Schizophrenia - Physiology, Pathophysiology and Pharmacological Therapies

University Degree Subjects allied to Medicine

Schizophrenia

Physiology

Schizophrenia has been known to be a psychiatric disorder affecting 1% of the world’s population1, which affects the brain in a physiological approach and it’s known to be a progressive life-long illness1. The brain is part of the nervous system. The central nervous system (CNS) and the peripheral nervous system (PNS) make up the nervous system. The central nervous system consists of both the brain and the spinal chord while the peripheral nervous system consists of the network of nerves, which are all linked to the spinal chord and the brain. The CNS makes up the largest part of the nervous system, which controls everything in the body, both the CNS and the PNS has major impact in the way our behaviour and emotions are controlled (all activities of the body)2.

The brain, which controls our emotions, thoughts and movement, can be found in the cranial cavity, the brain is also known to control the autonomic functions which are our unconscious actions such as heart rate, digestion, breathing etc2. The brain consists of soft delicate neural tissues, which is protected by the skull, meninges and the cerebrospinal fluid. The brain can be divided into three main parts, which are: the forebrain which consist of the cerebrum, thalamus, hypothalamus and the limbic system, the midbrain which consists of the tectum and tegmentum, they tend to make the largest part of the brain stem, and the hindbrain which is made up of the cerebellum, pons and medulla oblongata. The midbrain, the pons and the medulla are sometimes known as the brain stem2

A normal healthy brain functions quickly and automatically by receiving electrical signals from the neurons3. Neurons are known to be electrical nerve cells that can gather information and transit electrical signals. There are lots of different neurons in our brain and body in which they pass electrical signals to other cells through the synapses, once it reaches the end of the axons, it stimulates tiny sacs which are known as neurotransmitters into the synapses, this then allows information to be carried to receptors on the other cells in our brain/body2. The neurotransmitters in our brain include amino acids, monoamines, peptides and acetylcholine, some of these neurotransmitters are known to be excitatory (glutamate) while some are known to be inhibitory (GABA) and some are known to depend on their receptor in order to determine if the transmitter is inhibitory or excitatory (dopamine) neurotransmitter4.

Structure of a typical NEURON

A basic neuron contains the cell body, which is the main part of the neuron as it contains all the necessary parts of the cell i.e. nucleus, mitochondria, ribosomes etc, followed by the axons, which usually carries electrical message, axons are usually covered with myelin, which is made of fat, it helps to speed transmission of a nerve impulse down the axons, followed by the dendrites, which allows connection to other cells as they are arranged at the end of the cell in a branch-like fashion, and finally the axon terminals, which are located at the end of an axon for information output2,6.

These neurotransmitter chemicals in our brain are released and they tend to bind to the receptor sites onto the postsynaptic neurons by crossing the synaptic cleft, the changes that occur when the binding takes place can either continue or inhibit the transmission of the impulse5. An uptake can occur when the function of the neurotransmitter is completed. Once any of these neurotransmitters are altered at the postsynaptic receptor, it can lead to a disease i.e. Schizophrenia3.

Pathophysiology

Schizophrenia was first termed by a Swiss Psychiatrist named Eugen Bleuler in 19117 and it’s known to affect both men and women equally but it tends to affect men at a much earlier stage than women usually in early adulthood8. The precise cause of schizophrenia is unknown but there are a number of factors / hypothesis discovered by various researchers, which include:

Genetics9 - which can run in the family only if one of the parents suffers from the disease in which the children will have approximately 9-10% chance of developing the disease. The monozygotic and dizygotic twin study is another part of research that has shown that there is a 40 - 50% chance of a monozygotic twin having the disease and a 9 - 12% chance of a dizygotic twins having the disease, therefore, an individual with a closer genetic information compared to the infected patient has a higher chance of getting the disease9.
Stimulant drugs such as cocaine and cannabis10, although these drugs cannot be a direct cause of the disease but it tends to be one of the factors that can lead to increased risk of schizophrenia, it can also lead to some of the negative symptoms observed in the schizophrenic patient and can cause relapses11.
Biochemical factors can also lead to schizophrenia such as Chemical imbalance in the brain i.e. dopamine12,14.
Brain injury and stress13.

Schizophrenia patients can experience either the negative symptoms, positive symptoms and cognitive symptoms14 the positive symptom which is caused by increased dopaminergic activity in the brain includes hallucinations, delusions, thought disorder while the negative symptom which is caused by reduced activation of prefrontal cortex might include emotional and social withdraw14 and the cognitive symptoms can include decrease verbal learning, memory difficulties, loss of concentration, problem solving etc, this disorder prevents sufferers from thinking clearly and recognising reality14,.

Schizophrenia patients are known to have part of their brain affected compared to normal brain. The cerebral ventricles of the brain tends to become larger, which tends to alter the brain structure associated with the disorder, they tend to have reduced brain activity of the frontal lobes of the brain, it is also known that schizophrenia patients tend to have less grey matter in their brain, both the hippocampus and the amygdala are found to be smaller compared to normal brain15,16.

The area of the brain, which tends to be affected in schizophrenia, includes the frontal lobe (prefrontal ...

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The area of the brain, which tends to be affected in schizophrenia, includes the frontal lobe (prefrontal cortex), thalamus, temporal lobe, cerebellum and the cingulated gyrus. All these features observed in schizophrenia brain shows that some connections in the brain are

abnormal, which gives rise to the symptoms of schizophrenia15. Several other method has also shown that these part of the brain is affected in schizophrenia patient, such as positron emission tomography (PET), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) scanning techniques has widely been used in order to understand better the structure and function of the affected brain to be examined in detail, a number of brain-imaging has helped in showing that abnormal brain morphology is involved in the development of schizophrenia18,19.

Dopamine which partly governs the brain activity has become one of the neurotransmitter known to affect schizophrenia patients, which proposes that the disorder is caused by increased level of dopamine in the brain between neurons, which results in excessive stimulation by combining with receptor on the brain cell. Excessive dopamine in the brain can disrupt emotional functioning as dopamine is involved in mood and control of complex movements, which can lead to schizophrenic psychosis21. The increase in dopamine concentration in affected patients is known to be mostly associated with increased activity of D2 dopamine receptors in the prefrontal cortex, which is found in the region of the frontal lobe, prefrontal cortex is also associated with memory, hence the disordered thinking and thoughts of an affected patient21.

Research has also shown that another neurotransmitter called serotonin is involved in causing symptoms of schizophrenia; various researches indicated that patients with schizophrenia felt better with drugs that affect the serotonin in the brain22,23. Other neurotransmitters that might be involved in the pathogenesis of schizophrenia include GABA, glutamate and acetylcholine. GABA is now known to be another hypothesis for the aetiology of the disease24.

Although there is no cure for schizophrenia but there are variety of drugs that can be used to treat schizophrenia most of which have similar mode of action and effects. Antipsychotic drugs (Neuroleptic drugs) are the first generation of primary treatment for the symptoms of this disorder; they are only used to control the symptoms but not to cure it. Antipsychotic drugs mainly depresses the action of dopamine which they can disturb its balance with another chemical in the brain (Ach), if an imbalance occurs, it can result in extra-pyramidal side effect, which include restlessness, disorder of movement and parkinsonism.

The drugs also occupy the dopamine D2 receptors by binding onto them, which prevents the effects of excess dopamine in the brain by reducing the transmission of nerve signals; this effectively makes the brain cells become less sensitive to dopamine. Another neurotransmitter blocked by these drugs is the serotonin 2 receptors, which is also involved in causing symptoms of the disorder.

Antipsychotic drugs are known to have a response delay of 2 – 3 weeks from administering the drug into observing therapeutic effects26,27,28.

Pharmacological Therapies

There are varieties of antipsychotic drugs, which is on the market for the treatment of schizophrenia, the much older drugs are known as typical antipsychotics and the much newer drugs are known as atypical antipsychotics. Some of the typical antipsychotic drugs include Chlorpromazine, Haloperidol, Sulpiride, Thioridazine, Pericyazine, Pimozide, Perphenazine and Flupentixol. The typical antipsychotic drug i.e. Haloperidol is known to cause tardive dyskinesia which consists of repeated movements of the mouth, tongue, face and sometimes hand and feet, this tends to be the most adverse long term risk of antipsychotic treatment, other common side effects include motor stiffness and twisting movement. They also have less effect on the negative and cognitive symptoms29.

Some atypical antipsychotic drugs include Olanzapine, Quetiapine, Risperidone, Clozapine, Amisulpride and Zotepine. The atypical antipsychotics are known to have advantage over the conventional drugs in which they tend to have less long-term risk observed in the much older drugs (Tardive dyskinesia, extra-pyramidal symptoms EPS), they are also better than the conventional antipsychotics at relieving patients of the negative symptoms although equally effective in relieving positive symptoms and they are better at preventing relapses. Some of the atypical antipsychotics are also known to reduce cognitive symptoms of the disease as they have less affinity for D2 dopamine receptors and higher for serotonin receptors leading to reduced EPS30,31.

Clozapine was the first atypical neuroleptic drug to be developed in 1990 having a broad binding profile; other neuroleptic drugs were then developed using the Clozapine profile as a starting point.

Research has shown that Clozapine been the first atypical drug has few extrapyramidal side effects compared to Haloperidol because it has low affinity for the dopamine D2 receptor but higher affinity for D4 receptor. It can also bind to other dopamine receptors at a much lesser extent such as D1, D3 and D5, due to its broad binding profile, it also has an affinity for the serotonin receptor subtypes; 5HT2, 5HT3, 5HT6, 5HT7 and also adrenergic (alpha 1 and 2), muscarinic (M1) and histaminergic (H1) receptors32. It’s an antagonist for both the D2 dopamine receptor and the 5HT2A serotonin receptor, which significantly works well by reducing the suicidal, violence and aggressive part of a schizophrenic patient; it also works well by reducing both the positive and negative symptoms of schizophrenia. Clozapine is also known to be more effective in the limbic than the striatum dopamine receptor. Clozapine has been proven to be well tolerated in the long-term use as it has a good patient compliance; hospitalisation rate for patients tends to be much lower, adverse side effects were reduced compared to Haloperidol, which shows less patient compliance and more side effects, although both drugs proved to have therapeutic efficacy in successfully preventing relapse32. Due to the major side effect observed by Clozapine, agranulocytosis, it can only be used as a first line treatment when other antipsychotic medication has proved insufficient33.

Amisulpride is another type of atypical antipsychotic drug, which is also used in reducing more of the negative symptoms of schizophrenia. Amisulpride is known to be selective for dopamine receptors having a high affinity for D2 and D3 dopamine receptors and not so well with serotonin receptors, the dose effect of Amisulpride is very important as if given at a higher dose, it blocks the postsynaptic dopamine D2 receptor in the limbic system which leads to reduced dopamine transmission but at a lower dose, it blocks the presynaptic D2 autoreceptors that is involved in the release and synthesis of dopamine which can effectively lead to reduced negative symptoms. It is also used in first episode patients with schizophrenia. The common side effect of this drug includes weight gain and hyperprolactinemia34.

Olanzapine is another type of atypical antipsychotic which is known to be a better treatment for negative symptoms compared to typical neuroleptics but for the positive symptoms, treatments are equivalent with typical antipsychotics. It tends to have high affinity for 5HT2 serotonin receptors than dopamine D2 receptors, it is also known to be an antagonist for other serotonin and dopamine subtypes also for muscarinic, histaminergic and adrenergic receptors35. Various research and studies has shown Olanzapine to be more effective more when compared to Haloperidol and Risperidone. Olanzapine has also been compared to Clozapine in patients failing to respond to antipsychotic medication, but no significant difference in efficacy was observed, which shows that Olanzapine was a safe medication for schizophrenics. Various studies have also shown that Olanzapine when compared to Haloperidol or other typical antipsychotics shows reduced extra-pyramidal symptoms (EPS) and a higher clinical response with first episode patients. Common side effect includes dizziness, weight gain and sedation36.

Risperidone is another type of atypical antipsychotic drug that also act as an antagonist for both dopaminergic D2 receptor and the serotonin 5HT2 receptor. It is a much newer drug making it have lesser side effects. It relieves patient with both the positive and negative symptoms but compared to Clozapine, Risperidone is more effective in treating the positive symptoms but as effective in the treating negative symptoms. It has a better advantage over typical antipsychotics such as Haloperidol and Perphenazine as they are less effective in treating negative symptoms but the effectiveness of both drugs has no significant difference compared to Risperidone. It is also known that Risperidone can act as an atypical antipsychotic if given at a lower dose but at higher dose, it tend to be more of a typical antipsychotic causing increased risk of EPS. Studies have also shown Risperidone to be safe with first episode patients with schizophrenia. Common side effect includes sedation, sexual dysfunction and weight gain35,37.

Newer Therapies

The second-generation drugs are widely used than the first generation drugs due to adverse side effects observed with the first generation antipsychotic drugs. There are now newer therapies that have been developed for the treatment of schizophrenia, which has different mechanism to the way the atypical antipsychotic drug works. Some of the newer drugs include Aripiprazole, Ziprasidone38 and Paliperidone.

Aripiprazole mode of action is different to the atypical drugs as it does not act fully as a dopamine antagonist but it also acts as a partial agonist for dopamine and serotonin receptors. It acts as a partial agonist at the D2 dopamine receptor and at the 5HT1A serotonin receptors; it acts as a full antagonist at the 5HT2A serotonin receptor. The agonistic effect helps to moderate dopamine level in areas where there is high dopamine ie the mesolimbic and mesocortical areas in the brain, and the antagonistic effect at the serotonin receptor usually relieves the negative symptoms of the disease and reduces the risk EPS, hyperprolactinaemia and weight gain39,40.

Paliperidone is another new antipsychotic drug on the market for schizophrenia, its mode of action is unknown, but because it is an active metabolite of risperidone, it’s known to work in a similar approach by been an antagonist at the dopamine D2 receptor and serotonin 5HT2A receptor. Paliperidone is known to be developed as an extented release tablet (ER) and tests has shown that it is a good treatment for individuals with acute schizophrenia41.

Potential New Therapies

Newer drug therapies include Asenapine, iloperidone, paliperidone, and ocaperidone which are known to be an antagonist at the serotonin 5HT2A and dopamine D2 receptors, bifeprunox is known to be a partial antagonist and agonist at the dopamine receptor and an antagonist at the 5HT1A serotonin receptor42.

Schizophrenia has been proven to be a brain disorder via the PET scans performed on individual with the disease. Different drugs have been developed for the treatment of schizophrenia in which the first generation drugs are known as typical antipschotics. These drugs were effective in the treatment of schizophrenia but due to their adverse seide effect such as EPS, tardive dyskinesia, this led researchers in developing the newer drugs called atypical antipsychotics. The atypical antipsychotic drugs displayed less adverse side effect of the typical drugs but the major side effect of the atypical drugs was weight gain, sedation, agranulocytosis etc. They tend to be better at treating the positive symptoms of schizophrenia except from Clozapine. Psychological treatments can also be used in the treatment of the disease psychotherapy and family intervention.

More research and development of newer drugs are still in progress and to also determine the actual cause of the disease.

Schizophrenia Brain

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