neuropsychiatric disorders: neuropharmacology, novel ...central nervous system diseases...

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?