neuropsychiatric disorders: neuropharmacology, novel ...central nervous system diseases...
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Neuropsychiatric Disorders: Neuropharmacology, novel therapeutics, interventionsAMBER FIFER, PHARMD
Neuropsychiatric DisordersCentral nervous system diseases characterized by disturbances in emotion, cognition, motivation and socialization.
Genetic risk comprises 20-90% of disease vulnerability
Broad heterogeneous syndromes that currently lack well-defined neuropathology and biologic markers
There is increasing agreement that the DSM classification does not accurately reflect the underlying biology of these disorders
Neuroimaging methods are beginning to provide evidence of brain pathology
Progress is being made in understanding the genetic and neurobiologic basis of mental illness
Neuropsychiatric DisordersFor discussion today:◦ Anxiety Disorders◦ Generalized Anxiety Disorder (GAD)◦ Panic Disorder◦ Social Anxiety Disorder◦ Posttraumatic Stress Disorder (PTSD)
◦ Major Depressive Disorder◦ Bipolar Disorder◦ Schizophrenia
Anxiety DisordersA constellation of disorders in which anxiety and associated symptoms are irrational or experienced at a level of severity that impairs functioning
The most prevalent psychiatric illnesses in the general community
Present in 15-20% of clinic patients
In general these disorders develop before age 30 and are more common in women, individuals with social issues and those with a family history
Consist of:◦ Generalized Anxiety Disorder◦ Panic Disorder◦ Social Anxiety Disorder◦ Posttraumatic Stress Disorder (PTSD)
Anxiety Disorders - PathophysiologyNoradrenergic Model – the autonomic nervous system is hypersensitive and overreacts to various stimuli. The locus ceruleus may have a role as it activates norepinephrine (NE) release and stimulates the sympathetic and parasympathetic nervous systems
γ-Aminobutyric Acid (GABA) Receptor Model – GABA has a strong regulatory effect on the 5-HT, NE and dopamine (DA) systems. When GABA binds to the GABA receptor neuronal excitability is reduced
Serotonin (5-HT) Model – Abnormalities in serotonergic functioning may play a role in anxiety disorders
Neuroimaging studies – Functional neuroimaging studies support the crucial role of the amygdala, anterior cingulate cortex and insula in the physiology of anxiety
Generalized Anxiety Disorder - TreatmentGoals of Treatment◦ Reduce severity, duration and frequency of
symptoms◦ Improve functioning◦ Prevention of recurrence◦ Improved quality of lifeAvoid◦ Caffeine◦ Stimulants◦ Excessive alcohol◦ Diet pills
Nonpharmacologic Treatment◦ Psychotherapy◦ Counseling◦ Stress management◦ Cognitive therapy◦ Meditation◦ Supportive therapy◦ Exercise
Generalized Anxiety Disorder - Treatment
Generalized Anxiety Disorder-Treatment
Anxiety Disorders - Treatment
Anxiety Disorders – Treatment
Anxiety Disorders – Treatment Monitoring
Anxiety Disorders – Treatment Monitoring
Anxiety Disorders – Treatment Monitoring
Anxiety Disorders – Treatment Monitoring
Panic Disorder - TreatmentGoals of Treatment◦ Complete resolution of panic attacks◦ Marked reduction in anticipatory
anxiety◦ Elimination of phobic avoidance◦ Resumption of normal activities
General Approach◦ SSRIs are first-line agents◦ Antidepressants, especially SSRIs are
preferred in elderly patients or youths◦ Usually patients are treated for 12-24
months before discontinuation is attempted over 4 to 6 months
◦ Many people require long-term therapy single weekly doses of fluoxetine have been used for this
Panic Disorder - Treatment
Panic Disorder - Treatment
Social Anxiety Disorder - TreatmentGoals of Treatment◦ Reduce symptoms and phobic
avoidance◦ Increase participation in desired social
activities◦ Improve quality of life
General Approach◦ Response is often slower and less
complete than with other anxiety disorders
◦ 1 year of maintenance treatment is recommended
◦ Long-term treatment may be needed for some patients
Social Anxiety Disorder - Treatment
Algorithm for the pharmacotherapy of social anxiety disorder. Strength of recommendations: A, directly based on category I evidence (ie, meta-analysis ofrandomized controlled trials [RCT] or at least one RCT); C, directly based on category III evidence (ie, nonexperimental descriptive studies); D, directlybased on category IV evidence (ie, expert committee reports or opinions and/or clinical experience of respected authorities). SSRI, selective serotoninreuptake inhibitor. (Adapted from References 2, 3, 22, and 56.).
Social Anxiety Disorder - Treatment
Posttraumatic Disorder - TreatmentGoals of Treatment◦ Decrease core symptoms, disability and
comorbidity◦ Improve quality of life
General Approach◦ Immediate treatment after the trauma
may prevent PTSD◦ If symptoms persist for 3 to 4 weeks,
then long-term pharmacotherapy may be warranted
Posttraumatic Stress Disorder - Treatment
Posttraumatic Stress Disorder - Treatment
Major Depressive Disorder - Pathophysiology
Biogenic amine hypothesis – decreased brain levels of norepinephrine, serotonin (5-HT) and dopamine may cause depression
Dysregulation hypothesis – a failure of homeostatic regulation of neurotransmitter systems may cause depression
5-HT/norepinephrine link hypothesis – 5-HT and norepinephrine activities are linked and that both serotonergic and noradrenergic systems are involved in the antidepressant response.
Major Depressive Disorder - TreatmentGoals of Treatment◦ Reduce symptoms of depression◦ Minimize adverse effects◦ Ensure adherence to the prescribed regimen◦ Facilitate return to pre-morbid functioning◦ Prevent further depressive episodes
Major Depressive Disorder - TreatmentGeneral Approach◦ Antidepressants are equal in efficacy when
administered in comparable doses◦ Choice of antidepressant is influenced by◦ History of response◦ Concurrent medical conditions◦ Presenting symptoms◦ Potential for drug interactions◦ Side effect profiles◦ Patient preference◦ Cost
◦ Between 65% and 70% of patients improve with drug therapy
◦ It typically will take 2-4 weeks to see a response
◦ A 6-week trial of an antidepressant at max dose is considered and adequate trial
◦ Decrease initial dose by half in elderly patients
◦ Lifelong therapy may be required
Major Depressive Disorder - Treatment
Suggested algorithm for treatment of uncomplicated MDD. (SSRI, selective serotonin reuptake inhibitor.) Note: both the BAP guidelines and the STAR*Dtrial suggest that switching and augmentation strategies are supported by stronger evidence compared to dose increases (among poor antidepressantresponders).
Major Depressive Disorder - Treatment
Major Depressive Disorder – Treatment cont.
Major Depressive Disorder – Treatment cont.
Major Depressive Disorder – Treatment Side Effects
Major Depressive Disorder – Treatment Side Effects
Major Depressive Disorder – Treatment Monitoring
Major Depressive Disorder – Treatment Monitoring
Major Depressive Disorder – Treatment Monitoring
Major Depressive Disorder – Foods to Avoid with MAOIs
Major Depressive Disorder – MAOI drug interactions
Major Depressive Disorder – Treatment Pharmacokinetics
Major Depressive Disorder – Treatment Pharmacokinetics
Major Depressive Disorder – CYP P450 inhibition
Major Depressive Disorder - TreatmentSpecial Populations:◦ Elderly – SSRI’s are considered first choice. Bupropion, mirtazapine and venlafaxine are also well
tolerated◦ Pediatrics – Fluoxetine and escitalopram are the only FDA approved antidepressants in patients below
18 years of age◦ Pregnancy – Nondrug approaches are preferred. Weigh the risks vs benefits of continuing anti-
depressants during pregnancy.
Bipolar DisorderInfluenced by developmental, genetic, neurobiological and psychological factors
Fluctuations between mood episodes:◦ Major Depressive Episode – delusions, hallucinations and suicide attempts◦ Manic Episode – bizarre behavior, hallucinations, paranoid or grandiose delusions,
impairment in functioning. May be precipitated by stressors, sleep deprivation, antidepressants, CNS stimulants or bright light
◦ Hypomanic Episode – No marked impairment in social or occupational functioning, no delusions or hallucinations
Bipolar Disorder - Treatment
Bipolar Disorder - Treatment
Bipolar Disorder - Treatment
Bipolar Disorder - Treatment
Bipolar Disorder - Treatment
Bipolar Disorder - Treatment
Bipolar Disorder - Treatment
Bipolar Disorder - Treatment
Schizophrenia - PathophysiologyIncreased ventricular size and decreased gray matter have been reported
Causation theories:◦ Genetic predisposition◦ Obstetric complications◦ Increased neuronal pruning◦ Immune system abnormalities◦ Neurodevelopmental disorders◦ Neurodegenerative disorders◦ Dopamine receptor defects◦ Regional brain abnormalities◦ Glutamatergic dysfunction◦ Serotonin abnormalities
Schizophrenia - TreatmentGoals of Treatment◦ Alleviate target symptoms◦ Avoid side effects◦ Improve psychosocial functioning and
productivity◦ Achieve compliance with the prescribed
regimen◦ Patient involvement in treatment
planning
General Approach◦ Second generation antipsychotics
(SGAs), except clozapine, are the first choice agents
◦ SGAs cause few or no acutely occurring extrapyramidal side effect, minimal to no tardive dyskinesia and have less effect on serum prolactin
◦ SGAs increase risk for weight gain, hyperlipidemia and diabetes
◦ Selection is based on side effects, concurrent medical disorders and history of response
Schizophrenia - Treatment
Schizophrenia - Treatment
Schizophrenia – Treatment algorithm
Suggested pharmacotherapy algorithm for treatment ofschizophrenia. Schizophrenia should be treated in the context of aninterprofessional model that addresses the psychosocial needs ofthe patient, necessary psychiatric pharmacotherapy, psychiatric co-occurring mental disorders, treatment adherence, and any medicalproblems the patient may have. See the text for a description of thealgorithm stages.
Schizophrenia – Treatment Pharmacokinetics
Schizophrenia – Treatment Pharmacokinetics
Schizophrenia – Treatment Side Effects
Schizophrenia – Treatment of Extrapyramidal Side Effects
Schizophrenia - Treatment
Schizophrenia - Treatment
Schizophrenia - Treatment
Schizophrenia - Treatment
Novel Drug Approvals for 2019Caplyta (lumateperone)• Indication: Atypical antipsychotic indicated for the treatment of schizophrenia in adults• Dose: 42mg once daily with food• Dose titration not required• Increased risk of stroke in elderly• Avoid in mod/severe hepatic impairment• CNS side effects• CYP3A4 inducer• 2 trials showed statistically significant reduction from baseline of the Positive and Negative Syndrome
Scale (PANSS)
Questions?