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The Egyptian Journal of Hospital Medicine (October 2017) Vol.

69 (6), Page 2640-2646

Schizophrenia: Etiology, Pathophysiology and Management - A Review


Bayan Zaid Fatani1, Razanabdullah Aldawod2, Fatimah Abdulwahab Alhawaj2, Sajedaali Alsadah3,
Fatimah Radi Slais3, Eman Nasser Alyaseen4, Abdulaziz Sami Ghamri1, Jumanaahmad Banjar1,
Yahya Alhussain Qassaim6
1 Um AlQura University, 2 Imam Abdulrahman Bin Fasial University, 3 Alamal Complex for
Mental Health, 4 Alamal Complex for Mental Health, 5 Ibn Sina National College, 6 Royal College of
Surgeons in Ireland,
Corresponding Author: Bayan Zaid Fatani–email: Bayan.z.f@gmail.com- mobile:0599433733

ABSTRACT
Introduction: Diagnosis of schizophrenia is largely a clinical assessment of a group of signs and symptoms.
There are various factors that can be a cause or a risk factor for creating this disorder; some preventable and
some non-preventable. The treatment options are diverse and are continuously being studied in order to
enhance results and minimize adverse effect of various forms of therapy.
Methodology: We conducted this review using a comprehensive search of MEDLINE, PubMed, and
EMBASE, January 1987, through March 2017. The following search terms were used: schizophrenia,
etiology of schizophrenia, pathophysiology, clinical features, and treatment of schizophrenia
Aim: Our aim in this study was to understand the etiology, pathophysiology, and study various lines and
advancement in management of schizophrenia. Conclusion: In the recent years, many treatment options are
emerging where newer drugs and their combination with or without non-pharmacological therapy have
shown promising results. More studies must be done to implement advanced regimens for treatment of
schizophrenia.
Keywords: schizophrenia, genetic cause of schizophrenia, pharmacologic management of schizophrenia

INTRODUCTION may show no symptoms at all. A psychotic


The fundamental features of Schizophrenia are: episode is described by patient-specific symptoms
1. Positive symptoms which include delusions
and hallucinations, also called the psychotic and signs (known as psychotic features) that
symptoms where there is a loss of contact with mirror the ―false reality‖ formed in the patient’s
reality. awareness. The first episode of psychosis typically
2. Negative symptoms which includes in specific happens in late adolescence or early adulthood but
impaired motivation, drop in spontaneous speech, is often headed by a prodromal phase known as ―at
social withdrawal. risk mental state‖.
3. Cognitive weakening. Additionally in some examples premorbid
The positive symptoms have a tendency to impairments in social functioning and/ or
relapse and remit, although some patients feel cognition go back several years. Still, in other
residual prolonged psychotic symptoms. The examples onset is abrupt in formerly well-
negative and cognitive symptoms have a tendency functioning individuals[2].
to be chronic and are related to long-term effects Substance-abuse disorders happen most
on societal function. Cognitive signs are the up-to- frequently amongst these patients; such disorders
date classification in schizophrenia. These can involve a range of substances, which includes
symptoms are not specific and therefore, they alcohol, prescription medication, and
should be severe enough for the others to notice tobacco. Anxiety, obsessive-compulsive disorder,
them. Cognitive symptoms comprise disorganized depression, and panic are also noticeable in
speech, attention, and thought, eventually patients with schizophrenia and may worsen the
impairing the person’s capability to symptoms of their disorder. Such patients also
communicate[1]. have an overall lack of mindfulness of their
Among additional abnormal (schizoid) disease. This mindset has been associated to great
actions, social withdrawal usually leads a person’s rates of non-adherence, poor psychosocial
first psychotic episode; nevertheless, some patients

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Received: 16/09/2017 DOI: 10.12816/0042241
Accepted: 25/09/2017
Bayan Fatani et al.

function, relapse, bad hygiene, and worse disease There is evolving proof that the deficit-like
prognosis[3]. and psychotic-like symptoms might have
The prognosis for patients with autonomous heritability in both normal and
schizophrenia is usually unpredictable. Merely schizophrenia spectrum subjects. The twin studies
20% of patients notice favorable treatment of normal subjects and family studies of
results. The other patients experience many schizophrenic patients with propose that there are
psychotic episodes, long term symptoms, and a at least two heritable influences in schizophrenia:
meager response to antipsychotics[1]. In this review - related to the positive symptoms and
we will study the etiology, pathophysiology, and - related to the cognitive impairment and negative
management of schizophrenia. symptoms of the spectrum[5].
The frequency of both the schizophrenia-
METHODOLOGY related personality disorders and psychosis are
• Data Sources and Search terms higher among the relatives of schizophrenia
We conducted this review using a probands as compared to among the relatives of
comprehensive search of MEDLINE, PubMed, affective
and EMBASE, January 1987, through March disorder probands, however the schizophrenia
2017. The following search terms were used: spectrum personality disorders, categorized by
schizophrenia, etiology of schizophrenia, eccentricity and social deficits, and psychotic
pathophysiology, clinical features, and treatment disorders do not essentially happen between the
of schizophrenia. same relatives. These data are in agreement with
partially independent transmission of one set of
• Data Extraction genetic factors mutual to the spectrum that mostly
Two reviewers have independently reviewed manifest in social and cognitive deficits and
the studies, abstracted data, and disagreements among another set of separate genetic factors
were resolved by consensus. Studies were associated to psychosis [5].
evaluated for quality and a review protocol was
followed throughout. Developmental and Environmental Factors
The study was done after approval of ethical The leading example for analyzing the
board of King Abdulaziz University. environmental factors that contribute to
schizophrenia etiology for three decades has been
ETIOLOGY the neurodevelopmental hypothesis. This guides
Genetics attention in the direction of recognized risk factors
Though genetic studies have evidently for schizophrenia affecting initial
recognized a genetic origin for the schizophrenia neurodevelopment at the time of pregnancy. These
spectrum of disorders, the character of these comprise maternal stress, nutritional
genetic reasons and their variety of phenotypic deficiencies, maternal infections ,intrauterine
expression continue to be unclear. The study of growth retardation, and complications of
schizophrenia in identical twins also proposes that pregnancy and birth. However, socio-economic
other non-genetic factors must impact the causes, childhood difficulty, and
expression of this illness[3].Both family and 1stand2ndgeneration immigrant background have
adoptive studies propose a bigger prevalence of also been linked with schizophrenia.
schizotypal personality disorder among the Social stressors, for example discrimination or
relatives of the patients with schizophrenia economic hardship, may incline individuals in the
compared to control groups. In case of direction of delusional or paranoid
monozygotic twins, the possibility of one twin thinking[6].There are also reliable reports of higher
suffering from schizophrenia is as high as 48% if prevalence of schizophrenia in individuals born
the other twin has the disorder, while the risk is during late winter or in early spring, among
12% - 14% among dizygotic twins. In case of both individuals born and raised in urban areas, and in
parents having schizophrenia, the possibility that subject where the age of the father was relatively
their child will suffer from schizophrenia is around old, but also a relationship with young parents has
40%[4]. been noticed. The link with advanced paternal age

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has been attributed to the amplified amount of de Furthermore, pharmacological, and other,
novo mutations in their offspring, but different indication indicates that dopaminergic dysfunction
explanations have been suggested. More recently, is questionable to describe the full range of clinical
indication has accumulated associating cannabis manifestations of the disorder. Proof from clinical
use in adolescence, in particular abuse of pharmacology, physiology, brain imaging has
compounds with high THC content. Likewise, recommended that disturbed glutamatergic
several other influences such as head function may add to the biological processes
injury, autoimmune diseases, epilepsy, and severe essential some clinical features, in specific
infections have been related with increased risk[7]. cognitive dysfunction[9].One notion is that
glutamatergic dysfunction in schizophrenia is
PATHOPHYSIOLOGY OF SCHIZOPHRENIA associated to dysfunction of parvalbumin-positive
Anatomical Abnormality interneurons inside the cerebral cortex and
Several brain imaging and neuro-pathological hippocampus, which are subtle to alterations in
studies have tried to relate the signs of NMDA-type glutamate receptors. These fast
schizophrenia to different structure or function of spiking neurons harmonize the firing of pyramidal
specific brain regions and circuits. There has been neurons and cause the production of gamma
advancement in connecting some aspects of the oscillations, which is vital to proper cognitive
disorder to particular underlying neurobiology and function. Subsequently, dysfunction of this
numerous lines of evidence associate the population of neurons may cause the cognitive
participation of the prefrontal cortex, in specific deficits seen in schizophrenia[10].
the cognitive deficits (for example working Atypical activity at dopamine receptor sites
memory and executive control)[8]. specifically in D2 is understood to be linked with
many of the symptoms of schizophrenia. Four
Nonetheless, delicate reductions in grey matter dopaminergic pathways have been involved:
and irregularities of white matter have been found 1. The nigrostriatal pathway initiates in the
across many brain areas and circuits. The decrease substantia nigra and finishes in the caudate
of grey matter progresses with the period of nucleus. Low dopamine levels inside this
illness, particularly in the temporal lobe, and pathway are understood to affect the
seems to be related with antipsychotic extrapyramidal system, causing motor
treatment. Conversely, even drug-naïve patients symptoms[11].
display volume decreases (although not as 2. The mesolimbic pathway may play a role in the
pronounced as treated patients), exclusively in the positive symptoms of schizophrenia in the
caudate nucleus and thalamus. Furthermore, in existence of excess dopamine[11].
spite of many hundreds of studies, no restricted 3. Negative symptoms and cognitive deficits in
anatomical or functional abnormalities have been schizophrenia are said to be initiated by low
identified that are specific to the disorder. mesocortical dopamine levels[12].
This is expected to reflect the difficulty and 4. A reduction or blockade of tubero-infundibular
heterogeneity of the psychopathology and related dopamine outcomes in elevated prolactin levels
cognitive deficiencies, and the lack of clear resulting in galactorrhea, amenorrhea, and
margins separating schizophrenia from the other decreased libido[13].
disorders [8]. The serotonin theory for the development
of schizophrenia was thought as a result of the
Dysfunctional Neurotransmission detection that lysergic acid diethylamide
There is a logical body of proof from heightened the effects of serotonin in the brain.
pharmacological and brain imaging literatures Later research led to the formulation of drug
associating dysfunction of dopaminergic compounds that blocked dopamine and serotonin
neurotransmission in the beginning of psychotic receptors both, unlike older medications, which
symptoms like delusions and had effects on dopamine receptors only. The
hallucinations. Though, while these happen in the newer drugs were found to be beneficial in
majority of cases of schizophrenia, they are also relieving the positive as well as negative
noticed in a range of other psychiatric conditions. symptoms of schizophrenia[12].

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also obsessive-compulsive disorder. Hence


Stress-associated Signaling Cascades schizophrenia can be distinguished from these
Stress-associated signaling cascades are comparable conditions with the help of a careful
renowned to control the development and examination of the duration of the illness, the
maintenance of connectivity of synapses, period of delusions or hallucinations, and the
especially those that involved inflammatory intensity of depressive and manic symptoms. For
processes and oxidative stress. Microglia involved instance, in the DSM-5, a patient may meet
in synaptic preservation and destruction, diagnostic criteria for schizophrenia, but does not
specifically synaptic pruning in adolescence, and necessarily meet the 6 month duration of
the major histocompatibility complex I and symptoms; therefore a diagnosis of
complement system implying synaptic plasticity schizophreniform disorder is provisionally made.
are two such examples. Besides, the sharp rise of If symptoms persevere for 6 months a judgment of
parvalbumin-positive interneurons which are schizophrenia is made. Additionally, the clinician
referred to above the principally vulnerable to must approve that the offering symptoms are not
oxidative stress can also disrupt appropriate due to substance abuse or some other medical
formation and preservation of condition[16].
myelination. Suggestion for the participation of
these mechanisms has come from the new studies TREATMENT OF SCHIZOPHRENIA
of preclinical models[14]. The objectives in treating schizophrenia
comprise managing symptoms, avoiding relapse,
DIAGNOSIS and growing adaptive functioning so the patient
Schizophrenia is a chronic disorder with can be assimilated back into the community. As
several symptoms, where these symptoms are not patients seldom come back to their standard level
pathogenic, therefore a diagnosis of schizophrenia of adaptive functioning, both non-pharmacological
is made by a full assessment of patient-specific and pharmacological managements must be used
signs and symptoms, as pronounced in to enhance long-term results. Pharmacotherapy is
the Diagnostic and Statistical Manual of Mental the backbone of schizophrenia treatment, but
Disorders, Fifth Edition (DSM-5). The DSM- remaining symptoms may continue. For that
5 mentions that the diagnostic criteria must reason, non-pharmacological treatments, for
include the existence of two or more of these example psychotherapy, are also vital[17].
active-phase symptoms each remaining for a major In most schizophrenia patients, it is hard to
portion of minimum one-month duration. The implement beneficial rehabilitation programs
symptoms include delusions, hallucinations, without the help of antipsychotic agents. Quick
grossly disorganized or catatonic behavior, initiation of drug treatment is important, mainly
disorganized speech, and negative symptoms‖ within five years after the initial acute episode,
[2]
.At least one of the mentioned symptoms must since that is when most illness-related variations in
be disorganized speech, delusions, or the brain occur. Predictors of an unfortunate
hallucinations. Furthermore, the DSM-5 demands prognosis comprise the illicit use of amphetamines
that, to confirm a diagnosis of schizophrenia, the and other stimulants of central nervous system, as
patient should also show a reduced level of well as drug and alcohol abuse. Alcohol, nicotine,
functioning concerning work, interpersonal and caffeine also have the risk to cause drug
relationships, or care of self. There should further interactions[18].
be continuous manifestations of schizophrenia for
a minimum duration of six months[15]. Pharmacological Therapy
An inclusive differential diagnosis of In the occasion of an acute psychotic
schizophrenia is essential to differentiate the episode, medication therapy should be
disorder from other mental disorders, for example administered instantly. During the first seven days
major depressive disorder with catatonic or of management, the goal is to decrease aggression
psychotic features, or schizoaffective disorder, and to attempt to return the patient to regular
body dysmorphic disorder, or schizophreniform functioning (such as sleeping and eating). At the
disorder, and post-traumatic stress disorder, and

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beginning of treatment, proper dosing must be equivalent of the LAI to determine acceptability
titrated based on the patient’s response[19]. [23]
.
Treatment through the acute phase of A recent meta-analysis of randomized
schizophrenia is shadowed by maintenance controlled trials (RCTs) decided that results with
therapy, which must be intended at increasing LAIs are comparable to those with oral
socialization and at cultivating self-care and antipsychotics. The authors supposed, conversely,
mood. Maintenance therapy is necessary to help that RCTs might not replicate the ―real world‖
avoid relapse. The occurrence of relapse among effectiveness and safety of LAIs. Consequently,
patients who are on maintenance therapy, versus they conducted a meta-analysis of twenty five
those not receiving such therapy, is found to be mirror-image studies, where a total of 5,940
18% to 32% compared to 60% to 80%, subjects served as their own controls in realistic
respectively. Drug therapy must be continued for settings. This analysis established the advantage of
at least one year after the remission of the initial LAIs over oral antipsychotics in avoiding
psychotic episode[20]. hospitalizations (risk ratio [RR] = 0.43) and in
Second-generation (atypical) antipsychotics dropping the number of hospitalizations (RR =
(SGAs)—with the exemption of clozapine—are 0.38)[24].
the drug of choice for first-line management of
schizophrenia. Clozapine is not suggested because Treatment-Resistant Schizophrenia
of its hazard of agranulocytosis. SGAs are Between 10% and 30% of individuals with
typically preferred over the first-generation schizophrenia display little symptomatic
(typical) antipsychotics (FGAs) since they are upgrading after multiple trials of FGAs, and an
associated with rarer extrapyramidal extra 30% to 60% acknowledge partial or
symptoms.[21] Nevertheless, SGAs demonstrate insufficient improvement or intolerable side
metabolic side effects, like weight gain, diabetes effects during antipsychotic treatment. Clozapine
mellitus, and hyperlipidemia. These adverse is the most efficient antipsychotic in terms of
effects can add to the augmented risk of handling treatment-resistant schizophrenia. This
cardiovascular mortality perceived in drug is around 30% effective in adjusting
schizophrenia patients[18]. schizophrenic episodes in treatment-resistant
Combination therapy is suggested only in the subjects, equaled with a 4% efficacy amount with
later stages of the management algorithm. The the mixture of chlorpromazine and
prescription of more than two antipsychotics is not benztropine. Clozapine has also shown to rise
advised because it may upsurge the risk of drug serum sodium concentrations in patients with
interactions, medication errors, and non- polydipsia and low sodium[25].
adherence[22]. Before a new antipsychotic agent is Nevertheless, as indicated earlier, clozapine has a
started, the patient’s whole medication history difficult safety profile. For instance, patients
must be obtained. Whether the patient has treated with this drug are at amplified risk of
presented a favorable or unfavorable reaction to facing orthostatic hypotension, which can
previous antipsychotic treatment will aid the necessitate close monitoring. Furthermore, high-
guidance of the selection of a new drug[18]. dose clozapine has been related to serious adverse
effects like seizures[26].
Long-Acting Injectable Antipsychotic Agents
Long-acting injectable (LAI) antipsychotic Augmentation and Combination Therapy
drugs offer a viable opportunity for patients who Both augmentation therapy (medication with
are non-compliant to an oral medication. Medical ECT or a mood stabilizer) and combination
staff should regulate whether the patient’s non- therapy (along with antipsychotics) may be taken
compliance is due to the adverse effects of in consideration for patients who fail to display a
management. If so, then the clinician must satisfactory response to clozapine. Treating staff
consider an oral drug with a more favorable side- should witness the following guidelines while
effect profile. Before transferring to LAI therapy, administering augmentation treatment[27]:
a small trial should be directed with the oral  The therapy must be used only in patients with
an insufficient response to preceding therapy.

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 Augmentation agents are infrequently operative pharmacological therapy has shown promising
for schizophrenia symptoms when given alone. results. More studies must be done to implement
 Patients who respond to augmentation therapy advanced regimens for treatment of schizophrenia.
usually improve quickly.
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