Case #1. Case #1. Case #1. Discussion. DSM IV Overview of PD. Psychopharmacology of Panic Disorder and Generalized Anxiety Disorder 09/03/2012

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1 Case #1 Psychopharmacology of Panic Disorder and Generalized Anxiety Disorder Smit S. Sinha MD Assistant Professor A 33 year old male engineer presents to an outpatient clinic for consultation for severe anxiety and distress, and had recently been discharged from the emergency room for evaluation of disabling chest pain and shortness of breath. He was put on Sertraline 75 mg but he discontinued it after 2 days. Case #1 He currently is not on any medication, but was also given a prescription of Lorazepam 1mg. He was reluctant to be seen without his wife present. He states several times a day he is experiencing attacks of increased heart rate, chest pain, sweating, dyspnea, fear of going crazy and dying. The attacks often wake him from sleep. Case #1 He has become increasingly fearful of unfamiliar environments and gets very anxious when travelling even short distances. He is reluctant to travel unless accompanied by his wife. Recently he has been granted a leave from work, and now is fearful for his job s security. On presentation he is extremely distressed. What are the important points regarding presentation and diagnosis in this case? What aspects of the PD syndrome does this case illustrate? What type of behavior is this patient exhibiting? DSM IV Overview of PD Recurrent panic attacks Attacks are followed by at least one month of persistent concern re: additional attacks, worry about implications/consequences of the attack, or significant change in behavior related to the attacks Not better explained by another psychiatric disorder, substance use, or general medical condition Specify with or without agoraphobia 1

2 Panic Attack DSM IV definition: Rapid crescendo(2-5 min) of intense fear, anxiety or discomfort Out of the blue At least 4 somatic and cognitive symptoms: Heart racing, pounding heart, shortness of breath, choking, chest pain, sweating, trembling, nausea, abdominal distress, dizziness, unsteadiness, depersonalization Flight to ER common Panic Attack Cognitive symptoms (fears of dying, going crazy, losing control) prominent Symptoms often cluster: cardiorespiratory most common Subjective urge to escape/flee Distinct from normal fear/fight or flight: categorical vs. continuum model Panic Attack Situationally bound attacks: invariably and immediately upon exposure to a trigger Common in specific phobias and social anxiety disorder Tend to not involve dyspnea or fears of dying Situationally predisposed attacks: more likely to occur in certain situations Variants: Limited Symptom Attacks DSM IV four symptom cutoff arbitrary LSAs are attacks that fall below this threshold Very common, associated with significant impairment and agoraphobia just like full blown PAs Often occur early in the illness Variants: Non-fearful Panic Panic attacks can occur without fear; DSM IV defines a period of intense fear OR discomfort Freud: patients with severe, short-lived palpitations without overt anxiety as suffering from anxiety neurosis Concept: from cardiac patients with no organic pathology: full range of somatic panic symptoms but no fear Commonly present to ER: lack of overt anxiety signifies a medical condition Variants: Nocturnal Panic Panic sometimes occurs while asleep Characterized by sudden awakening, terror and intense physiological arousal Usually in non-rem sleep and not preceded by dreams or nightmares Signifies greater severity of illness and occurs more often in its early stages 2

3 What are the fundamental points of agoraphobia and how do these affect treatment considerations? Panic Disorder with Agoraphobia Panic attacks, anticipatory anxiety and agoraphobia are the core components Disorder starts with the initial panic attack; fear of subsequent attacks develops (anticipatory anxiety) Then, avoidance of situations that are associated with the attack occurs (agoraphobia) Strict conditioning model of agoraphobic development Agoraphobia Definition: Fear about being in places or situations from which escape may be difficult or embarassing, or in which help may not be available in the event of a panic attack or panic symptoms Typical course: avoidance behavior linked to a few situations where panic attacks have occurred. avoidance then generalizes Often mistaken for social anxiety: identify core fear Agoraphobia: Etiology? Simple conditioning model may not be sufficient If so, agoraphobia should rarely, if ever, antecede panic attacks Contradictory Data: ECA study showed high prevalence of agoraphobia alone Marked variability in development of agoraphobia Avoidance behavior can precede the onset of panic Comorbidity Major Depression Other Anxiety Disorders: 30-40% of PD have SAD Bipolar Disorder: 20% of Bpd have PD (ECA) Occurs in depressive or manic phases increases suicide risk; self medication with clonazepam? Preferential response to valproate vs. lithium Other common comorbid conditions: 20% develop hypochondriacal elaboration of benign physical sensations 20% develop alcohol dependence; episodes of withdrawal may sensitize and ultimately worsen panic Brief review of some distinguishing neurobiological aspects of PD and their relationship to pharmacological treatment 3

4 Respiration Shortness of breath key symptom High rates of panic symptoms in patients with genuine respiratory illness CO2 inhalation reliably produce panic attacks in PD (60-70%) compared to other psychiatric disorders and normal controls CO2 hypersensitivity is attenuated by antidepressant treatment, and is evident before clinical improvement Neuroendocrinology-PD Naturalistic panic attacks and CO2/lactate panic attacks not associated with HPA activation Yet, stress system activation (specifically CRH from hypothalamus) is consistently invoked to explain the physiologic and cognitive manifestations of panic Role of CRH is ambiguous in PD, despite its clear involvement in animal models of anxiety Different hypotheses re: CRH antagonists What commonly precipitates PD and leads them to seek pharmacological treatment? Precipitants Stressful Life Events Theme of separation critical Panic often arises in the context of separation from and loss of significant others (move away from home, divorce) 40-50% have dependent personality only anxiety disorder where distress is alleviated by presence of a trusted companion Childhood separation anxiety common antecedent Childhood SA differentially responsive to CO2 What would be the first line treatment for this patient? What would be the expected response pattern for his symptoms? How would you categorize the severity of his symptoms? Treatment Available treatments are profoundly effective Mainstay is pharmacologic SSRIs are first line treatment Pattern of response: first, panic attacks decrease in frequency and intensity second, anticipatory anxiety regarding future attacks diminishes third, reduced fear of subsequent attacks leads to reduction in avoidance behaviors and agoraphobia 4

5 Pattern of Treatment Response In many instances, panic attacks decrease significantly but significant agoraphobic behaviors persist Despite removal of the unconditioned stimulus (PA), phobic avoidance often resistant to extinction Divergence from typical response pattern common What was the likely reason he discontinued his sertraline after 2 days? Treatment PD exquisitely sensitive to side effects: initial jitteriness (shakiness, agitation, anxiety) very common during SSRI initiation; PD hypersensitive to minute changes in bodily sensations Main reason for poor compliance and inadequate trials Important to start low, go slow; patients generally work through the initial hypersensitivity SSRI/SNRI starting doses in PD Sertraline 25 Paroxetine 10mg/12.5 mg CR Fluvoxamine 50 mg Fluoxetine 20 mg Citalopram 10 mg Escitalopram 5 mg Venlafaxine 37.5mg He is currently not on any medications. What would be a good approach to this patient s pharmacological management? Treatment SSRIs/SNRIs are first line No differential efficacy among SSRIs Anecdotal evidence of differential tolerability and side effects profile Sertraline was better tolerated and associated with less clinical worsening during taper than paroxetine (Bandelow) 5

6 SSRIs/SNRIs Sertraline, paroxetine, fluvoxamine, fluoxetine and citalopram efficacious Paroxetine CR (25-75mg/day) was superior to placebo (Sheehan) Venlafaxine also very effective and is considered first line SSRIs and venlafaxine: no difference in efficacy SSRIs/SNRIs One study showed that venlafaxine at high dosage (225mg) superior to paroxetine 40mg (Pollack) Both SSRIs and SNRIs are effective with co morbid depression Onset of action generally slow; assessment of response made after several weeks SSRIs/SNRIs Antipanic Dosages Sertraline 100 mg Paroxetine mg Fluoxetine 20 mg Fluvoxamine mg Citalopram mg Escitalopram 10 mg Venlafaxine mg Assuming you have restarted him on a first line treatment such as an SSRI, what other treatment considerations would be important at this point? Would one medication be adequate? What would be the approach if panic symptoms worsen in the next two weeks? Treatment: Benzodiazepines Extremely effective (particularly high potency), rapidly acting, with favorable side effect profile When to use: to augment SSRIs during initiation phase (moderate to severe cases); in ER for acute management; or for partial/nonresponders to antidepressants alprazolam at mean dose of 5.7 mg/day equivalent to imipramine and superior to placebo Alprazolam far better tolerated than imipramine Treatment: Benzodiazepines Most effective antipanic benzodiazepines are alprazolam and clonazepam Clonazepam (1-3mg qd) may be preferable due to long half life No tolerance to therapeutic effects with benefits maintained over long term Can often decrease the dose during maintenance treatment 6

7 Benzodiazepines Alprazolam 4-6mg (start at 1.5mg) Clonazepam 2-3mg (start at 1mg) Lorazepam 2-4 mg (start at 1mg) Diazepam mg (start at 5-10mg) Treatment Main drawback: physiological dependence all studies show withdrawal problems with tapering benzodiazepines; Also, depression with long term use PD without history of substance abuse are unlikely to abuse benzodiazepines, in fact find doses above what is needed to be unpleasant and associated with increased side effects Lack of efficacy for comorbid depression Main Indication for Benzodiazepines in PD Severe illness necessitating rapid amelioration of panic (1-2 weeks) During first few weeks of antidepressant therapy to protect against hypersensitivity As a therapeutic adjunct for partial responders to AD As a second line treatment if AD intolerant After 8 weeks his panic attacks have decreased, but there is still extensive avoidance behavior. Is this a reasonable period of time to assess treatment response? What would be a good approach at this point? What would be the optimal duration of treatment? What is key for the treatment of persistent phobic avoidance behavior? Optimal Duration of Pharmacotherapy in PD Relapse following discontinuation a significant problem 50% of patients relapsed within 6 months of venlafaxine discontinuation (Ferguson) One third relapsed within one year of imipramine discontinuation (Mavissakalian) 7

8 Duration During maintenance, further improvements observable (Ballenger) Optimal duration not known and an understudied area Most guidelines recommend continuation for at least one year; no critical period Gradual discontinuation recommended Maintenance Therapy Maintenance treatment with lower dosages may be sufficient to maintain therapeutic gains observed in the acute phase One study demonstrated this at half-dose imipramine; also benzodiazepines Exploratory area Second LineTreatments Imipramine: the first antidepressant with demonstrable antipanic efficacy most extensively studied Clomipramine: has equivalent or greater efficacy compared with imipramine (150mg/day) Long term treatment studies suggest continuation for 1-2 years after initial antipanic response Imipramine/clomipramine Adverse side effect profile the main reason for second line status 30% dropout rate in clinical trials No demonstration of SSRI superiority for efficacy One study suggested a slower time to response than SSRIs (Lecrubier) Imipramine/Clomipramine Imipramine mg (start at 25 mg) Clomipramine mg (start at 25 mg) No difference in efficacy between imipramine and sertraline for PD comorbid with depression (Lepola) Other Treatment Buspirone: ineffective (Sheehan) Nefazodone: modest efficacy Buproprion: likely ineffective and can worsen panic; a few studies are positive MAOIs: phenelzine effective, but should be reserved for patients non responsive to other classes B-blockers: not effective 8

9 What are options for the treatment refractory patient? Treatment Refractory PD Ensure adherence to treatment Optimize regimen; add BDZ Add modality (CBT) Small evidence but insufficiently investigated: mirtazapine, trazodone B-blocker augmentation of SSRI effective in one study (Hirschmann) Treatment Refractory PD-Atypicals Treatment resistant patients assigned to SSRI plus 5mg olanzapine (fixed dose); beneficial effects at 12 weeks (Sepede). Olanzapine augmentation in severe cases; better for PTSD (hyperarousal, fear based) Olanzapine monotherapy Risperdone augmentation (Simon) Case #2 You are asked to see a 43 year old patient in consultation with debilitating headaches and fatigue. He finds that he cannot concentrate, is very irritable, and is not sleeping. He states he worries constantly and is especially concerned about his finances. His significant other is frustrated with his ruminative tendencies. What notable component of GAD is missing from this patient s presentation? How does functional impairment in GAD compare to that seen in depression? How would you approach the pharmacological treatment of this patient? 9

10 Benzodiazepines Diazepam, alprazolam and lorazepam have all demonstrated efficacy Advantages are fast onset of action and good side effect profile Drawbacks are physiological dependence Diazepam and alprazolam similar efficacy to buspirone He is concerned about side effects, so you start him on monotherapy with a benzodiazepine and there is minimal response. What could be impeding the benzodiazepine s efficacy? What symptoms of GAD do benzodiazepines work best for? Antidepressants Imipramine, trazodone and diazepam were compared in GAD comorbid with depression Imipramine was superior to diazepam in the comorbid group Benzodiazepines not sufficient for GAD comorbid with depression Antidepressants Antidepressants surpass benzodiazepine efficacy at 6-12 weeks Paroxetine 20-50mg effective (Rickels) Reduction in anxious mood in 1 week SSRIs sustain therapeutic effect with incremental improvement over a 24 week period Antidepressants Sertraline mg/day effective in moderate to severe GAD (Dahl) Sertraline compared to buspirone: faster effects with buspirone but no difference at 8 weeks (Mokhber) Escitalopram superior to placebo (Davidson) What is another important option for first line pharmacotherapy of GAD? 10

11 SNRIs Venlafaxine XR mg/day superior to placebo (Sheehan) Venlafaxine comparable in efficacy to paroxetine, with slightly greater likelihood of a discontinuation syndrome Duloxetine mg superior to placebo, equivalent to venlafaxine Both helpful in relapse prevention for GAD Patient is not adequately responding to an SSRI or SNRI. What are other treatment options? Treatment Non response Buspirone (Chessick); Buproprion XR equivalent to escitalopram in one study (Bystritsky) Imipramine Valproate superior to placebo for acute tx of GAD in one study (Aliyev) Adjunctive olanzapine with SSRI increased response rates (Pollack) Limited evidence for augmentation with quetiapine (Simon) Treatment Non-response Adjunctive risperdone potentially beneficial (Pandina) Atypical antipsychotics used at lower doses in refractory GAD (2.5-10mg olanzapine, 0.5-3mg risperdone, mg quetiapine) Improvement should occur within 2 weeks, better for anxiety symptoms than worry Consider another modality (CBT) Case #3 46 female professor presents to you in consultation for severe panic attacks, significant interattack anxiety, and depression. She is taking clonazepam 0.5 mg per day. You start her on an SSRI and her panic symptoms worsen. You try lowering the dose of the SSRI but she reports increased irritability and a noticeable surge in energy. What has the initiation of an SSRI in this patient induced? What was the role of the clonazepam? Would you continue it? How would you approach the treatment of this patient? 11

12 Treatment Options Some evidence of preferential response to valproate compared to lithium Olanzapine alone or as adjunctive to lithium effective in reducing panic attacks Optimal treatment of panic attacks in bipolar illness an understudied area 12