Mechanism Action Therapeutic Use Olazanpine Ariprpazole Treatment Schizophrenia Biology Essay

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In pharmacology, drug is a substance used for the prevention, diagnosis, cure and treatment of disease and for the relief of symptoms. It could also enhance physical or mental well-being.

There are many mental disorders, a state in which an individual's mental orientation is disrupted.  Examples of mental disorders include; Acute mania, bipolar, schizophrenia, depression,

For this particular essay I will be talking about schizophrenia, its symptoms, proposed aetiology and examples of the 2nd generation drug therapies being used to manage the condition.

Schizophrenia is a collection of symptoms characterised by thought disorders reflecting a break between the cognitive and emotional sides of one's personality (Kathryn L. McCance, 2010). Schizophrenia is classified into positive and negative symptoms using two systems, namely; ICD-10 and DSM-IV (Horton, Schizophrenia, 2011).

Positive symptoms which are abnormal experiences not experienced by other people include

HALLUCINATION: Described as a perception experienced in absence of an external stimulus and characterized mostly as auditory with patients suggesting that they hear voices talking to them, about them, commanding them, commenting or an echo of their thoughts

DELUSION: False belief that they are under the control of an external influence or their thoughts are known to other people i.e. paranoia of the radio or TV

FORMAL THOUGHT DISORDER: A disorder of conceptual thinking reflecting difficulty to understand speech and rapid shift from a topic of subject to another i.e. lack of awareness. New words are also invented (neologisms) (Horton, Schizophrenia, 2011, pp. 1-2)

Negative symptoms are normal experiences which are not experienced by schizophrenic patients which include;

SOCIAL WITHDRAWAL/ANHEDONIA: suggesting they isolate themselves from the world

LACK OF MOTIVATION: lack of interest in things that previously interested them

BLUNTED EFFECT: Inability to react normally to emotional stimuli e.g. when informed of the death of someone they laugh instead of sympathizing

 INSIGHT: schizophrenia patients do not belief anything is wrong with them or the need for treatment

UNDER ACTIVITY: Do less and speak less than normally

COGNETIVE DEFICITS: Deficits in attention, memory and problem solving (Horton, Schizophrenia, 2011, p. 2)

EPIDEMIOLOGY: An incidence rate of 25 per 100,000 per year with Life risk 1%, common in both sexes but onset earlier in men [mean age 28years] whilst women [32years], common in lower socio-economic groups and urban areas (Horton, Schizophrenia, 2011, p. 2).

Genetic epidemiologic studies indicate it is a heritable disorder. Lifetime event risk indicates 8-10% for siblings with schizophrenia, one parent with schizophrenia 12-15% whist with both parents ~40%. In monozygotic twins the concordance rate was 60% compared to 10% in dizygotic twins and Adoption studies illustrate that genes are more critical compared to environment (Horton, Schizophrenia, 2011, p. 4). However, it differs from simple genetic and Mendelian disorders because it involved several genes located on different chromosomes (Kathryn L. McCance, 2010). Therefore, no single gene has a major effect but they include 8p, 13q and 22q (Horton, Schizophrenia, 2011, p. 4).

Pathological studies have observed the following evidence in the brain of schizophrenic patients and they include enlarged ventricles (~ 40%), reduced brain weight (~ 30%), reduced cortical grey matter (~ 4%), abnormal clustering of neurones in the cortex, small cell bodies and reduced basal dendrites (Horton, Schizophrenia, 2011, p. 4).



DOPAMINE THEORY: Hypothesized as due to over activity of dopamine in the mesolimbic-mesocortical pathway with cell bodies in the ventral tegmentum of the midbrain which projects to the amygdala, nucleus accumben, hippocampus, frontal cingulate and entorhinal complex (Horton, Schizophrenia, 2011, p. 3) (Kathryn L. McCance & section editors, 2010). The evidence is supported by looking at the effect of amphetamine in releasing dopamine from dopaine receptors [subtyped D1, D2, D3, D4 and D5] in the brain leading to schizophrenic like symptoms (Horton, Schizophrenia, 2011, p. 3). However, evidence against based on looking at the CSF concentration of HVA found not to be elevated as expected, no change in DA receptors in PET scans of drug-free schizophrenics but reports show that increased numbers of D2 receptors in post mortem sample were due to drug treatment (Horton, Schizophrenia, 2011, p. 3).

In conclusion, it is hypothesized that hypodopaminergic transmission in the dorsal prefrontal cortex leads to negative symptoms whilst hyperdopaminergic transmission in the mesolimbic pathways such as the temporal lobe, hippocampal, Amygdala, nucleus accumbens and anterior cingulated cortex leads to positive symptoms (Kathryn L. McCance, 2010).  

GLUTAMATE: Evidences indicate an under activity of glutamate transmission such as decreased cerebrospinal fluid [CSF] glutamate, loss of glutamate neurons in medial temporal regions, increase in certain types of glutamate receptors to compensate for decrease in transmission, glutamate receptor subtype [NMDA] antagonist phencyclidine makes schizophrenic symptoms worse (Horton, Schizophrenia, 2011, p. 3)

GABA [gamma-aminobutyric acid]: Evidence of reduced GABA transmission due to dorsal prefrontal cortex alterations/ hypoactivity such as diminished functions of Glutamic acid Decarboxylase needed in biosynthesis of GABA lead to the negative symptoms (Kathryn L. McCance, 2010). 

5HT [serotonin]: Evidence show an increase in 5HT [serotonin] transmission (Horton, Schizophrenia, 2011, p. 4).


ENVIRONMENTAL FACTORS: These include malnutrition in pregnancy, influenza in 1st trimester, winter/spring births, delivery complications, head circumference at birth and minor physical alterations (Horton, Schizophrenia, 2011, p. 5)


Antipsychotic drugs also called Neuroleptics 'to clasp the neuron' which are effective in treating acute psychosis and reducing the risk of future psychotic episodes (MedicineNet, 2011).  Olanzapine and Aripiprazole are both 2nd generation atypical antipsychotics which exert their effects on a range of neurotransmitter receptors i.e. non selective compared to typical 1st generation neuroleptic which mainly block D2 receptors. There is a preferential action on the DA mesolimbic/mesocortical pathway over a nigro-stratial pathway but research in animal studies is unclear (Horton, Major Tranquillizers, 2011, p. 4). Atypical neuroleptics which have relatively high 5HT2A binding affinity to D2 receptors produce lower EPS [exptrapyramidial symptoms and depress negative symptoms. Upon entry into the synaptic space, the antipsychotic drug must compete with endogenous dopamine for the receptor. Thus, therapeutic concentration needed to block 50% of dopamine receptors in the presence of dopaminewill be higher than that needed in its absence (Philip Seeman, 2004). This falls in accordance with the equation C50% = Ki ´ [1+D/D2 high], where D is the dopamine concentration in the synaptic space whilst D2 high is the dissociation constant of dopamine at the high-affinity state of the dopamine D2 receptor (Philip Seeman, 2004).


INDICATION: Relieve positive symptoms related to excess dopamine and negative symptoms towards dopaminergic hypofunction. It is given at a daily dose range of 10-30mg but starting dose could be 10 to 15mg per day (Kaplan, 2008). 

MECHANISM: Aripiprazole is a quinolinone derivative. Partial agonist at dopamine D2 and 5-HT1A receptors upon entry into the synaptic space and as an antagonist competes with the endogenous serotonin at 5-HT2 receptors. Described as a dopamine system stabiliser, in high levels of dopamine will act as an antagonist (Horton, Major Tranquillizers, 2011, p. 5) such as the mesolimbic pathway but not in regions with normal dopamine levels such as nigrostratial and tuberoinfundibular pathways. Thus, a D2 partial agonist is expected to reduce the positive symptoms of schizophrenia without producing movement disorders or elevated prolactin levels. In areas where dopamine activity is low, will act as an agonist to release dopamine neurons from inhibition. The D2 receptor is coupled to inhibitory G-proteins [Gi], which upon agonist binding, dissociates from the receptor to inhibit secondary messenger signalling mechanisms leading to further inhibitions. At 5HT1A receptors, aripiprazole also acts as a partial agonist, hypothesized to correlate with overall efficacy against the symptoms of schizophrenia including depression, anxiety and negative symptoms (MJ., 2000).The antagonistic effect on 5HT2 receptors are believed to be associated with a low liability for extrapyramidial side effects [EPS] and beneficial for relieving negative symptoms by disinhibiting the dopamine system in the striatum and prefrontal cortex (Horton, Major Tranquillizers, 2011, p. 4). Normally, DA neurons in the nigrostriatum and prefrontal cortex are inhibited by serotonin heteroreceptors but antagonism of 5HT2 receptors means the release of dopamine neurones, lower D2 receptor blockage. It also does not induce weight gain or QT prolongation (Horton, Major Tranquillizers, 2011, p. 5).

PHARMACOKINETICS: High absorption reaching peak plasma concentrations after 3 to 5 hours, protein binding is 99% and its half life is about 31 to 146 hours making it suitable for once daily dosing, clearance is affected by age reducing greatly in the elderly. It is extensively metabolised by Cytochrome P450 3A4 and 2D6 enzymes with active metabolite, dehydroaripiprazole (Burns, 2004).

SIDE EFFECTS: orthostatic hypotension, increased risk of seizures, sedation

OLANZAPINE (Druglib, Zyprex (Olanzapine) -Description and Clinical Pharmacology, 2006)

Indication: negative and positive symptoms of schizophrenia, acute mania with bipolar disorder, agitation and psychotic symptoms in dementia. It is given at a daily dose range of 5-20mg (Burns, 2004).

Class of drug: Atypical psychotics, ATC Therapeutic Category N05AH: Diazepines, oxazepines and thiazepines (PharmGkB, 2010-2011)  

MECHANISM: Antagonist enters the synaptic space and competes with the endogenous ligands to inhibit α-1 adrenoceptors and 5-HT2C which both mediates their actions by association with G proteins [Gq/11] that activate a phosphatidylinositol- calcium second messenger system whilst at 5-HT2A promotes dopamine release (Druglib, 2007). In the nigrostriatal pathway increased DA reduces EPS and tardive dyskinesia (Yogesh Dwivedi, 2005) but in the mesocortical pathway, increased DA release may ameliorate negative symptoms, that "neuroleptic induced deficit syndrome" (Voruganti L, 2004). Olanzapine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents but instead blocks 5-HT2A receptors (Druglib, 2007).

As an antagonist of D1 Gs-coupled proteins receptor it prevents activation of Adenylyl cyclase and DARPP-32 (dopamine and cAMP regulated phosphoprotein of 32 kD).  Dopamine binding activates the second messenger cAMP to activate Protein Kinase A (PKA) which phosphorylates DARPP proteins at Threonine residue 34 to inhibit phosphatase protein (PP1) allowing PKA to have a longer active life and overall, enhance the neuron's sensitivity to dopamine signalling. In contrast, dopamine binding to D2 receptors has an opposite effect: the second messenger phosphorylates DARPP on Thr75, causing it to act as a protein kinase inhibitor and decrease the neuron's sensitivity to signalling. The D2 and D4 receptor are coupled to inhibitory G-proteins, which dissociate from the receptor on agonist binding and inhibit secondary messenger signalling mechanisms causing further signalling inhibition (Greengard, 2011). Antagonist binding inhibits this process, resulting in cell depolarisation. They also cause dopamine to reduce DARPP-32 phosphorylation (Sarah M. Clinton, 2005).  

In addition, it antagonises histamine H1, Muscarinic M1 [mediate their actions through G-protein-Gq/11 [in some instances Gs and Gi].  Therefore, olanzapine can be seen to have multiple receptors activities.

SIDE EFFECTS: CNS depression which is due to it antagonistic effects on H1 receptors, orthostatic hypotension, reflex tachycardia and nasal congestion due to alpha1 inhibition whilst blurred vision and urine retention due to M1 inhibition, weight gain, increased QT intervals observed in ECG and increased risk of stroke in dementia elderly patients (Horton, Major Tranquillizers, 2011, p. 4)

PHARMACOKINETICS: its half life is 20-70 hours, plasma clearance is 12 to 47L/h and its protein binding is 93%. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation by enzymes; Cytochrome P450 2D6 and 1A2 with no active metabolite (Burns, 2004).


Olanzapine and aripiprazole are therapeutically used orally to treat schizophrenia and have different mechanisms of action. Olanzapine is a multireceptor antagonist, inhibiting M1, H1, α-1, D1, D2, D4 and 5-HT2A/2C receptors whilst Aripiprazole is a breakthrough neuroleptic with partial agonist activity on 5-HT1A and D2 receptors allowing it to alternate its actions and an antagonist of 5-HT2 receptors. They are both used to relieve positive and negative psychotic symptoms presented in schizophrenia and both have a relatively high 5HT2A binding affinity to D2 receptors produce lower EPS [exptrapyramidial symptoms] and depress negative symptoms. More so, they share side effects such as orthostatic hypotension,. Therefore, close monitoring of patients is necessary to ensure they get the best out of their treatments with control over their symptoms and possible drug induced side effects. NICE guidelines published 2002, "it is recommended that oral atypical antipsychotic drus are considered in the choice of first-line treatments for individuals with newly diagnosed schizophrenia" or "considered as treatment options for individual currently receiving classical antipsychotic drugs who, despite adequate symptom control, are experiencing unacceptable side effects and for those in relapse who have been previously experienced unsatisfactory management or unacceptable side effects" (Horton, 2011).