PHARMACOTHERAPY - I PHCY 310 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY - I PHCY 310 Lecture -10 Psychiatric Disorders “Insomnia & Anxiety” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Describe sleep physiology; classify insomnia and its common causes, Describe the diagnosis, non-pharmacological and pharmacological treatment for insomnia, Classify anxiety disorders, various causes, non-pharmacological and pharmacological treatment for different classes of anxiety disorders.

Insomnia SLEEP PHYSIOLOGY Humans have four to six cycles of non–rapid eye movement (NREM) and rapid eye movement (REM) sleep each night, each cycle lasting 70 to 120 minutes. Stage 1 of NREM is the stage between wakefulness and sleep. Stage 3 and 4 sleep is called delta sleep (i.e., slow-wave sleep). In the elderly, sleep is lighter and more fragmented with more arousals and a gradual reduction in slow-wave sleep. Sleep is reduced when there is decreased serotonin activity or destruction of the dorsal raphe nucleus.

Dopamine has an alerting effect. Neurochemicals involved in wakefulness include norepinephrine and acetylcholine in the cortex and histamine and neuropeptides (e.g., substance P and corticotropin-releasing factor) in the hypothalamus. Insomnia refers to difficulty in falling asleep or staying asleep, or to lack of refreshment from sleep. Persistent or chronic insomnia and transient or short-term insomnia are the common types. Clinical Presentation: Patients with insomnia complain of difficulty falling asleep, maintaining sleep, or not feeling rested in spite of a sufficient opportunity to sleep. Transient (two to three nights) and short-term (less than 3 weeks) insomnia is common and is usually related to a precipitating factor. Chronic insomnia (greater than 1 month) may be related to medical or psychiatric disorders or medication, or it may be psychophysiologic.

Common Causes of Insomnia

NONPHARMACOLOGIC THERAPY Behavioral and educational interventions that may help include short term cognitive behavioral therapy, relaxation therapy, stimulus control therapy, cognitive therapy, sleep restriction, and sleep hygiene education. PHARMACOLOGIC THERAPY (Hypnotics) The ideal hypnotics should induce sleep rapidly after ingestion, maintain sleep for entire duration expected, without lasting so long that it produces a “morning hang-over” and impaired day time performance. It should not induce development of tolerance or dependence when used over a number of consecutive nights, and abrupt discontinuation should not result in withdrawal or rebound insomnia. It should be safe and should make abnormal sleep normal and also should offer no potential for drug-drug interactions. Nonbenzodiazepine Hypnotics Antihistamines (e.g.,diphenhydramine, doxylamine, and pyrilamine) are less effective than benzodiazepines, but side effects are usually minimal. Their anticholinergic side effects may be problematic, especially in the elderly.

Antidepressants are good alternatives for patients with poor sleep who should not receive benzodiazepines, especially those with depression or a history of substance abuse. Amitriptyline, doxepin,and nortriptyline are effective, but side effects include anticholinergic effects, adrenergic blockade, and cardiac conduction prolongation. Trazodone, 25 to 100 mg, is often used for insomnia induced by selective serotonin reuptake inhibitors or bupropion. Side effects include serotonin syndrome (when used with other serotonergic drugs), over sedation, and dizziness. (Serotonin syndrome is a potentially life threatening drug reaction that causes the body to have too much serotonin, a chemical produced by nerve cells that causes Agitation or restlessness, Diarrhea, Fast heart beat, Hallucinations, Increased body temperature, Loss of coordination, Nausea, Overactive reflexes, Rapid changes in blood pressure, Vomiting).

Cases of psychotic reactions and sleep-eating have been reported. Zolpidem, acts selectively at the γ-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Given in low doses(5-10mg) it provides a full night of sleep with little or no day time impairment and few effects on memory and has lower abuse potential than BZDs. Cases of psychotic reactions and sleep-eating have been reported. Benzodiazepine Hypnotics Benzodiazepines bind to GABAA receptors, and have sedative, anxiolytic, muscle relaxant, and anticonvulsant properties, increase stage 2 sleep and decrease REM and delta sleep. Triazolam is has a short duration of effect. Erythromycin, nefazodone, fluvoxamine, and ketoconazole reduce the clearance of triazolam and increase plasma concentrations.

Estazolam and temazepam are intermediate in their duration of action. The effects of flurazepam and quazepam are long because of active metabolites. Side effects include drowsiness, psychomotor in coordination, decreased concentration, and cognitive deficits. Tolerance to the daytime CNS effects (e.g., drowsiness, psychomotor impairment, decreased concentration) may develop in some individuals. Anterograde amnesia (Impaired ability to learn new information) has been reported with most benzodiazepines. Using the lowest dose possible minimizes amnesia. Impaired ability to learn new information following the onset of amnesia (anterograde amnesia) Impaired ability to recall past events and previously familiar information (retrograde amnesia)

Anxiety disorders describe several different forms of abnormal fear and worry. Anxiety involves two basic components: mental features (e.g., worry, fear, difficulty concentrating) and physical symptoms (e.g., racing heart, shortness of breath, trembling, pacing). Pathogenesis of anxiety symptoms may be linked to chronic noradrenergic over activity, under activity of GABA (inhibitory effect) systems or its receptor down regulation, excessive 5-HT transmission or over activity of the stimulatory 5-HT pathways.. Investigations History Nature of symptoms and onset Presence of comorbid medical or psychiatric conditions -Medication history for drug induced anxiety Classification of Anxiety Disorders 1) Panic Disorder 2) Phobic Disorders 3) Obsessive–Compulsive Disorder (OCD) 4) Post-traumatic Stress Disorder (PTSD) 5) Generalized Anxiety Disorder (GAD)

Therapeutic Choices Relatively mild anxiety states in response to life events are frequently time-limited, and many patients respond to anxiety management strategies without medication. Nonpharmacologic Choices 1- Caffeine use should be avoided or reduced. 2- Alcohol use should be avoided, and should not be used to control anxiety. 3- Reduce the “as-needed” use of short-acting BDZs as much as possible (not longer than 4 days). 4- Relaxation training and time management. 5- Cognitive behavioural therapy (CBT). Pharmacologic Choices Benzodiazepines are the first choice for patients with GAD and panic disorder. SSRIs are first line agents in treatment of SAD, panic disorders, OCD, GAD and PTSD. SNRI (Venlafaxine) also can be used as first-line in GAD.

1) Panic Disorder Symptoms usually begin as a series of unexpected panic attacks, reaches peak within 10 minutes and usually last no more than 20 or 30 minutes. Many patients eventually develop agoraphobia, which is avoidance of specific situations (e.g., crowded places, bridges) where they fear a panic attack might occur. SSRIs are first-line agents, but BZs are the most commonly used drugs for panic disorder. Alprazolam, clonazepam, sertraline, paroxetine, and venlafaxine are FDA approved for this indication. If agoraphobia present, CBT typically is initiated at the same time and is less likely to relapse. Patients must be educated to avoid caffeine, drugs of abuse, and stimulants. Antidepressants, especially SSRIs, are preferred in elderly patients and youth. BZs are second line because of potential problems with disinhibition.

BZs should not be used as monotherapy in panic disorder patients with a history of depression or alcohol or drug abuse. The Tricyclic antidepressants (TCAs) can also reduce the frequency and severity of panic attacks and are inexpensive. Mirtazapine has been also effective. The initial dose of antidepressant should be as low as possible and then increased, as tolerated, to the usual dose range. If a higher starting dose is used, patients may become extremely agitated and discontinue treatment abruptly. The antidepressant medication is usually required for months or years as the majority of patients could suffer relapse after the antidepressant is discontinued.

Benzodiazepines Low doses benzodiazepines can be used to abort the initial panic attacks. E.g. alprazolam , clonazepam, lorazepam and diazepam. Benzodiazepines are reserved for short term use if SSRI treatment has not been successful or where there is need for augmentation of an antidepressant response. 2) Phobia (Social and Specific) A- Social Anxiety Disorder (SAD) (Social Phobia) An excessive fear of being criticized or negatively evaluated by others presents as shyness, avoidance of social contact or difficulty dealing with authority figures. SSRIs are the mainstay of medical treatment for social phobia.

B- Specific Phobia There is usually no indication for medication to treat the specific fear of heights, animals, injections or others. As little as 6 hours of CBT is often successful in treating specific fears. 3) Obsessive–Compulsive Disorder (OCD) An anxiety disorder characterized by intrusive (disturbing) thoughts or obsessions (unwanted feeling) that produce anxiety. Compulsions are repetitive behaviors due to doubts. The SSRIs are recommended as first-line treatment (fluoxetine, paroxetine, sertraline), but it may take 6–8 weeks to produce significant change in symptoms, and if successful, the SSRI medication may continue for years. An SSRI trial, at full dosages, for at least 6 weeks is required to assess the effect of that SSRI before shifting to another SSRI. Second-line options include TCAs, or mirtazapine .

Augmentation of SSRIs could be done with BDZs or atypical antipsychotics to increase the response in OCD. 4) Post-traumatic Stress Disorder (PTSD) PTSD presents following exposure to a traumatic event in which there is threat or occurrence of injury or death to someone. SSRIs have been shown to reduce the severity of all the symptoms of PTSD. The atypical antipsychotics risperidone and olanzapine, as well as benzodiazepines are effective augmenters of antidepressants in PTSD.

5) Generalized Anxiety Disorder (GAD) GAD is characterized by excessive and uncontrollable worry related to everyday-life concerns, such as safety of family members, financial and job security and health. SSRIs are first-line drug treatment for generalized anxiety disorder. Because of its side effects and safety concerns in overdose, imipramine, an effective agent in generalized anxiety disorder, is usually reserved for when first-line choices are not effective. Low-dose benzodiazepines (e.g., alprazolam, bromazepam, diazepam, lorazepam) can be used for few weeks for symptom relief. Venlafaxine, the serotonin and norepinephrine reuptake inhibitor (SNRI) was the first antidepressant to be used for GAD. It is also indicated in SAD (extended release tablet 37.5mg/day).

Questions to Answers Drug withdrawal insomnia and Rebound insomnia with examples. Important questions to ask in monitoring Hypnotic therapy. DSM-IV-TR classification of anxiety disorders. Triazolam discontinuation method. Reference: Richard A. Helms, David J. Quan, Eric T. Herfindal, Dick R.Gourley. Textbook of Therapeutics. Drug and Disease Management. 8th Edition. Lippincott Williams and Wilkins. Barbara G.Wells, Joseph T. Dipirio et al. Pharmacotherapy Hand Book-7th Edition. McGraw-Hill (2009).