These serious adverse effects, both physical and mental, of antipsychotics are in themselves persuasive evidence against the disease-centred model as indeed is the curiously equivocal evidence for the long-term benefits of antipsychotic therapy. Thus, Dr Moncrieff points out that the only study lasting longer than 12 weeks comparing chlorpromazine with psychotherapy—conducted by the California-based British psychiatrist Phillip May in the late s—certainly favoured drug therapy as measured by the outcome of discharge from hospital. This could be a factor in the favourable outcome of the clinical trials organized and funded by the pharmaceutical industry demonstrating their dual advantage of both being more potent and with fewer side effects.
There is, to be sure, no novelty in being critical about psychiatry and its practice and one might readily wonder what more there is to add to the many revelations in recent years of the devious methods and sharp practices by which a powerful pharmaceutical industry has subverted the intellectual apparatus of science to its own considerable advantage. This schematic account cannot do justice to the tightness of the arguments and numerous illustrative examples with which Dr Moncrieff charts the all-important transition from the drug-centred to the disease-centred model and its adverse consequences.
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Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases
View Metrics. Email alerts New issue alert. Advance article alerts. Article activity alert. Subject alert. Receive exclusive offers and updates from Oxford Academic. Mutations in this gene may, therefore, cause protein accumulation and eventually promote the development of PD. The PINK protein is implicated in the translocation of parkin to the mitochondria [ , ]. Studies have shown that PINK is involved in the mitophagy of dysfunctional mitochondria [ , ].
Psychiatric Manifestation in Patients with Parkinson's Disease
Mutations in this gene disrupt the integrity of the mitochondria and may result in oxidative stress and eventually to neuronal damage [ , ]. Altogether, this implies that PD genetic mutations increase cell susceptibility to stress and favor cascade of events that are known to interfere with the stress response system. LRRK-2 mutation promotes an increase in its kinase activity which may result in dopaminergic neuronal loss and gliosis in the substantia nigra [ , ]. LRRK-2 mutations can unable the organism to efficiently respond to these events and have been connected to the early onset of PD where patients exhibit pre-motor symptom such as depression [ , , ].
DJ-1 functions as a redox sensor and protects against oxidative damage [ 59 , , , ].
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It has been shown that exposure to stress plays a role in the modification of genetic composition by altering epigenetic mechanisms thus leading to altered gene expression [ ]. Therefore, in PD, it is accepted that under stress circumstances, DJ-1 gene mutations may result in mitochondrial dysfunction and hence increased susceptibility to oxidative stress which exacerbates neuronal cell death [ 59 , ].
Neuronal cell death in PD may also be triggered by exposure to toxic substances or environmental factors which precipitate the symptoms of the disease as they render the brain vulnerable to subsequent physiological chronic stress [ 87 , , , ]. The environmental cause of PD mainly refers to exposure to dopaminergic toxins 6-hydroxydopamine 6-OHDA , 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP , paraquat and rotenone as these toxins are known to induce formation of reactive oxygen species ROS and oxidative stress which may result in neuronal cell death [ 87 , , ].
DA is one of the common neurotransmitters present in most parts of the central nervous system [ 71 ]. The mesocortical, mesolimbic, nigrostriatal and tubero-infundibular pathways are the four main pathways that play a key role in dopaminergic signaling [ 71 ]. DA cannot cross the blood brain barrier, therefore, it is synthesized from tyrosine which is carried into the brain via amino acid transporters [ 71 , 80 ]. DA is then stored in the vesicle until an action potential allows the vesicle to be discharged into the synapse [ 71 ].
Monoamine oxidase MAO is the enzyme that is responsible for breaking down excess DA and is known to similarly act on 6-OHDA inducing oxidative stress resulting in apoptosis [ ]. In animal studies, to create a parkinsonian rat model, an intracerebral injection of 6-OHDA into the medial forebrain bundle MFB has been widely used to study the destruction of dopaminergic neurons in the nigrostriatal pathway [ 27 , 35 , ].
This model has also been used to evaluate the effects of pharmacological agents in ameliorating motor deficits associated with PD [ 88 ]. Some studies have even shown that in a 6-OHDA parkinsonian rat model, prenatal or early postnatal stress exacerbated the neurotoxic effect of 6-OHDA [ 19 , 27 , 35 , 36 , , ]. The neurotoxin 6-OHDA may cause neuronal cell death by two main pathways. Firstly, it can enter the mitochondria, and inhibit mitochondrial complexes I and IV of the mitochondrial respiratory enzymes resulting in impairment of neuronal function [ 80 , ].
Secondly, 6-OHDA can accumulate within the cytosol causing auto-oxidation which will result in the formation of reactive oxygen species and oxidative stress and thereafter will cause neuronal death by apoptosis [ 80 , ]. MPTP has been shown to produce symptoms nearly identical to PD in humans and non-human primates [ 87 , ]. MPTP was formed from an analog of the narcotic meperidine during an unconventional preparation of 1-methylphenylpropionoxypiperidine MPPP [ ].
Under stress conditions, clinical studies have shown that MPTP can cross the blood brain barrier and accumulate in the mitochondria, the cytosol and the synaptic cleft [ 87 , ]. MPTP is then oxidized to 1-methylphenyl Rotenone is a cytotoxic compound extracted from tropical plants, which is widely used as an insecticide and fish poison [ 87 ].
Altogether, it has become apparent that both the genetic and the environmental factors associated with PD can be influenced by stress and lead to complications. However, as all the above-mentioned factors produce oxidative stress, increased levels of oxidative stress in the brain is critical for the initiation and development of neurodegeneration and can contribute importantly to reducing the pathophysiological dysfunctions in PD.
Oxidative stress is the result of an imbalance between the production of reactive oxygen species free radicals and the body capacity to counteract their harmful effects through neutralization by antioxidant defenses [ ]. Brain neurons are constantly exposed to reactive oxygen species and reactive nitrogen species as a result of endogenous or exogenous exposure to oxidative stress [ ].
Chronic psychological stress increases neuroinflammation which may facilitate nigral cell death in PD [ 19 , 36 ]. In PD, plus oxidative damage to lipids, proteins, and DNA, oxidative damage such as 4-hydroxynonenal HNE , can react with proteins to impair cell viability [ , ]. Oxidative stress can then contributes to the cascade leading to DA cell degeneration through mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation [ ].
For example, due to its high lipid composition, the brain is highly susceptible to lipid peroxidation [ ]. There is evidence of lipid peroxidation in the substantia nigra induced by high levels of trace elements such as ferrous iron which can exacerbate cell damage in PD [ , ]. Studies have also shown that other trace elements such as manganese, selenium, copper, aluminum or zinc also play a role in neurodegeneration [ , ].
Their abnormal metabolism sometimes results in pathological conditions including depression and PD [ , ]. In a new perspective, since oxidative stress plays a key role in dopaminergic neurotoxicity, lipid peroxidation may, therefore, be an intermediate step in the neurodegeneration observed in PD associated with depression.
PD research is often directed towards the prevention of DA neuron degeneration [ 19 , 87 , , ]. However, all current treatments only address the symptomatic effects of the disease, none of which neither halt nor retard DA neuron degeneration [ 87 ]. The point of view in favor of exposure to stressful events early in life predisposing an individual to develop neurodegenerative disorders later in life seems to emphasize that PD is much more than just a DA-dependent motor deficit.
Studies have shown that the 5-HT transmission system also undergoes degeneration in PD [ , ]. The neuronal degeneration in the midbrain raphe nuclei where 5-HT is mainly produced is known to lead to reductions in 5-HT and 5-HT transporter levels in brain areas such as the striatum and prefrontal cortex [ , ].
However, 5-HT neurons have the ability to store and release DA synthesized from systematically administered DA medication such as levodopa [ , ]. For instance, in a 6-OHDA lesioned rat model of PD with severe nigrostriatal dopaminergic neuron degeneration, it has been shown that striatal reuptake of levodopa-derived DA can occur through 5-HT transporters [ 78 , ]. Further, it has been shown that monoamine transporter inhibitors such as selective serotonin reuptake inhibitors SSRIs can modify striatal dopamine reuptake and metabolism so as to improve motor symptoms of PD [ ].
Progress Regarding Parkinson's Disease Psychosis: It's No Illusion
The altered serotonergic transmission that has been implicated in a number of non-motor and motor symptoms of PD may also be the result of weak neuromodulation by the DA neurons [ ]. Zou et al. In early onset PD, since stress increases the extracellular availability of DA and 5-HT all these have the capability to harm neurons separately or synergistically , stress may cause or exacerbate neuronal damage [ 5 ].
The possibility that depression is a harbinger of PD and that treating depression may help in the management of Parkinsonism is therefore of great importance. Studies have shown that the pathophysiology of PD goes beyond the basal ganglia and results in non-motor dysfunction coexisting with motor symptoms [ ].
Evidence has emerged suggesting that the burden of non-motor symptoms may negatively impact the quality of life of patients with PD [ , , , ]. There are a number of non-motor symptoms associated with PD; however, few studies have investigated their role in the disease process. These non-motor symptoms have been under-reported thus frequently not treated by clinicians [ ]. Non-motor symptoms commonly associated with PD include a range of symptoms from neuropsychiatric to autonomic dysfunctions where the most cited are depression, anxiety, apathy, pain, bowel incontinence, sleep disorder and most recently erectile dysfunction [ 10 , 59 , , , , , , ].
These two non-motor symptoms associated with PD can be managed by various drugs including antidepressants [ ]. Antidepressants are a popular treatment for moderate to severe forms of depression in PD [ , , , , ]. Several classes of antidepressants are available and they work in a slightly different way with different side-effects.
Neurotransmitters DA, 5-HT, and norepinephrine are associated with the pathogenesis of depression in PD [ 43 , , ]. Antidepressants relieve the symptoms of depression by targeting these neurotransmitters [ 58 , 74 , 78 , , , ].
Related Psychiatry of Parkinsons Disease (Advances in Biological Psychiatry)
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