A ROAD BACK TO REALITY

A road back to reality

Rihab FELLAH

Our ability to distinguish reality from fiction is a blessing we know little of, and like many blessings, only those who live each day without it can appreciate the real meaning of its loss. Therefore, because this loss is the result of a dysfunction in one of the most mysterious, most intriguing and most controversial organs ever to be studied in the history of medical science, and that is the brain, we will be talking about one of the most stigmatizing, scaring and historically misunderstood mental illness and that is schizophrenia.

Schizophrenia is?

The word “schizophrenia” is the combination of two Greek words. “Schiz” which means split, and “phren” which means mind. It first saw light in 1908 and was the invention of the German psychiatrist Bleuer who defined the schizophrenic patient as “one who has simultaneously opposing thoughts”. It is what we call commonly suffering from “split personality”.

Schizophrenia is a disease that touches young adults and manifests itself in an individual having both: 

1) genetic abnormalities (explaining thus its recurrence in certain families) originating in a molecular dysfunction in his brain. 

2) being exposed to certain environmental factors such as psychological stress or substance abuse. 

What are its signs and symptoms? 

The clinical manifestation of this disorder is the presence of either positive symptoms and/or negative symptoms through at least a 6 month period. 

The positive symptoms or psychotic symptoms are symptoms that are “added” .They consist mainly of delusional ideas and hallucinations. While delusional ideas are the misinterpretation of real existing stimuli by the brain, such as seeing a monster or a man in a simple shadow, hallucinations however are any stimuli perceived by the individual with no real ground whatsoever. In this case, the stimulus most frequently found in schizophrenics is auditory: The patient often complains of hearing voices that are not originating from him. Another common positive symptom is paranoia or excessive suspiciousness. It manifests as an individual who always thinks Negative symptoms are, on the other hand, what lacks in the individual’s behavior, such as the lack of affect (a “don’t care” attitude), the lack of initiative or avolition which is an unusual disinterest in any activity or hobby, and attentional problems or the inability to focus. 

Clinically speaking, we can notice that a patient who has negative symptoms alone differs completely from a patient presenting predominantly positive symptoms. Therefore we can only imagine what a wide range of manifestation this disorder includes, and the great challenge presented to psychiatrists by its diagnosis. The solution presented itself through the use of a revolutionary manual: the Diagnostic and Statistical Manual of mental disorders (or DSM), created by The American Psychiatric Association. It contains diagnostic criteria for schizophrenia, among other mental disorders, and has made it a lot easier to retain a certain diagnosis, in a very efficiently rapid way, while allowing physicians to use the samevocabulary. 

Clinicians thrive today to do more than mere diagnosis, because they noticed the existence of a prodromal phase; in which the individual presents early signs of schizophrenia or pre-psychotic signs, such as a decline in academic functioning, an increase in social isolation, and a subtle change in behavior or thought patterns. Therefore, it is psychiatrists’ general ambition to find a way to diagnose the disorder at this stage and delay the onset of schizophrenia or even stop it. 

What causes it? 

Efforts have been made and theories have been speculated on the origin of schizophrenia. It was thought to be the result of abusive, emotionally un-nurturing environment in the early upbringing of the person. The notion of the schizophrenogenic mother was even introduced in the early 1960’s, and describes a hard cold mother whose children are more prone to developing schizophrenia. Other theories proclaimed that children who were often faced with double bind situations (which are situations you cannot win no matter the choice you make), were at higher risk of becoming schizophrenic. But these theories were not specific to schizophrenia and thus didn’t stand long as rational explanations for it. 

The admitted theory today is what is called “the Dopamine theory” which was accidently discovered and led to a breakthrough in both the understanding and treating of the malady. 

In the 1950’s, a molecule named chlorpromazine was discovered and was intended to be used as a pre-anaesthetic drug. It came into observation by psychiatrists that it reduced positive symptoms in schizophrenic patients. It later led to the discovery of the molecular explanation of schizophrenia by understanding the pharmacology of the medication: this molecule causes a reduction in the dopamine activity in the brain! Therefore leading to the logical conclusion that schizophrenia is mainly due to an excess in the activation of this system. This theory has won Carlson a well-deserved Nobel Prize in the early 1960’s.

Let us talk about dopamine. There are two kinds of dopamine receptors in the central nervous system: D1 receptors and D2 receptors. The latter type can be found in various regions and pathways of the brain: in the mesolimbic pathway, in the striatal pathway and in the tubero-infundibular pathway. The former type are mostly found in the mesocortical pathway. Each pathway has a certain function: the nigrostriatal pathway is important in motor control; the mesolimbic pathway, running from groups of cells in the midbrain (or mesencephalon) to parts of the limbic system is involved in emotion and reward ; the mesocortical pathway, that runs from the midbrain to the cortex, involved in emotion and decision-making and the tuberoinfundibular neurons, running from the hypothalamus to the pituitary gland, whose secretions they regulate.

It is treatable, isn’t it?

The many molecules that came after were very similar to Chlorpromazine in their pharmacological activity, and constituted a family known as typical antipsychotics. They have more important antagonizing activity on the D2R than that on the D1R, but they have all the side effects that come with blocking the majority of these receptors, especially the extrapyramidal syndrome (EPS) which is most bothersome to both patients and doctors putting often an end to treatment.

Chlorpromazine was the first in a long line of antipsychotics to be discovered, as we have said before. Because schizophrenia’s positive symptoms are due to an excessive dopamine activity in the D2 receptors, present in the mesolimbic pathway, antagonizing dopamine’s activity in this region would be the logical way with which the medicine must proceed in order to reduce those symptoms. Their activity however does not extend to the mesocortical pathway, because the predominant receptors there are the D1 receptors, which explains their little effect on negative symptoms.

This inconvenience is explained by the following fact: their antagonizing activity is not directed to the mesolimbic receptors specifically, and ends up acting on all D2 receptors in the brain causing side effects. When they block D2R in the striatal pathway, we have extrapyramidal symptoms resembling those of Parkinson’s disease, and when they block D2R in the tubero-infundibular pathway, they lift all inhibition on prolactin’s release by the pituitary gland, thus causing hyperprolactinemia. 

Later came Clozapine and its comrades, known as atypical neuroleptics, which won themselves the “atypical” adjective because they reduce positive symptoms without causing EPS, contradicting thus the same theory that explains their mechanism of action. However, that could be explained by the following notion: These drugs not only block D2R in a more specific way than the previous family, they also have a muscarinic and serotonin-like activity that reduces the side effects caused by D2R general blockade. This effect is due to the fact that the serotoninergic and muscarinic systems cause a release of dopamine, which lessens the side effects by counteracting the excessive blocking of the other pathways. Nevertheless, they do not come without cost. Their most undesired effect is weight gain, metabolic syndrome, diabetes mellitus and cardiovascular disease, which is the first mortality cause among this group of patients.

Hopes for the future 

Having talked about the leap made by neuroleptics’s use in the treatment of schizophrenia and their effectiveness on positive symptoms, the problem of negative symptoms remains the same, as both typical and atypical antipsychotics do little in this regard. It is in fact one of the major flaws in the dopamine theory, that seems to explain only a part of schizophrenia’s symptomatology. It is not a surprise that another theory is being considered. A theory known as the glutamate theory: It has been observed, 20 years ago, that substances such as ketamine and phencyclidine that act by antagonizing certain NMDA receptors (N-Methyl D-aspartate), belonging to the glutamate system, produce positive and negative symptoms similar to those found in schizophrenia. It is very suggestive that the illness is due to a defect in these NMDA receptors. Glutamatergic neurons and GABAergic neurons play complex roles in controlling the level of neuronal activity, in both the mesocortical and the mesolimbic dopaminergic pathways. NMDA receptor hypofunction is thought to reduce the activity in mesocortical dopaminergic neurons. This would result in a decrease in dopamine release in the prefrontal cortex, and causes negative symptoms of schizophrenia. On the other hand, NMDA receptor hypofunction is thought to elevate the level of activity in the mesolimbic dopaminergic pathway, perhaps because NMDA receptors are located on GABAergic interneurons, which have an inhibitory activity. Thus NMDA receptor hypofunction would result in reducing the GABAergic inhibition of mesolimbic dopaminergic neurons and therefore give rise to elevated dopamine release in limbic areas, resulting in the production of positive symptoms .That is why, it has been suggested that the possible solution lies in creating a drug that can induce a glutamate-like effect in this dysfunctional system. 

Many such molecules are in clinical trials, presenting hopeful results.

Living as a schizophrenic is a great burden because 

Many challenges still exist and are present especially on a social level. The attempt to integrate the patient into society remains a main one. It requires not only a supportive and encouraging family, but also a more understanding environment. For many years, the only way to deal with this disease was to confine these patients to asylums, where they were treated not in the most humane way. Moreover, the first-line therapy at the time consisted of electroshock therapy, psychosurgery (frontal lobotomy), and insulin coma. These therapies were extremely controversial because they can cause permanent damage and sometimes lead to death, which is extremely unfortunate given that schizophrenia is an illness that mainly touches young adults. 

It is true that the discovery of neuroleptics has led to a drastic decline in the number of schizophrenics detained in asylums, and rendered the use of those extremely disabling measures mentioned above a thing of the past. This being said, the pharmacological treatment of schizophrenia did not make it more socially acceptable and there still is fear and misunderstanding related to it. Sadly, this prejudice has been observed in the medical field, and has led to a bad follow-up of many schizophrenics for their non-psychiatric conditions. The most prominent one being cardiovascular disease for it remains the first cause of death among them. It is, in fact, the reason why a schizophrenic person lives thirty years less than the average individual.

I believe that most of you are familiar with John Nash’s battle with schizophrenia. (For those who are not, I recommend watching “A beautiful mind“). The Nobel-prize-winning mathematician who has successfully but not easily reintegrated himself back into reality. His story, as exceptional and contradictory as it is, remains indeed a positive and beautiful model in its outcome and shows that a long way is still ahead in order to make more similar results.

Bibliohrapgy 

• Rang, H. P., and M. Maureen. Dale. Rang and Dale's Pharmacology. Edinburgh: Elsevier/Churchill Livingstone, 2012. 

• Laura WeissRoberts - Jinger G.Hoop - Thomas W.Heinrich - Wolters Kluwer Health/Lippincott Williams & Wilkins - 2010 

• Joshua T. Kantrowitz, MD Daniel C. Javitt, MD, PhD. "Glutamate: New Hope for Schizophrenia Treatment. Research on Glutamatergic Dyfunction May Lead to Therapies Targeting Negative and Cognitive Symptoms." Current Psychiatry. Apr. 2011. Web 

• Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Arlington, VA, American Psychiatric association, 2013. 

• http://www.schizophrenia.com/