Clinical Psychopharmacology

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PBI288

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Psychology

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Oct 30, 2023

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Clinical Psychopharmacology The big 5 -Schizophrenia -Depression -Bipolar Disorder -Anxiety Disorder -Attention Deficit/Hyperactivity Disorder

Cognitive impairments in schizophrenic patients include deficits in memory, abstraction, and attention Schizophrenia Schizophrenia spectrum disorders are defined by abnormalities in at least one of the five domains: delusions, hallucinations, disorganized thinking (speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms (flattened affect, alogia, apathy, avolition and social withdrawal) • Criterion A: At least two of the previous five domains (one of which must be either delusions, hallucinations, or disorganized speech) • Criterion B: Impairment for a significant portion of time in a major area of functioning • Criterion C: Signs of the disturbance continuously for at least six months • Criterion D: Schizoaffective, depressive, or bipolar dis- order with psychotic features have been ruled out • Criterion E: The symptoms are not attributed to the effects of some substance (medications) or medical condition • Criterion F: There is no history of autism spectrum disorder or a communication disorder during childhood dopaminergic pathway includes the connections between the ventral tegmental area (VTA) and the nucleus accumbens and mostly the D1 and D2 receptors mesocortical pathway includes connections from the VTA to the temporal cortex, frontal cortex, and PFC, and mostly D1 receptors with some presence of D2 and D5 receptors substantia nigra to the corpus striatum (the nigrostriatal) and from the hypothalamus to the anterior pituitary (the tuberoinfundibular)

Two Main Categories of Antipsychotics 1. First generation (FGA, typical ) -FGAs, like chlorpromazine and haloperidol, have high affinity for dopamine receptors, specifically the D2, especially within the mesolimbic path- way, thereby decreasing the presence of positive symptoms 2. Second generation (SGA, atypical ) -SGAs (like clozapine, risperidone, olanzapine, quetiapine, and aripiprazole) have slightly decreased affinity for the D2 receptors, but are believed to have some serotonin antagonism Main Side Effect of FGAs include: 1. Extrapyramidal side effects (EPS). EPS is defined as parkinsonism (rigidity, bradykinesia, shuffling gait, tremor), dystonia (fixed upper gaze, neck twisting, facial muscle spasms), and akathisia (inability to sit still, restlessness, tapping of feet). It is believed that it is D2 inhibition within the basal ganglia that leads to EPS, as is similar to Parkinson’s disease EPS is mostly treated with anticholinergic drugs, although some studies have shown that these may lead to further cognitive impairment 2. Tardive dyskinesia (TD) is defined as involuntary movements, especially of the lower face. One proposed etiol- ogy of TD is an adaptive hypersensitivity of D2 receptors in the striatum. Main Side Effect of SGAs (main benefit no EPS or TD- increased serotonergic inhibition of dopamine block) include: sedation, weight gain, and diabetes mellitus type II https://www.frontiersin.org/articles/10.3389/fnins.2014.00395/full

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Cognitive impairments: overall poor performance on cognitive tests; issues with - psychomotor speed, attention, and visual learning, memory, executive dysfunction Depression Depression, as defined in the DSM-5, consists of a pervasive feeling of sadness or irritability that results in significant disturbances in energy, sleep, appetite, sexual drive, weight, or the ability to express or seek pleasure • Major depressive disorder (MDD) is defined as depression that lasts for at least a two-week period, with symptoms that cause clinically significant impairment at work, with the family, or in other important areas • MDD Types: typical (melancholic), atypical, and psychotic • MDD can present at any age, but has an increased likelihood during puberty • MDD is also highly associated with many other health issues, including coronary artery disease, metabolic syndrome, diabetes, and other chronic illness Norepinephrine: molecule mostly produced in the locus ceruleus (LC) and is involved in vigilance, stress response, neuroendocrine function, pain control, and the sympathetic nervous system Serotonin, on the other hand, is produced within the raphe nucleus, and is involved in modulation of mood, the sleep–wake cycle, motivation and reward, cognition function, and pain perception, as well as neuroendocrine function After being released into the synaptic cleft, these molecules are then transported back through a nonspecific transporter, vesicular monoamine transporter (VMAT), or through specific serotonin trans- porter (SERT) and norepinephrine transporters (NET). Both of these molecules then get degraded intracellularly by an enzyme called monoamine oxidase (MAO), of which there are two types: MAO-A degrades serotonin, norepinephrine, and dopamine, while MAO-B degrades dopamine only!

Three main types of medications that treat depression 1. MAO inhibitors: inhibit the breakdown of the monoamines once they have been taken back up by the pre- synaptic cell, thereby increasing their availability for release back into the synapse 2. Reuptake inhibitors (Four Types: Tricyclic antagonists (TCAs), selective serotonin reuptake inhibitors (SSRIs-don’t show effects for several weeks), serotonin-norepinephrine reuptake inhibitors (SNRIs), and heterocyclics: Mechanism explanation in box 3. Atypicals: Act in a diverse way to increase the levels of serotonin and dopamine in the synaptic cleft **misdiagnosis of MDD, with an underlying bipolar disorder (BPD), and treatment with MAO-Is, SSRIs, and TCAs (and some heterocyclics) can precipitate manic and hypomanic symptoms Older MAO’s: side effects like hypertension, headache, tachycardia, nausea, cardiac arrhythmias, and stroke - Less of a risk in newer MAO’s Atypical Side Effect Could Include : seizures, insomnia, electrolyte abnormalities, weight loss, eating problems, sedation, headache, and dizziness TCAs: Block serotonin, norepinephrine and dopamine transporters resulting in increased levels of 5-HT, NE and DA in the synaptic cleft TCAs SIDE EFFECTS: nausea, vomiting, hypotension, anorexia, dry mouth, blurred vision, confusion, constipation, tachycardia, urinary retention, sedation, weight gain, and confusion in the elderly SSRIs : Block serotonin transporters resulting in increased levels of 5-HT (best with melancholia type) SSRIs SIDE EFFECTS: sexual dysfunction and gastrointestinal (GI) problem ,possible link withincreased risk of suicide SNRIs and heterocyclics: Block serotonin, and norepinephrine and resulting in increased levels of 5-HT, NE SNRIs and heterocyclics SIDE EFFECTS: hypertension, sweating, weight loss, GI distress, blurred vision, nervousness, and sexual dysfunction

Cognitive impairments of BPD depend on the specific stage. The manic and depressed stages are associated with moderate deficits in executive function, memory, and attention Bipolar Disorder BPD is characterized by three stages: periods of mania that percolate periods of depression, surrounded by periods of euthymia (mood defined as neither depressed nor excessively elevated) -Mania: elevated levels of euphoria or mood and energy that last at least one week that is characterized with an inflated self-esteem, little need for sleep, inability to stop talking, racing thoughts, distractibility, involvement in dangerous or negative activities, and an increase in goal-directed activity -BPD requires that these manic periods cause impairment in social and occupational realm • BPD is most frequently diagnosed prior to the age of 30, usually around 18 years old • Most patients present during periods of depression, and so it is important to probe for previous manic or hypomanic episodes • lifetime prevalence of about 1%–2% worldwide Network 2: orbitofrontal cortex and is called the inter- nal emotional control network, as it is more involved in the emotional response to certain cues Network 1: external emotional control network arises from the ventrolateral PFC. This external control includes functions such as understanding facial emotion. Networks are connected with the limbic system, which involves the hippocampus, thalamus, cingulate gyrus, limbic cortex, and hypothalamus. It is believed, therefore, that there is impaired regulation of the amygdala from both networks, allowing overactivation of the amygdala and its control over the limbic system . This increased amygdala activity is usually only seen during manic episode . Dysregulation of two networks that results in the symptoms seen with BPD (centers around limbic system and amygdala)

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Treatment = 2 options + Antipsychotics 1. Lithium -lithium has been shown to be effective for acute mania, psychotic symptoms associated with BPD, and even perhaps maintenance therapy (it helps to decrease manic and depressive relapse between 28% and 38%, it has been shown to have less of an effect with bipolar depressive symptoms 2. Antiepileptic: Seem to be effective for acute manic and psychotic symptoms of bipolar and may be more effective for depressive symptoms than lithium-may help restore the balance between glutamate and GABA inputs, thereby decreasing the postulated overactivity in the amygdala *antipsychotics, both FGAs and SGAs, have also been effective in treatment of acute mania Main Side Effect of Lithium 1. Lithium is associated with adverse events, including dangerous effects on the thyroid, cardiac abnormalities, and GI dysfunction, along with many others 2. Concomitant treatment with NSAIDs can lead to acute lithium toxicity, which includes symptoms of tremor, ataxia, dysarthria, renal insufficiency, confusion, delirium, neuromuscular dysfunction, and seizures Anitepileptic Side Effects: Dizziness. Drowsiness. Fatigue Most effective in treating manic phase -psychiatry’s “wonder drug”: does not suppress normal feeling or emotion, leaves individual with ability to feel and express joy and sadness, does not impair intellectual processes , can be taken for years without ill affects between 70 to 80% of ppt with BD show a positive response -pharmacological effects yet to be fully elucidated: drugs stabilize certain classes of neurotransmitters preventing shifts in neural sensitivity, increase near protective factors,

Each anxiety disorder presents with its own unique list of cognitive impairments, but overall, the anxiety disorders present with impairments in executive function and verbal episodic memory Anxiety Disorders Anxiety disorders are mental disorders that are characterized by anxiety and fear. Anxiety is defined as the fearful behavioral response to a potential future threat and the uncertainty of the effects of the threat, whereas fear is related to the emotional response to current events. Anxiety disorders can be broken up into about six different major sub-categories; namely, panic disorders (PD), generalized anxiety disorders (GAD), social anxiety disorder (SAD), PTSD, OCD, and specific phobias. • Most of the anxiety disorders can present at childhood and continue to present into adult hood • Females are twice as likely to have anxiety disorders than males • Prevalence of 28%, most common psychiatric disorder • Females are twice as likely to have anxiety disorders than males The hyperactivity in the amygdala and hypoactivity in the PFC are most likely due to decreased inhibition of the fear circuitry due to dysfunction of the GABAergic system. GABA ( -aminobutyric acid) is the main inhibitory neurotransmitter in the central nervous system (CNS). There are two types of GABA receptors: Type A and Type C, both of which are ligand-gated ion channel (although GABA A is the main one found in the CNS), and Type B, a metabotropic G-protein coupled receptor. Deficits in the number of GABA A receptors have been found in various anxiety disorders such as PTSD, and have been correlated with anxiety symptoms Each of the individual anxiety disorders have their own unique neural correlates, most of them center around the amygdala–PFC circuitry: hyperreactivity in the amygdala to stimuli and hypoactivity in the PFC

Three Main Treatments 1. Benzodiazepines, which act to enhance the GABA transmission in the CNS: mainly anxiolytic, sedative, hypnotic, amnestic, and muscle-relaxant effects. Their main mechanism of action is to bind to GABA A receptors and to increase the chance of the channel being open at low GABA concentrations as well as slowing down the receptor deactivation. 2. SSRIs: Serotonergic fibers from the raphe nucleus are believed to modulate both the GABA interneurons that modulate the fear circuitry and the neurons within the lateral amygdala 3.Tricyclic antidepressants block serotonin, norepinephrine and dopamine transporters resulting in increased levels of 5-HT, NE and DA in the synaptic cleft *can have specific treatments for specific ADs Main Concerns of Benzodiazepines 1. Limited by their potential for tolerance, dependence, and addiction, and are therefore best used intermittently 2. Benzodiazepines should be tapered slowly due to potential for a withdrawal syndrome that includes symptoms of confusion, seizures, anxiety, agitation, and insomnia SSRI Side Effects: sexual dysfunction and gastrointestinal (GI) problem ,possible link withincreased risk of suicide TCAs SIDE EFFECTS: nausea, vomiting, hypotension, anorexia, dry mouth, blurred vision, confusion, constipation, tachycardia, urinary retention, sedation, weight gain, and confusion in the elderly

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Cognitive impairments: Attention, impairment in working memory and processing speed Deficits in executive function and with difficulties in organization, planning, initiating, and completing tasks, shifting tasks, self-monitoring and self- inhibition may be observed concurrently Attention Deficit/ Hyperactivity Disorder ADH is characterized by symptoms of poor impulse control, impaired attention regulation, excessive motor activity, and restlessness DSM-5 lists nine symptoms of inattention and nine symptoms of hyperactivity/impulsivity: at least six in both groups of symptoms for patients under the age of 17 years; the required symptom thresh- old is five and not six symptoms for patients 17 and older Prevalence of the disorder range from about 6%–9% in childhood to about 4.4% in adult The dopaminergic system is believed to be involved in weakening and suppressing irrelevant signals, while the adrenergic system may help enhance and strengthen behaviorally appropriate systems. Not only have studies shown that the PFC in ADHD subjects is reduced, but also that is has reduced functional activity, most likely due to decreased signaling from these two systems

Three Main Treatments 1. Stimulants: Stimulants (methylphenidate (increases the release of dopamine (and norepinephrine at higher doses) from the presynaptic neuron) and amphetamine): block dopamine and norepinephrine reuptake into presynaptic neuron 2. Non-Stimulant (atomoxetine): selective norepinephrine reuptake inhibitor, which is believed to have some effect on dopamine concentration within the synapse 3.Atypical: Other categories of effective medications that have been shown to be effective in off-label studies in adults with ADHD (and generally have not been extensively studied, as stimulants or atomoxetine) include antidepressants (specifically TCAs and bupropion) and the adrenergic agonists Stimulant Side Effects: Potential side effects include nausea, difficulty falling asleep, anorexia, obsessiveness, headaches, dry mouth, rebound phenomena, anxiety, nightmares, dizziness, irritability, dysphoria, cardiovascular effects, and weight loss - and misuse Non Stimulant Side Effects: Cardiovascular effects, with modest elevations of blood pressure and pulse, suggesting the need to monitor these measures during treatment - not as effective as stimulants TCAs SIDE EFFECTS: nausea, vomiting, hypotension, anorexia, dry mouth, blurred vision, confusion, constipation, tachycardia, urinary retention, sedation, weight gain, and confusion in the elderly pharmacological treatment of ADHD generally aims to enhance or mimic catecholaminergic signaling, specifically within the PFC