Neurochemical Disorders and Schizophrenia PDF

Neurochemical disorders I: affective disorders Dr. Jose Sapien, MD. Lecturer 2 NA Pathways 3 Mood/ Affective Disorder ‘Affect’ refers to mood and affective disorders comprised of both: A pathological lowering (depression) A pathological elevation (mania) of mood. Accurate diagnosis of a mood disorde...

Neurochemical disorders I: affective disorders Dr. Jose Sapien, MD. Lecturer 2 NA Pathways 3 Mood/ Affective Disorder ‘Affect’ refers to mood and affective disorders comprised of both: A pathological lowering (depression) A pathological elevation (mania) of mood. Accurate diagnosis of a mood disorder requires a careful past medical and psychiatric history to detect past mood episodes and to rule out whether these episodes were secondary to substance use, a medical condition, etc 4 Bipolar affective disorder (manic-depression) refers to an oscillation between depression and mania. Diagnostic and Statistical Manual of Mental Disorders, 5th edition; (DSM-V) Criteria for mood episodes are used for assessment and diagnosis. 5 Types of mood disorders Depressive (major depressive disorder, persistent depressive disorder). Bipolar (bipolar I/II disorder, cyclothymia). Induced by or due to (“secondary to”) a general medical condition, substance, medication, other psychiatric condition. 6 7 Both depression and mania may be accompanied by features of psychosis (delusions and hallucinations). The nature of the psychosis tends to be mood-congruent: Depression: believes that he or she is guilty of something or hear voices that are critical and unpleasant. Mania: may be accompanied by grandiose delusions. 8 Depression – Epidemiology Lifetime prevalence: 12% Peak prevalence age 15-25 yr (M:F = 1:2) More than 700 000 people die due to suicide every year and suicide is link to this mental disorder. 9 Depression - Etiology It can occur in response to psychosocial (reactive depression), as well as for biological factors (endogenous depression). 10 Biological Genetic: 65-75% MZ twins; 14-19% DZ twins Neurotransmitter dysfunction: decreased activity of 5-HT, NE, and DA (monoamines) at the neuronal synapse. Neuroendocrine dysfunction: abnormal HPA axis activity Neuroanatomy and neurophysiology: decreased hippocampal volume, increased size of ventricles. 11 Neurochemical basis of depression The monoamine theory of depression suggests that the illness is caused by reduced monoamine transmission. The serotonin hypothesis suggests that depression is linked to reduced serotoninergic function. Temporary depletion of tryptophan (a precursor of serotonin) levels → Depression The neurotrophic hypothesis suggests that genetic vulnerability and chronic stress cause impairments in neuroplasticity in the brain (specifically in the hippocampus). 12 13 Psychosocial: Cognitive (i.e. Beck’s cognitive triad: negative views of the self, the world, and the future) Environmental factors (i.e. job loss, bereavement, history of abuse or neglect, early life adversity) Comorbid psychiatric diagnoses (i.e. anxiety, substance abuse, developmental disability, dementia, eating disorder) 14 Additional signs in depression Cognition impairments or changes in performance on several tests of cognitive function. Memory deficits are prominent and occur across memory domains (working memory and episodic memory) and across modalities (verbal and visuospatial). Negative thoughts are kept. 15 Additional signs in depression Psychomotor retardation and apparent lack of motivation Marked slowing of speech and motor functions. Inattention, as may planning and problem-solving. 16 Treatment Psychotherapy , pharmacologic and electroconvulsive therapy (ECT) Amine uptake inhibitors (SSRIs, SNRIs): inhibit the re-uptake of noradrenaline (norepinephrine) and/or serotonin (5-hydroxytryptamine; 5-HT). Monoamine oxidase inhibitors Atypical antidepressants 17 18 19 20 Bipolar treatment In mania and bipolar affective disorders, lithium has a mood-stabilizing action. Carbamazepine valproate and lamotrigine also have mood-stabilizing actions and can be used in cases of non-response or intolerance to lithium. 21 22 Schizophrenia Dr. Jose Sapien, MD. Lecturer It is a common disorder with a lifetime prevalence of 1% and an incidence of 2–4 new cases per year per 10,000 population. It is more common in men and typically presents early in life. Like all psychiatric disorders, there is no diagnostic test for this condition, which is defined by the existence of key symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-V). 24 25 It is a psychotic disorder characterized by a significant impairment in reality with: Positive symptoms (abnormal behavior): Delusions: False beliefs that are strongly held despite evidence to the contrary. Hallucinations: Sensory perceptions that occur in the absence of external stimuli. The most common type of schizophrenia is auditory hallucinations. Disorganized behaviors: These include behaviors that are chaotic, unpredictable, or inappropriate to the situation. Formal thought disorder: Individuals may experience disorganized thinking, tangential or irrelevant speech, or difficulties in maintaining a coherent conversation. 26 Negative symptoms (low ‘normal behavior’): Affective flattening: Reduced or absent emotional expression. Blunting of mood: Similar to affective flattening, but specifically refers to a reduction in the intensity of emotional responses. Anhedonia: The inability to experience pleasure or enjoy previously enjoyable activities. Apparent apathy: Lack of motivation or interest in engaging in activities. Lack of spontaneous speech and action: leading to decreased social interaction and engagement. Disordered speech: Impairments in language production or communication. 27 28 Etiology The cause of schizophrenia is unknown but both biological and environmental factors have been suggested. Genetic factors: first-degree relatives of people with schizophrenia have a greatly increased risk of developing the disease Recent genome-wide association studies (GWAS) have also confirmed a genetic basis for the condition, including genes that are involved in inflammation and myelination. 29 30 Mesolimbic dopamine system: This pathway is associated with reward processing, motivation, and emotional responses. Dysfunction in this pathway has been implicated in positive symptoms of schizophrenia, such as delusions and hallucinations. Mesocortical dopamine system: This pathway is involved in cognitive functions, including executive function, working memory, and decision-making. Dysfunction in this pathway has been linked to negative symptoms and cognitive deficits in schizophrenia. 31 The dopamine hypothesis of schizophrenia Basic model: excess activity in the mesolimbic dopamine pathway may mediate the positive symptoms of psychosis, while decreased dopamine in the prefrontal cortex may mediate negative and cognitive symptoms. Projections from the ventral tegmental area (VTA) 32 The dopamine hypothesis of schizophrenia Revised model: GABA, glutamate, and ACh dysfunction are also thought to be involved. Glutamate receptor hypofunction → may account for both up-regulation of the mesolimbic dopamine system, and down-regulation of the mesocortical system because of diminished direct drive (the ‘activating’ system). 33 Neurodevelopment theory: neurons fail to migrate correctly, make inappropriate connections, and apoptosis in later life. 34 Treatment Antipsychotics or neuroleptics drugs: block dopamine receptors (side effect of parkinsonism), of which there are at least five subtypes in the brain (D1–D5 receptors). They require several weeks to control the symptoms of schizophrenia and most patients require maintenance treatment for many years. D2 receptors are found in the limbic system and in the basal ganglia. D3 and D4 receptors are found mainly in the limbic areas. Relapses are common even in drug-maintained patients. 35 Atypical drugs Some newer drugs have a reduced tendency to cause movement disorders and are referred to as atypical agents (e.g. clozapine, risperidone, olanzapine, quetiapine, aripiprazole). 36