebo. Risperidone doses of 6 to
16 mg showed marked antidyskinetic effects in patients with sever dyskinesia,
whereas the use of haloperidol resulted in significantly greater parkinsonism
than placebo or risperidone 2, 6, or 16 mg. The results suggest that
risperidone is effective at reducing both positive and negative symptoms of
schizophrenia without an increase in parkinsonian symptoms and with
beneficial effects on tardive dyskinesia.
Tran, et al. (1997) conducted a double blind study comparing the effects of
risperidone and olanzapine on the treatment of schizophrenia and other
psychotic disorders. Participants in this 28 week study were 339 patients
meeting DSM IV criteria for schizophrenia, schizophreniform, and
schizoaffective disorders. This study found that olanzapine was superior at
managing negative symptoms, and that participants receiving olanzapine
experienced fewer extrapyramidal side effects and sexual dysfunction than
participants receiving risperidone.
Risperidone and other atypical antipsychotics appear to promote a higher
quality of life when compared to conventional antipsychotics. Physical well
being, social life, and everyday life have been rated as having twice as many
quality adjusted years in a comparative study using risperidone and first
generation antipsychotics (Franz et al. 1997). However, in certain individuals,
the hallucinogenic drug lysergic acid diethylamide (LSD) is associated with
lifelong HPPD, and patients who had been treated with Risperidone in a study
showed an exacerbation of LSD like panic and visual symptoms and concluded
that HPPD not be treated with risperidone (Abraham, Mamen,1996). Other
common side effects are insomnia, agitation, anxiety, and headache. Less
frequent side effects include somnolence, tiredness, and poor concentration.
OLANZAPINE/ZYPREXA
Olanzapine (Zyprexa) underwent premarketing trials that included (in
overlapping categories) short term and longer term exposure, open label and
blind studies, inpatient and outpatient studies, and fixed dose and dose
titration studies. Over 6,000 patients with schizophrenia, bipolar mania, and
Alzheimer?s were assessed. Olanzapine has not been systematically studied in
humans for the risk of abuse; however, multiple studies involving rats and
rhesus monkeys found there to be little or no potential for abuse or
dependence (http://rxlist.com/cgi.generic_ad.htm).
Tollefson, et al. (1997) compared the therapeutic effects of the atypical
antipsychotic, olanzapine, with a conventional dopamine D2 antagonist,
haloperidol. One thousand nine hundred and ninety six patients at 174 sites in
North America and Europe were randomly assigned to treatment in this double
blind 6 week long study. Results demonstrated that olanzapine decreased
psychotic symptoms more effectively and with fewer side effects than
haloperidol.
In a double blind study involving 335 patients, Beasley, et al. (1996) compared
three dosages of olanzapine versus placebo and haloperidol. Each patient met
the DSM III R criteria for schizophrenia. It was found that with regard to
overall symptomatology all dosages of olanzapine and haloperidol were more
effective than placebo. Additionally, with regard to negative symptoms, the
highest and lowest dosages of olanzapine were more effective than both
haloperidol and placebo, and far fewer parkinsonism occurred with patients
receiving olanzapine than with patients receiving haloperidol.
Tohen, et al. (2000) compared the efficacy and safety of olanzapine in acute
bipolar mania. One hundred and fifteen patients with a DSM IV diagnosis of
bipolar disorder, manic or mixed, participated in this four week, randomized,
double blind, parallel study. Results indicated that olanzapine treated patients
yielded higher rates of response, euthymia, and rates of general improvement
on the Young Mania Rating Scale than placebo treated patients.
ARIPIPRAZOLE/ABILIFY
Aripiprazole underwent premarketing trials that included (in overlapping
categories) short term and longer term exposure, comparative and
noncomparative open label and blind studies, inpatient and outpatient studies,
and fixed and flexible dose studies. Five thousand five hundred and ninety two
(5592) patients with schizophrenia, bipolar mania, and dementia were
assessed. Aripiprazole has not been systematically studied in humans for the
risk of abuse, however studies involving monkeys found there to be withdrawal
symptoms upon abrupt cessation (http://rxlist.com/cgi/generic/abilify_ad.htm).
In a study focusing on patients with schizophrenia and schizoaffective
disorder, Kane, et al. (2002) tested the efficacy, safety, and tolerability of
aripiprazole and haloperidol versus placebo. A total of 414 patients were
involved in a randomized, four week, double blind study. Results indicated
that both aripiprazole and haloperidol were effective at reducing both positive
and negative symptoms, and that aripiprazole was associated with fewer
extrapyramidal symptoms than was haloperidol.
Keck, et al. (2003) compared the safety and efficacy of aripiprazole versus
placebo in a three week, multicenter, double blind study. Participants were
262 bipolar disorder patients in either acute manic or mixed episodes. On
scores for severity of illness and change from preceding phase, aripiprazole
was found to have greater efficacy than placebo, and it was suggested that its
use was also safe and tolerable.
The adverse side effects of aripiprazole on the nervous symptoms were
reported as follows: 1/100 patients experienced depression, nervousness,
schizophrenic reaction, hallucination, hostility, confusion, paranoid reaction,
suicidal thought, abnormal gait, manic reaction, delusions, and abnormal
dream. 1/100 to 1/1000 patients experienced emotional lability, twitch,
cogwheel rigidity, impaired concentration, vasodilation, parathesia,
impotence, extremity tremor, hypesthesia, vertigo, stupor, bradykinesia,
apathy, panic attack, decreased libido, hypersomnia, dyskinesia, manic
depressive reaction, ataxia, visual hallucination, cerebrovascular accident,
hyperkinesias, depersonalization, impaired memory, delirium, dysarthria,
tardive duskiness, amnesia hyperactivity, increased libido, restless leg,
neuropathy, dysphoria, hyperkinesia, cerebral ischemia, increased reflexes,
kinesis, decreased consciousness, hyperesthesia, and slowed thinking. Fewer
than 1/1000 patients experienced blunted affect, euphoria, incoordination,
oculogyric crisis, obsessive thought, hypotonia, buccoglossal syndrome,
decreased reflexes, derealization, intracranial hemorrhage.(Healthy Place,
2005).
Various studies have supported the benefits of aripiprazole. ?In short term (6
week), placebo controlled trials, somnolence was reported in 11% of
(psychotic) patients on Abilify compared to 8% of patients on placebo;
somnolence led to discontinuation in 0.1%(1/926) of patients on Abilify in short
term, placebo controlled studies. Despite the relatively modest increase of
somnolence compared to placebo, Abilify, like other anti psychotics, may have
the potential to impair judgment, thinking, or motor skills. Patients should be
cautioned about operating hazardous machinery, including automobiles, until
they are relatively certain that therapy with Abilify does not affect them
adversely.? (HealthyPlace, 2005). Dose related adverse events in placebo
controlled trials of schizophrenia; the incidence of reported Extrapyramidal
Symptoms (EPS) for aripiprazole treated patients was 6% versus 6% for
placebo. In the short term, placebo controlled trials in bipolar mania; the
incidence of reported EPS related events excluding events related to akathisia
for aripiprazole treated patients were 17% versus 12% for placebo. The
placebo controlled trials in bipolar mania the incidence of akathisia for
aripiprazole treated patients was 15% versus 4% for placebo. Similar results
were found in a longer 26 week double blind aripiprazole/placebo trials
(HealthyPlace, 2005).
ABILIFY/ARIPIPRAZOLE DESCRIPTION
Abilify, known by the generic name aripiprazole, is a psychotropic drug that is
available as tablets for oral administration. Aripiprazole is 7 [4 [4 (2, 3
dichlorophenyl) 1 piperazinyl] butoxy] 3, 4 dihydrocarbostyril. The formula is
C23H27Cl2N3O2. The chemical structure is:
Figure 1
Ability tablets are available in 5mg, 10mg, 15mg, 20mg, and 30mg
strengths. Inactive ingredients include lactose monohydrate, cornstarch,
microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate.
Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum
Lake. (Rxlist "Abilify," 2004)
CLINICAL PHARMACOLOGY
PHARMACODYNAMICS
Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5HT1A and
5HT2A receptors, a moderate affinity for dopamine D4, serotonin 5HT2C and 5HT7,
alpha1 adrenergic and histamine H1 receptors, and moderate affinity for the
serotonin reuptake site. Aripiprazole has no appreciable affinity for
muscarinic receptors. Aripiprazole functions as a partial agonist at the
dopamine D2 and the serotonin 5HT1A receptors, and as an antagonist at
serotonin 5HT2A receptor.
The mechanism of action of aripiprazole, as with other drugs having efficacy in
schizophrenia, is unknown. However, it has been proposed that the efficacy of
aripiprazole is mediated through a combination of partial agonist activity at
dopamine and some serotonin receptors and antagonist activity at other
serotonin receptors. Actions at receptors other than these may explain some
of the other clinical effects of aripiprazole, e.g., the orthostatic hypotension
observed with aripiprazole may possibly be explained by its antagonist activity
at adrenergic alpha receptors. (Rxlist "Abilify," 2004)
PHARMACOKINETICS
Abilify activity is primarily due to the parent drug, aripiprazole, and to a lesser
extent, to its major metabolite, dehydro aripiprazole, which has been shown to
have affinities for dopamine receptors similar to the parent drug. The mean
elimination half lives are about 75 hours and 94 hours for aripiprazole and
dehydro aripiprazole, respectively. (Rxlist "Abilify," 2004)
Absorption
Aripiprazole is well absorbed, having peak plasma concentrations within 3 to 5
hours; the absolute oral bioavailability of the tablet formulation is 87%.
Metabolism and Elimination
Three biotransformation pathways metabolize Aripiprazole: dehydrogenation,
hydroxylation, and N dealkylation. Based on in vitro studies, two enzymes
CYP3A4 and CYP2D6 are responsible for dehydrogenation and hydroxylation of
aripiprazole, and the enzyme CYP3A4 catalyzes N dealkylation. Aripiprazole is
the predominant drug of the two in the systemic circulation. At steady state,
dehydro aripiprazole, the active metabolite, represents only about 40% of
aripiprazole in plasma.
Following a single oral dose of aripiprazole, approximately 25% and 55% of the
administered drug was recovered in the urine and feces, respectively. Less
than 1% of unchanged aripiprazole was excreted in the urine and
approximately 18% of the oral dose was recovered unchanged in the feces
(Bristol Meyers Squibb Company "Abilify," 2004).
ZYPREXA/OLANZAPINE DESCRIPTION
Zyprexa known by the generic name olanzapine is a psychotropic agent that
belongs to the class of drug thienobenzodiazepine. The chemical designation
is 2 methyl 4 (4 methyl 1 piperazinyl) 10H thieno [2, 3 b] [1, 5] benzodiazepine.
The molecular formula of olanzapine is C17H20N4S. The chemical structure is:
Figure 2
Olanzapine is a yellow crystalline solid, which in water is insoluble. Zyprexa
tablets are intended for oral administration only. (Rxlist "Zyprexa," 2004)
Zyprexa tablets are available containing 2.5mg, 5mg, 7.5mg, 10mg, 15mg, or
20mg of olanzapine. Inactive ingredients are carnauba wax, crospovidone,
hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate,
microcrystalline cellulose. The colored shell of the pill contains Titanium
Dioxide, FD&C Blue No. 2 Aluminum Lake, or Synthetic Red Iron Oxide. The
2.5, 5.0, 7.5, and 10mg tablets are also imprinted with edible ink, which
contains FD&C Blue No.2 Aluminum Lake.
CLINICAL PHARMACOLOGY
PHARMACODYNAMICS
Olanzapine is a selective monoaminergic antagonist with high affinity binding
to the following receptors: serotonin, dopamine, muscarinic, histamine, and
adrenergic alpha receptors. Olanzapine binds weakly to GABAA, BZD, and b
adrenergic receptors.
The mechanism of action of olanzapine, as with many other drugs having
efficacy in treating schizophrenia, is unknown. However, it has been proposed
that olanzapine?s efficacy in schizophrenia is mediated through a combination
of dopamine and serotonin antagonisms slowing the responses of effected
neurons. The mechanism of action of olanzapine in the treatment of acute
manic episodes associated with Bipolar I Disorder is also unknown. (Rxlist
"Zyprexa," 2004)
Antagonism at receptors other than dopamine and serotonin with similar
receptor affinities may explain some of the other therapeutic and side effects
of olanzapine. Olanzapine?s antagonism of muscarinic receptors may explain
its anticholinergic effects. Olanzapine?s antagonism of histamine receptors
may explain the somnolence observed with this drug. Olanzapine?s
antagonism of adrenergic alpha receptors may explain the orthostatic
hypotension observed with this drug. (Rxlist "Zyprexa," 2004)
PHARMACOKINETICS
Oral Administration
Olanzapine is absorbed very well and reaches peak concentrations in 6 hours
following an oral dose. It is mainly eliminated by first pass metabolism, with
approximately 40% of the dose metabolized before reaching the systemic
circulation. Pharmacokinetic studies showed that Zyprexa tablets and
Zyprexa Zydis (orally disintegrating tablets) dosage forms of olanzapine are
biochemically the same.
Olanzapine is the same kinetically over the clinical dosing range. Its half life
ranges from 21 to 54 hours.
Administration of olanzapine once daily leads to steady state concentrations
in about one week that are approximately twice the concentrations after one
single dose. Plasma concentrations, half life, and clearance of olanzapine may
vary between individuals based on smoking status, gender, and age.
Olanzapine is extensively distributed throughout the body. It is 93% bound to
plasma proteins by binding primarily to albumin and alpha one acid
glycoproteins. (Eli Lilly and Company "Zyprexa," 2004)
Intramuscular Administration
Zyprexa Intramuscular results in rapid absorption with peak plasma
concentrations occurring within 15 to 45 minutes of the initial injection.
Based upon a pharmacokinetic study in healthy volunteers, a 5mg dose of
intramuscular olanzapine produces a maximum plasma concentration
approximately 5 times higher than the maximum plasma concentration
produced by a 5 mg dose of oral olanzapine. The half life observed after
intramuscular administration is similar to that observed after oral dosing. (Eli
Lilly and Company "Zyprexa," 2004)
Metabolism and Elimination
Following a single oral dose of olanzapine, 7% of the dose of olanzapine was
recovered in the urine as unchanged drug, indicating that olanzapine is
efficiently metabolized. Approximately 57% and 30% of the dose was
recovered in the urine and feces, respectively.
RISPERIDONE/RISPERDAL DESCRIPTION
Risperdal also known by the generic name risperidone is a psychotropic agent
belonging to the chemical class of benzisoxazole derivatives. The chemical
designation is 3 [2 [4 (6 fluoro 1,2 benzisoxazol 3 yl) 1 piperidinyl]ethyl] 6,7,8,9
tetrahydro 2 methyl 4H pyrido[1,2 a] pyrimidin 4 one. Its molecular formula is
C23H27FN4O2. The structural formula is:
Figure 3
Risperidone is a white to slightly beige powder. It is practically insoluble in
water, freely soluble in methylene chloride, and methanol (Rxlist
"Risperidone," 2004).
Risperdal tablets are available in 0.25mg (dark yellow), 0.5mg (red / brown),
1mg (white), 2mg (orange), 3mg (yellow), and 4mg (green) strengths. Inactive
ingredients are colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate,
and starch. Tablets of 0.25, 0.5, 2, 3, and 4mg also contain talc and titanium
dioxide. For color the 0.25mg tablets contain yellow iron oxide, the 0.5 mg
tablets contain red iron oxide, the 2 mg tablets contain FD&C Yellow No. 6
Aluminum Lake, the 3mg and 4mg tablets contain D&C Yellow No. 10, and the
4mg tablets contain FD&C Blue No. 2 Aluminum Lake.
CLINICAL PHARMACOLOGY
PHARMACODYNAMICS
The mechanism of action of risperidone, as with all other drugs used in
treating schizophrenia and schizophrenic symptoms, is unknown. Although, it
has been proposed that the drug?s therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2
(5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2
may explain some of the other effects of risperidone.
Risperidone is a selective monoaminergic antagonist with high affinity for the
serotonin Type 2, dopamine Type 2, Type 1 and 2 adrenergic, and H1
histaminergic receptors. Risperidone acts as an antagonist at other receptors,
but with lower potency. Risperidone has low to moderate affinity for the
serotonin 5HT1C, 5HT1D, and 5HT1A receptors, a weak affinity for the dopamine
D1 and haloperidol sensitive sigma site and no affinity for cholinergic,
muscarinic or Beta 1 and Beta2 adrenergic receptors. (Janssen
Pharmaceutica "Risperidone," 2003)
PHARMACOKINETICS
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone
is 70%. Pharmacokinetic studies showed that Risperdal M Tab (Orally
Disintegrating Tablets) and Risperdal Oral Solution are bioequivalent to
Risperdal Tablets.
Following oral administration of solution or tablet, peak plasma concentrations
of risperidone occurred at about 1 hour. Steady state concentrations of
risperidone are reached in 1 to 5 days.
Distribution
Risperidone is rapidly distributed. In plasma, risperidone is bound to albumin
and alpha acid glycoprotein. The plasma protein binding of risperidone is 90%,
and that of its major metabolite, 9 hydroxyrisperidone is 77%. Neither
risperidone nor 9 hydroxyrisperidone displaces each other from plasma binding
sites. (Janssen Pharmaceutica "Risperidone," 2003)
Metabolism
Risperidone is extensively metabolized in the liver. The main metabolic
pathway is through hydroxylation of risperidone to 9 hydroxyrisperidone by the
enzyme, CYP 2D6. A minor metabolic pathway is through N dealkylation. The
main metabolite, 9 hydroxyrisperidone, has similar pharmacological activity as
risperidone. Consequently, the clinical effect of the drug results from the
combined concentrations of risperidone plus 9 hydroxyrisperidone.
CYP2D6, also called debrisoquin hydroxylase, is the enzyme responsible for
metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other
drugs. CYP2D6 is subject to genetic polymorphism and to inhibition by a
variety of substrates and some non substrates, notably quinidine. (Rxlist
"Risperidone," 2004)
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much
lesser extent, via the feces. As illustrated by a mass balance study of a single
1mg oral dose of risperidone administered as solution to three healthy male
volunteers, total recovery of risperidone at 1 week was 84%, including 70% in
the urine and 14% in the feces. The apparent half life of risperidone was 3 to
20 hours. The apparent half life of 9 hydroxyrisperidone was about 21 to 30
hours (Rxlist "Risperidone," 2004).
SIDE EFFECTS
Olanzapine and Risperdal are known as second generation atypical
antipsychotics (Rivas Vazquez, 2003). Rivas Vazquez (2003) suggests that
Aripiprazole is the first of the third generation of atypical antipsychotic, as it is
a dopamine system stabilizer. Aripiprazole is manufactured by the Bristol
Myers Squibb company and under the name Abilify by the Japanese
pharmaceutical company Otsuka (Rivas Vazquez, 2003).
The new atypical antipsychotics (also known as neuroleptics or major
tranquilizers) have shown evidence of identical or better therapeutic
effectiveness than the first generation or conventional antipsychotics, as their
side effects have a more positive report (Rivas Vazquez, Blais, Rey Gustavo,
Rivas Vazquez, 2000). Rivas Vazquez et al. (2000) believe that atypical
antipsychotics are better at managing psychotic symptoms than traditional
antipsychotics, because of patient compliance. Atypical medications were
first defined as relieving psychotic symptoms while cutting down
extrapyramidal side effects (EPS) and (TD) Tardive Dyskinesia (Rivas Vazquez
et al. 2000). Tandon (2002) concurred, finding that the advantages of atypical
antipsychotics of the newer generation are considerably greater than the
traditional medications when taking into account EPS. Tandon (2002, p.297)
states that atypical antipsychotics are better at treating the following
symptoms: lesser dysphoria, less impaired cognition, negative symptoms, and
a lower risk of TD. Rivas Vazquez et al.(2000)has expanded the description of
atypical antipsychotics to include the decreased occurrence of elevated
prolactin levels, reduction of negative symptoms, a lessening of
neurocognitive deficits, and a therapeutic effectiveness among patients who
are resistant to treatment with the first generation or traditional neuroleptics
(Rivas Vazquez et al. 2000). Doweiko (2002, p.55) states that one rule of
pharmacology is that there is risk on ones part when taking any medication.
To quote Doweiko (2002, p.55) (actual sentence): Every chemical agent has
the potential to harm the individual, although the degree of risk varies with
the specific chemical used, the individual?s state of health, and so on. The
side effects of atypical antipsychotics will be discussed in more detail later in
this paper.
A significant feature of all atypical antipsychotics is their high affinity
(resemblance or binding) for 5HT2A (serotonin) receptors over D2 (dopamine)
receptors (Rivas Vazquez et al. 2000) (Tandon, 2002). Tandon (2002) gives the
pharmacological profile for Risperidone D2 C 5HT2A, C 5HT2c, C alpha1 NE, and
Olanzapine D2 C 5HT2A, C 5HT2c, C (alpha1 NE) C (M1) C H1. Aripiprazole is an
agonist at the presynaptic D2 autoreceptors and as an antagonist at post
synaptic D2 receptors (Rivas Vazquez, 2003, p.4). Similar to Risperidone and
Olanzapine at the 5HT2A receptor Aripiprazole applies an antagonist, which
lessens the risk for attenuating negative symptoms and EPS (Rivas Vazquez,
2003). Aripiprazole may have a positive result on related symptoms of
schizophrenia, as for example the symptoms of anxiety, depression, cognitive,
and negative symptoms (Rivas Vazquez, 2003).
The hypothesis for the disorder of schizophrenia is believed to be caused by
the hyperactivity of dopamine synthesis and also the release of the
neuroreceptor dopamine (Rivas Vazquez, 2003). For all antipsychotics to be
successful, it is believed that they must be an antagonism or a blocker of
dopamine receptors (Rivas Vasquez, 2003). There are five dopamine receptors
according to (Rivas Vazquez, 2003), which are then divided into two subgroups
D1 (to be composed of D1 and D5 ) and D2 (to be composed of D2, D3, and D4,)which
are contained separately all through the dopaminergic system in the brain.
The D2 receptor also has an affinity for the serotonin subtype 2A (5HT2A) (Rivas
Vazquez, 2003).
The (D4) dopamine receptor is located in the frontal cortex and in the limbic
system, and not in the striatum (Rivas Vazquez et al. 2000). The dopamineric
neurons begin in the mesencephalon (midbrain, and which includes the
substantia nigra)and ventures from the ventral tegmental area to the cortical
regions (mesocortical pathways, which connects the midbrain to the prefrontal
cortex (Palfai and Jankiewicz, 2001)and to the limbic system (mesolimbic
pathways, which connects the midbrain to the ventral tegmental, the medial
forebrain bundle, and the nucleus accumbens which according to (Palfai and
Jankiewicz, 2001)is the area of the brain that is linked to pleasure, reward,
and has the reinforcing effect of drugs). Rivas Vazquez (2003) includes
emotions, cognition, and motivation as well as reward to the above mentioned
pathways. Rivas Vazquez (2003) believes that the positive symptoms of
schizophrenia, for example, delusions, hallucinations, or disorganized behavior
may originate in the cortical and limbic system. Other dopamineric neurons,
venture down the nigrostriatal pathway which connects the substantia nigra
with the basal ganglia, which also includes the striatal (Rivas Vazquez, 2003)
(Palfai and Jankiewicz, 2001, p.144). It is in this area that motor control and
motor initiation takes place according to (Rivas Vazquez, 2003). Palfai and
Jankiewicz, (2001) state that Parkinson?s disease, has been linked to
degeneration of (DA) dopamine neuroreceptors in the nigrostriatal pathway of
the brain. The dopamineric neurons then venture form the hypothalamus to
the pituitary (the tuberoinfundibular system, which starts in the ventral
tegmental region) where prolactin and other hormones are released (Rivas
Vazquez, 2003) (Palfai and Jankiewicz, 2001).
Eerdekens, Van Hove, Remmerie, and Mannaert (2004) study was an open
label, 15 weeks study to research the effects of long acting Risperdal. The 86
participants were between the ages of 18 and 65 years of age, and all had the
diagnosis of schizophrenia or a schizophrenia subtype, and which all met the
conditions of the DSM IV (Eerdekens et al. 2004). Participants were stabilized
on and given 2, 4, or 6mg a day of oral Risperidone for 4 weeks and then were
given (i.m.) inner muscular injections of 25, 50, or 75mg of long lasting
Risperidone in the order of, every 2 weeks (Eerdekens et al. 2004). The
researchers, (Eerdekens et al. 2004) found long acting Risperidone injections
of (i.m.) inner muscular injections of 25, 50, or 75mg to be equal to daily doses
of Risperidone of 2, 4, or 6mg. The researchers concluded that patients with
schizophrenia, schizoaffective disorder or schizophreniform disorder can be
easily changed form oral to long acting Risperidone (Eerdekens et al. 2004).
Participants and researchers reported little or no injection site pain or
unfavorable reactions (Eerdekens et al. 2004). Long acting Risperidone is
water based injection and seems to be less painful than oil based injections
(Eerdekens et al. 2004). According to (Eerdekens et al. 2004) the symptoms of
schizophrenia were not aggravated and were even improved after changing
from the oral to (i.m.) inner muscular injections, and the researchers report
that at the final (i.m.) injection 44 to 62 % of the participants demonstrated a
clinical improvement from baseline, notwithstanding their having been
clinically stable for at the most 4 weeks prior to the start of the research.
This study shows that patients may be helped with long acting Risperidone.
Inner muscular injections (i.m.) every two weeks may be a treatment therapy
that a patient could comply with, and an advantage to long acting Risperidone
is daily medications are not missed. Patients reported that the inner muscular
injections (i.m) were less painful than oil based medications. Patients may be
more compliant with taking long acting Risperidone with less pain and
soreness at the site of injection.
Yamada, Isotani, Irisawa, Yoshimura, Tajika, Yagyu, Saito, and Kinoshita
(2004) report that their study was to rate the differences of sedative effects
between the antipsychotic drugs using EEG as a measurement. The atypical
antipsychotics Olanzapine, Perospirone, Quetiapine, and Risperidone were
compared among their group and compared to the conventional antipsychotic
group of Chlorpromazine (Thorazine) and (Haldol) Haloperidol (Yamada et al.
2004). The participants were 14 right handed males with a mean age and s.d.
= 24.1 plus or minus 4.1 years (Yamada et al. 2004). The participants
completed a 7 day session with a one week gap between (Yamada et al. 2004).
In the session participants were orally given either 0.5mg Risperidone, 4mg
Perospirone, 33mg Quetiapine, 1.25mg Olanzapine, 50mg Chlorpromazine, 1mg
Haloperidol or a Placebo (Yamada et al. 2004). The researchers placed 19
scalp electrodes on each participants scalp, and EEG recordings with a band
pass filter of 0.3 to 60 HZ and a sampling rate of 128 HZ were recorded
(Yamada et al. 2004). According to (Yamada et al. 2004) the EEG recordings
were conducted 2, 4, and 6 hours after participants were administered the
antipsychotics. Twenty two second EEG data was observed for each period of
time (Yamada et al. 2004). Global field Power (GFP) was calculated for 7
frequency bands delta: 1.5 to 6 HZ, (delta is deep sleep of stage 3 and 4) (Von
Bozzay, 1980), theta: 6.5 to 8 HZ (theta is day dreaming, 4 and 7 HZ) (Von
Bozzay, 1980), alpha 1: 8.5 to 10 HZ (alpha is an alert but relaxed state of 8 to
13 HZ) (Von Bozzay, 1980), alpha 2: 10.5 to 12 HZ, beta 1: 12.5 to 18 HZ (beta
is state of concentration of 18 and 30 HZ)(Von Bozzay, 1980), beta 2:18.5 to 21
HZ, beta 3: 21.5 to 30 HZ (Yamada et al., 2004). The researchers state that
they used Low Resolution Electromagnetic Tomography (LORETA, according to
Pascual Marqui et al., 1999) to record and distinguish between cortical regions
that show the result of a test drug in a specific frequency band. The results of
(Yamada et al. 2004) study were that GFP in the delta band after the
administration of Risperidone and Quetiapine may well show sedative effects
on the brain. Risperidone and Quetiapine have a high affinity to A1 and H1
receptors (Yamada et al. 2004). The researchers found a positive correlation
between the Theta band (4 to 8 HZ) and D2 receptor affinity and among fast
beta band (24 to 30 HZ) and histiaminic H1 receptor affinity in patients who
have the schizophrenia disorder (Yamada et al. 2004; Small et al. 1996).
Yamada et al. (2004) admitted that the correlation among the receptor
bindings and EEG results of the antipsychotic medications are still not
completely understood.
In the (Yamada et al., 2004) study the results show that Risperidone can be
shown to have an affinity for A1 and H1 receptors. Although the researchers
have only a correlation between receptor bindings and EEG it is the beginning
of further research. Olanzapine was found to be helpful with negative
symptoms. With Olanzapine, EEG had shown physical changes in the brain,
the EEG showed that Olanzapine could sedate the posterior area while leaving
the frontal area unsedated.
Yamada et al.(2004)state in their research that the atypical antipsychotic
Olanzapine was shown to bring about a frontal shift of brain electrical activity
which may mean that Olanzapine may be helpful in avoiding the negative
symptoms of schizophrenia. Yamada et al. (2004) report that the sedative
effect of Olanzapine is spatially selective, that is Olanzapine inhibits the
posterior activity while leaving the frontal activity unharmed. Yamada et al.
(2004) believes that their LORETA results were the same as (Hubl et al. 2001)
for the atypical antipsychotic Olanzapine. This shows that there has been a
replication of other research.
Cerdan, Guevara, Sanz, Amezcua, and Ramos Loyo (2004) state that the
purpose of their study was to discover EEG brain electrical activity changes
which were produced by the atypical antipsychotic Olanzapine. Participants
were fourteen male patients (between the ages of 18 and 45 years of age) with
Treatment Refractory Schizophrenia (TRS), and who were selected from the
Guadalajara Mental Health Center of Mexican Social Security Institute.
According to (Cerdan, et al. 2004) patients met the TRS criteria if they had
the following symptoms: (a) no improvement of symptoms after a treatment
period of 6 weeks. (b) The patient needed a dosage of 40 mg of haloperidol or
more for a period of more than 1 day. (c) The patient score changes of 20 % or
less on the Brief Psychiatric Scale (BPRS). (d) A Clinical Global Impression
score of at least two points. Those participants who were selected, had
diagnosis of TRS from between 1 and 10 years (3.78 plus or minus 2.86), and
who were not reacting to other atypical antipsychotics. EEG trials were
conducted with eyes open and eyes closed in 2 sessions per participant: (1)
under atypical antipsychotics (pretreatment) and before the failure period; (2)
after 8 weeks with Olanzapine (post treatment) (Cerdan et al. 2004). The
researchers report that the trials started at 16.30 and lasted for about 1 hour
(Cerdan et al. 2004).
The patients in the (Cerdan et al. 2004) study improved by 57% (8 out of 14)
with Olanzapine, and on BPRS there was a decrease of 49% (p<0.008). On the
PANSS there was a decrease of 31% in positive and 24% in negative symptoms
(Cerdan et al. 2004). Participants who demonstrated improvement to
Olanzapine had a decrease of 45% on positive symptoms and 35% on negative
symptoms, those participants who had poor results demonstrated a decrease
of 18.2 and 18%, in that order (Cerdan et al. 2004). The Researchers report
that theta 1, theta 2, alpha 1 bands increased after therapy, and that the beta
2 band showed a decrease (Cerdan et al. 2004). There was an
interhemispheric correlation decrease for the theta 2, and an interhemispheric
correlation increase for different areas of the frontal area and posterior areas
(Cerdan et al. 2004).
This study shows that Olanzapine may help patients who may not be helped by
other atypical antipsychotics or conventional antipsychotics. Again the
researchers were able to see which areas of the brain were affected by
Olanzapine. The researchers stated that 30% of schizophrenic patients
showed no symptom relief from any atypical antipsychotics (Cerdan et al.
2004).Sadly not all of the patients in this study were helped.
As previously stated, no conventional or atypical antipsychotic is free from
side effects, including Olanzapine, Risperidone, or Aripiprazole. Aripiprazole is
fairly new to the market and so far there have been few studies which have
reported side effects, or should I say, none that I have found. Listed below are
the side effects of Olanzapine, Risperidone, or Aripiprazole.
According to (Preston and Johnson, 2004) atypical antipsychotics have three
major side effects: sedation, anticholinergic (ACH), and extrapyramidal effects
(EPS). The extrapyramidal system is a group of nerve fibers which includes
the basal ganglia and the substantia nigra (Palfai and Jankiewicz, 2001).
Preston and Johnson (2004) report that there are four types of extrapyramidal
effects (EPS), the following are: Parkinson like side effects, Akathisia, Acute
Dystonia, and Tardive Dyskinesia (TD):
1. Parkinson like side effects: Involve muscular rigidity, flat affect (a face
that looks like a mask, tremor, and brandykinesia (motor responses that
are slowed), (Preston and Johnson, 2004).
2. Akathisia: This is a feeling of agitation or restlessness, which the patient
sees as uncontrollable (Preston and Johnson, 2004). The researchers
(Preston and Johnson, 2004) state some physicians may incorrectly
diagnose akathisia as anxiety.
3. Acute Dystonias: Are protracted muscular contractions or muscle spasms,
which are usually of the neck and head (Preston and Johnson, 2004).
4. Tardive Dyskinesia (TD): The following symptoms are uncontrolled mouth
and lip sucking or smacking, and chorea (jerky spasmodic movements of
the limbs, trunk, and facial muscles) (Preston and Johnson, 2004).
According to (Preston and Johnson, 2004) TD is a late onset EPS. The
researchers state further that TD is very severe and is frequently an
irreversible side effect of neuroleptic medications.
Preston and Johnson (2004) suggest that, because of the possible risk of TD
patients should be treated with the lowest dose that gives relief of symptoms.
Rivas Vazquez (2003) acknowledges that the second generation of atypical
medications reduces the side effect of TD, although there is still a risk of TD.
Tandon (2002, p. 305) ranks the 5 atypical antipsychotic medications in order
of risk of EPS (aripiprazole or abilify was not mentioned in the journal article)
they are as followed: Risperidone > Olanzapine D Ziprasidone> Quetiapine>
Clozapine. PET scans studies have shown Risperidone to cause TD side
effects with dosages of over 10 mg a day (Rivas Vazquez et.al 2000). The
standard clinical dosage of 6 mg/day may create a risk of TD owing to
needlessly high D2 receptor occupancy (Rivas Vazquez et al. 2000).
Rivas Vazquez (2003) reports of studies, which had used PET scans to
measure dopamine receptor occupancy in participants who were given
Aripiprazole, the results, were that even at occupancy values of above 90% in
the nigrostriatal pathway, there was no indication of EPS. Aripiprazole or
Abilify has a reduced risk of TD as it does not seem to cause upregulation of D2
receptors (Rivas Vazquez, 2003). Aripiprazole or Abilify has verified and equal
effectiveness with Olanzapine and Risperidone with a propensity for fewer
unfavorable side effects (Rivas Vazquez, 2003).
Anticholinergic (ACH) Side Effect: Include dry mouth, urinary hesitation,
blurry vision, constipation, and infrequent delirium (Preston and Johnson,
2004).As well as side effects to cardiovascular systems (tachycardia,
tachyarrhythymias, etc., (Tandon, 2002; Rivas Vazquez, 2003). Tandon (2002,
p.308) has ranked the 5 atypical antipsychotic medications in order of risk:
Clozapine A Olanzapine> Quetiapine > Risperidone / Ziprasidone. Aripiprazole
or Abilify was not mentioned in the journal article (Tandon, 2002).
Weight Gain: Considerable weight gain is a frequent side effect of the use of
atypical antipsychotics. Preston and (Johnson, 2004; Tandon 2002) state that,
because of the side effects of weight gain there is an increased risk of
diabetes. Rivas Vazquez and Rey (2002); Rivas Vazquez, 2003) also include
diabetes, hyperglycemia, and dyslipidemia as added risks of weight gain.
Murashita, Kusumi, Inoue, Takahashi, Hosoda, Kangawa, and Koyama (2005) in
their study report that the atypical antipsychotic drug Olanzapine may
increase the secretion of ghrelin, and thereby increasing the appetite, which
consequently leads to a weight gain. Ghrelin is a hormone which motivates
appetite and eating. Murashita et al. (2005, p.2) report that the source of
ghrelin was first isolated from the rat and human stomach as a cognate
endogenous ligand for growth hormone (GH) screretagogue receptor. The
researchers report that ghrelin is a 28 amino acid peptide with an n octanoyl
modification of serine 3 essential for it biological action (Murashita et al. 2005,
p.2). Ghrelin makes available a peripheral signal to the hypothalamus to
encourage eating and adiposity. Under conditions of starvation and anorexia
nervosa ghrelin is increased and is decreased during eating and obesity
(Murashita et al. 2005, p.2). The participants in this study included 7 patients
(4 men and 3 women, with an age range from 25 to 69 years) who were
diagnosed with the disorder of schizophrenia, and who were outpatients from
the Hokkaido University Hospital. The daily Olanzapine dosage was 10 to
15mg/day (Murashita et al., 2005). It was found that excessive levels of
ghrelin enhances the appetite, and may lead to an increase in weight gain for
patients who take Olanzapine (Murashita et al. 2005).
Olanzapine has a high affinity for serotonin (5HT)2A, 5HT6, histamine (H) 1, and
5HT2c and a weak affinity for dopamine (D) 2 and cholinergic muscarine (AchM)
receptors (Murashita et al. 2005). According to (Murashita et al. 2005)
histamine (H1) receptor antagonists boost the appetite and 5HT2c receptor
antagonists have been connected to hyperphagia (compulsive over eating over
a period of time) and the increase in obesity. Murashita et al.(2005,p.5)believe
that Olanzapine may increase ghrelin by being in contact with the 5HT2A/2C, H1,
D2,AchM,and NPY, AGRP neuron receptors.
Rivas Vazquez (2002) reports that histamine (H1) receptors in the
hypothalamus exercise some control over appetite and arousal, as histamine
antagonists increase the desire to eat. Not only does histamine contribute to
increased appetite,H1 also brings about sedation which in turn leads to weight
gain through physical inactivity (Rivas Vazquez,2002). Serotonin 5HT has
also been linked to weight gain, the neurotransmitter has subtypes of 5HT2A,
5HT2C, and 5HT1A (Rivas Vazquez, 2002). According to the researcher (Rivas
Vazquez, 2002) 5HT2C was found to be the receptor which contributed to
weight gain. Rivas Vazquez, (2002) further states that the serotonin receptor
5HT1A is thought to influence glucose homeostasis. Antagonisms for the
muscarinic receptors which create anticholinergic side effects may be an
indirect cause of weight gain, as a dry mouth may increase the drinking of high
calorie drinks (Rivas Vazquez, 2002).
Rivas Vazquez, (2002) reports that Olanzapine has a strong binding for (H1) and
a high affinity for 5HT 2A, 5HT2C, and muscarinic receptors, as well as a
moderate affinity for [alpha] 1 adrenergic receptors, thus making
Olanzapine one of the most potent atypical antipsychotics for weight gain side
effects. Olanzapine was found to be second only to Clozapine as a contributor
to weight gain (Rivas Vazquez, 2002). Patients who were treated with
Olanzapine in one ten week study were found to have a mean weight gain of
4.2 kg. (Rivas Vazquez, 2002). Rivas Vazquez (2002) reports that there has
been a connection between Olanzapine and diabetes in addition to
hyperglycemia, as Olanzapine elevate leptin, insulin, and lipid levels.
Risperidone shows a very high affinity for 5HT2A receptors, high affinity for
5HT2C, and [alpha] 1 adrenergic receptors, as well as a moderate affinity
histaminergic, (H1) receptors. Risperidone has a slight affinity for muscarinic
receptors(Rivas Vazquez, 2002).In one study, there was a connection between
Risperidone and moderate weight gain, patients who were given Risperidone
for 10 weeks, had an average weight gain of 2.10 kg (Rivas Vazquez, 2002).
Risperidone was found to be somewhat less than the first generation
antipsychotic Chlorpromazine (Thorazine) with an average weight gain of 2.58
kg (Rivas Vazquez, 2002). According to (Rivas Vazquez, 2002)the average
weight gain had a propensity to peak at just about 2 to 3 kg through out the 8th
and 12th week of therapy and then the weight gain leveled off. The risk of
diabetes seems to be low as (Rivas Vazquez, 2002) reports of only 2 studies of
glucose dysregulation, and that the risk of hyperglycemia or diabetes seems to
be minor.
Tandon (2002, p.306,) has ranked the 5 atypical antipsychotic medications in
order of risk(Aripiprazole or Abilify was not mentioned in the journal article):
Clozapine> Olanzapine>Risperidone D Quetiapine > Ziprasidone;the average
weight gain for one year of treatment ranges from 33 lbs (Clozapine) to 2 lbs
(Ziprasidone) with Olanzapine (25 lbs) and Risperidone and Quetiapine (4 to 8
Lbs).Preston and Johnson (2004) have recommended two atypical
antipsychotic, to diminish the side effect of weight gain: Ziprasidone (smallest
amount of weight gain) and Aripiprazole (not linked with weight gain).
QTc Prolongation: Tandon (2002) lists the side effect QTc Prolongation (slowed
ventricular repolorarization. Tandon (2002, p.307) has ranked the atypical
antipsychotic medications (Aripiprazole or Abilify was not mentioned in the
journal article) in order of QTc risk as follows: Ziprasidone D Clozapine >
Quetiapine, Risperidone, and Olanzapine. Tandon (2002, p. 307) further states
that QTc prolongation linked with Olanzapine, Risperidone, and Quetiapine are
in the same range as Haloperidol (which has been shown to cause clinically
unrelated QT prolongation). Rivas Vazquez (2003) reports that the atypical
antipsychotic Aripiprazole was shown to be less potent than Haloperidol in
inducing inhibitory effects on cardiovascular system functioning.
According to (Tandon, 2002, p.307) prolactin elevation and related side effect
are as follows: menstrual symptoms, and sexual dysfunction. Rivas Vazquez
et al. (2000) includes galactorrhea (secretion of breast milk), because of the
side effect of increased prolactin levels. Side effects of increased prolactin
levels happen in about 25% to 30% of patients (Tandon, 2002). Risperidone
(Risperdal brand name) was the single atypical antipsychotic medication
mentioned by (Tandon, 2002, p.307) as increasing prolactin levels in patients.
As stated before in the paper aripiprazole or abilify was not mentioned in the
journal article (Tandon, 2002).
Hypotension and postural hypotension is a side effect of all atypical
antipsychotics and conventional medications (Tandon, 2002). Tandon (2002,
p.307) ranks the 5 atypical antipsychotic medications in order of risk of
hypotension: Clozapin > Queiapine> Risperidone > Olanzapine > D Ziprasidone.
Remember that Aripiprazole also known as Abilify was not mentioned in the
(Tandon, 2002) journal article. Tandon (2002) reports hypotension to be more
significant near the beginning phase of treatment with tolerance developing
over the course of treatment.
Tandon (2002) reports that each neuroleptic and conventional antipsychotic
varies in intensity of sedation side effects for the patient, although all atypical
antipsychotics are made to sedate patients. Sedation is most renowned
during the beginning phase of antipsychotic treatment, with some
development of tolerance over the course of treatment (Tandon, 2000). Again
remembering that Aripiprazole also known as Abilify was not mentioned in
(Tandon, 2000), the researcher ranks the 5 atypical antipsychotics in the
following order: Clozapine > Quetiapine > Olanzapine > Risperidone >
Ziprasidone (Tandon, 2002, p. 307). Preston and Johnson (2004) give the
customary daily oral dosage for the following atypical antipsychotics:
Olanzapine (Zyprexa) 5 to 20 mg, Risperidone (Risperdal) 2 to 10 mg, and
Aripiprazole (Abilify) 15 to 30 mg.
Other risks: Increased risk of heat stroke or hypothermia due to temperature
regulation (Preston and Johnson ,2004,p.45).Also quoting directly the author?s
Preston and Johnson,2004,p.45)description of the side effect of neuroleptic
malignant syndrome ( a very rare syndrome that presents fever,
extrapyramidal rigidity, severe autonomic dysfunction and in some cases
even death).Preston and Johnson (2004)believe that because of side effects,
patients with psychotic disorders should be treated by a psychiatrist.
This paper was written to inform the reader and myself about the atypical
antipsychotic medications Olanzapine (Zyprexa brand name), Risperidone
(Risperdal brand name), and Aripiprazole also known as Abilify. Please,
consult with your family physician about any concerns that you may have with
any medication that you or someone that you know may be taking. Do not stop
taking any medication without speaking to your physician.
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Copyright © 2005, Dr. John M. Morgan, All rights reserved -
This page last edited 02-23, 2004
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