4) Etiology and Treatments for Paranoid Schizophrenia

Etiology

There are many theories that suggest that paranoid schizophrenia is a multifactorial disorder. The earliest theory suggests that an abnormal expression of dopamine is the main cause of the symptomatic delusions that are commonly found in most patients with this mental disorder[1]. However, further studies have shown implications involving anomalies and defects in the GABA, and glutamate pathways [2][3]. In addition, new studies have shown that long-term use of cannabis may also be a defining risk factor for the development of this disease [4].

Treatments

It is difficult to treat this disorder especially since it is attributed to different factors, and people who suffer from this disorder often have a wide variety of different symptoms. Typical drugs were the earliest types of medication fabricated in order to treat this disorder, however, it was soon replaced by atypical drugs which proved to be just as efficient, if not better, than the typical drugs, and which also have less harmful side effects on the patients [5]. Cognitive behavioural therapy (CBT) is also often used in addition to pharmacotherapy in order to improve symptoms of delusion and auditory hallucinations [6]. However, new studies have shown that GlyT1 inhibitors, such as sarcosine, result to an enhancement in not just positive and negative symptoms, but also cognitive symptoms experienced by patients[7].

John Nash
Image Unavailable
Mathematical genius and Nobel Prize winner diagnosed with Paranoid Schizophrenia.
His life story is described in Sylvia Nasar's,
A beautiful mind.
Image source: Robert P. Matthews [25]

Current Hypotheses

Dopamine Hypothesis

The subsequent increase in dopamine synthesis due to the increase in transmission of the dopamine receptors, D1 and most especially D2, have an association to the positive symptoms, such as hallucinations and delusions, that are experienced by the patients during the course of their illness [8]. This was further proven by studies which showed that the efficacy of the antipsychotics used to treat the positive symptoms of schizophrenia was essentially due to the binding of dopamine receptors to these antipsychotics [8]. Thus, this idea led to the proposal of dopamine’s role as a risk factor for schizophrenia.

A Molecular variant of Dopamine

The specific causation of paranoid schizophrenia has yet to be determined. This task is made especially difficult due to the variability of symptoms experienced by every individual patient. Instead, most researchers focus on specific molecular anomalies, such as polymorphisms found in most patients to outline the pathways most important for the analysis of this disorder.
Further evidence was given to the dopamine hypothesis when the Ser/Cys311 variant of the dopamine-2-receptor was found in over 50 Japanese schizophrenia patients in a study written by Arinami et al. [9]. Majority of the patients who carried this allelic variant were classified as either having the catatonic or the paranoid subtype of schizophrenia. Supplementary studies have been done in order to replicate the results that were found in the previous paper. A meta-analysis conducted over 24 studies, including a diverse population with different ethnic backgrounds, also highlighted the role of Ser/Cys311 as a susceptibility gene in the development of schizophrenia [10].

GABA and Glutamate Hypotheses

A decrease in both GABA and NMDA function has also been implied in the pathogenesis of schizophrenia [11][3]. This was supported by findings of lower GABA levels in post-mortem studies as well as lower GAD67 enzyme activity – enzyme necessary for the production of GABA – in specific parts of the brain [3]. Likewise, symptoms primarily found in schizophrenia have been induced in ordinary participants with the application of low NMDA doses [3]. The connection between GABA and glutamate are further strengthened with the discovery of the Neuregulin-1 gene (NRG1) and its connection to the Erb4 receptor [12]. NRG1 is an important factor for neuronal growth and development, and plays an important role in the maintenance of the neuronal activity in the excitatory synapses, such as NMDA [12]. The rat models of NRG1 show a decrease in NMDA receptors in the brain, similar to the depletion shown by human schizophrenia patients [3]. This decrease in glutamate was also associated with various cognitive deficiencies and deficits in performances to specific maze tasks, which are also analogous to the symptoms experienced by individual patients [3].

» NRG1 and Erb4 association

Erb4 is the main receptor that binds to NRG1, and the majority of these receptors can be found on presynaptic terminals of GABAergic neurons [12]. Subsequent studies demonstrated a greater frequency of signalling between NRG1 and Erb4, which ultimately led to a down regulation of NMDA receptors, proposed to be a factor responsible for the negative and cognitive symptoms experienced by the patients [13][14]. The discovery of this gene and receptor has important implications in the future development of medicinal treatments for this disorder.

Cannabis Use - Effects on the progression of the disorder

Your Brain on Drugs: Marijuana
This video by AsapSCIENCE interactively highlight the effects of
Cannabinoids in specific pathways of the brain.

The association of cannabis use to the development of paranoid schizophrenia has been largely debated, especially since it is also believed to be beneficial in treating symptoms of other ailments, such as HIV and multiple sclerosis, in which most patients have claimed that the use of marijuana gives them some sort of relief from their symptoms especially the pain associated with their illnesses [15][16]. However, a long-term study of people who experienced psychosis-like symptoms after the chronic use of cannabis has shown an increase in susceptibility to developing this schizophrenia. Arendt et al.,followed at least 535 patients over the course of 3 years, and discovered that more than half of the patients initially diagnosed for psychosis due to cannabis use, eventually developed schizophrenia or its other subtypes, such as paranoid schizophrenia [17]. Moreover these patients experienced an earlier on-set of the disorder compared to the patients who have experienced psychotic episodes, but have never used cannabis. Thus, the use of cannabis may be predictive of the development of schizophrenia or any of its subtypes especially for people who may have a predisposition for this disorder.

»The role of CB1 receptor

The cannabinoid hypothesis postulated in the late 1990s focused on the role of delta-9-THC as a dopamine agonist which was believed to increase the severity of psychotic symptoms experienced by the patients [18][19]. When patients are given delta-9-THC, the positive, negative and cognitive symptoms that they experience increases in severity [19]. Further studies conducted in order to support this hypothesis have shifted their attention on the importance of the cannabinoid receptor type 1 (CB1R) and the effects it has on the symptoms associated with schizophrenia. CB1R is activated when it binds to endocannabinoids such as delta-9-THC and its activation is believed to be responsible for the psychosis experienced by cannabis users [19]. Post-mortem studies have shown a significant increase in these receptors found in schizophrenics especially in the dorsolateral prefrontal cortex, associated with cognition and memory[4]. Animal models have also shown impediments with motor coordination, similar to schizophrenics, in response to the application of cannabinoids that can be terminated with the use of antipsychotics [19]. These findings have significant benefits in the ongoing search for better pharmaceutical drugs for the treatment of schizophrenia.

Treatments

Pharmacotherapy

The treatment of schizophrenia is challenging due to the differences and variation of the symptoms that each afflicted individual experiences. Moreover, there is no cure for this disorder, thus, most of the drugs developed focuses on ameliorating the symptoms experienced by the patients instead [20]. The treatments may include typical or atypical antipsychotics, both of which work as a dopamine antagonists and believed to have the greatest influence on the positive symptoms of patients[20].

Typical (first-generation) versus Atypical (second-generation) antipsychotics

Although both antipsychotics are still currently used for the treatment of schizophrenia, several studies have outlined atypical antipsychotics as more highly favourable by patients [21]. When given to patients, the atypical antipsychotics, risperidone [20], and apiprazole [21], showed greater efficacy in treating the symptoms experienced by the individuals in comparison to haloperidol, a typical antipsychotic. Moreover, risperidone showed promise in treating the negative symptoms experienced by the patients, as well as producing less adverse motor deficiencies that include shaking and inflexibility. Apiprazole on the other hand, is a unique atypical antipsychotic in that it is a partial agonist of dopamine receptors and a partial antagonist of serotonin receptors. This allows the drug to specifically target areas where dopamine levels are the highest and avoid creating changes in areas that show normal transmission of dopamine [21]. Apiprazole is successful in treating not only the positive, but have also shown amelioration in the negative, depressive and cognitive symptoms, while withstanding the production of adverse side effects. The ability of atypical antipsychotics to produce less severe side effects have implications in the adherence of patients to their medical treatments [21], causing a decrease in the amount of individuals who stop treatment and subsequently become susceptible to relapse.

Cognitive-behavioural therapy (CBT)

Several studies have focused on the effect of cognitive behavioural therapy in comparison to counselling-like approaches in treating schizophrenia. CBT has been shown to be efficient in treating both the positive and negative symptoms of schizophrenia especially in the subset of patients who are classified as treatment-resistant [22]. In comparison to other interventions such as the befriending and supportive counselling (Valmaggia et al., 2005) – both of which aim to help the patient through encouraging and positive conversations – the CBT proved to be superior in treating the symptoms experienced by patients even after over 9 months after the initial treatment [22][23]. CBT has also shown to be a great advantage especially in decreasing the severity of auditory hallucinations in terms of its incidence, length and aggressiveness [23].

A New Contender: GlyT1 inhibitor (Sarcosine)

A study done by Tsai and his colleagues in 2004 revealed the importance of Sarcosine, a GlyT1 inhibitor, in treating not only the positive, but also the negative and cognitive symptoms experienced by patients. Sarcosine results to an increase in the NMDA transmission, thus, providing further evidence for the glutamate hypothesis [7]. The application of this novel drug showed superior improvement on the symptoms of the patients in comparison to the placebo group observed in the study. Moreover, even after increased dosages were given to the patients, no changes in the severity of the side effects that were already apparent due to the concurrent use of atypical drugs, were observed in the patients. Similar results were shown in an animal model of schizophrenia using a different type of GlyT1 inhibitor, ASP325. When ASP325 was administered to rat models of schizophrenia, subsequent improvements in their symptoms were observed [24]. In order to mimic the cognitive symptoms experienced by schizophrenics, the researchers injected MK-801 to rats which resulted to deficits in their performance in the radial arm-maze tasks. However, after the application of ASP325, an increase in their performance was immediately observed. Hence, the use of GlyT1 inhibitors may have an important implication for the treatment of schizophrenia because it has shown improvement in the negative symptoms, in comparison to most atypical drugs that mainly target dopaminergic pathways and has a greater effect on the positive symptoms.

» A broad horizon for GlyT1 inhibitors

The study by Harada and his colleagues using the animal models of schizophrenia in 2012 was also able to show ASP325’s potential in treating other diseases such as the Alzheimer's disease (AD)[24]. A decrease in NMDA receptors has been observed in post-mortem studies of AD. In the study, similar animal models used for schizophrenia were also used to study the cognitive deficits experienced in AD in terms of the rat’s performance in the Morris water maze. Likewise, the application of ASP325 resulted to improvement in working memory and proved to be beneficial in delaying the progression of Alzheimer’s.

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