Pharmacotherapy for Complex Trauma

Wendy Leopoulos, MD Medical Director, Inpatient Mental Health Michael E. DeBakey VA Medical Center Assistant Professor, Baylor College of Medicine August 2018 HOUSEKEEPING ITEMS

• No financial disclosures • No conflicts of interest • Off-label usage of psychotropic medications will be presented WHAT IS COMPLEX TRAUMA?

• A trauma that occurs repeatedly and can escalate over its duration • Women can suffer a wide range of psychiatric illnesses as a result of experiencing a complex trauma from depression to anxiety to a complex PTSD reaction • Examples of a complex trauma include: – Childhood physical or sexual abuse – Domestic violence – Political violence – Torture WHAT IS COMPLEX PTSD?

• Core symptoms of PTSD + disturbances in self- regulatory capacities • 5 domains of self-regulatory capacities 1) Emotion regulation difficulties 2) Disturbances in relational capacities 3) Alterations in attention and consciousness (e.g. dissociation) 4) Adversely affected belief system 5) Somatic distress or disorganization

Cloitre et al, www.istss.org. HOW DO I CHOOSE? AUDIENCE QUESTION

Per the 2017 VA/DoD PTSD Clinical Practice, which of the following medications are recommended in the treatment of PTSD? a) Mirtazapine b) Sertraline c) Quetiapine d) Topamax e) Venlafaxine QUICK REVIEW OF MEDICATIONS FOR PTSD: CLINICAL PRACTICE GUIDELINES FOR MONOTHERAPY

Quality of Recommend For Suggest For Suggest Recommend No recommend. For or Against Evidence Against Against Moderate Sertraline Prazosin (*except Paroxetine for NMs) Fluoxetine Venlafaxine Low Nefazodone Quetiapine Divalproex Eszopiclone Olanzapine Tiagabine Citalopram Guanfacine Amitriptyline Very Low Imipramine Lamotrigine Risperidone Bupropion Phenelzine Topiramate Benzos Desipramine D-cycloserine D-serine Hydrocortisone Escitalopram Ketamine Mirtazapine No Data Doxepin, duloxetine, trazodone, zolpidem, buspirone, hydroxyzine, cyproheptadine etc.

Clinicians Guide to Medications for PTSD http://www.ptsd.va.gov TRANSDIAGNOSTIC APPROACH TO TREATMENT?

Self-regulatory Capacities of Complex PTSD Borderline Personality Disorder (BPD)

1) Emotion regulation difficulties 1) Frantic efforts to avoid abandonment 2) Disturbances in relational capacities 2) Patterns of unstable and intense relationships 3) Alterations in attention/consciousness (dissociation) 3) Identity disturbances 4) Adversely affected belief systems 4) Impulsivity in at least 2 areas potentially self- 5) Somatic distress or disorganization damaging 5) Recurrent suicidal behavior or self-mutilating 6) Affective instability 7) Chronic feelings of emptiness 8) Inappropriate anger 9) Transient paranoid ideation or severe dissociative symptoms AUDIENCE QUESTION

Which medication is Food and Drug Administration (FDA) approved to target Borderline Personality Disorder? • Fluoxetine • Topamax • Olanzapine • Clonazepam • Duloxetine UK VERSUS US GUIDELINES 3 BEHAVIORAL DIMENSIONS OF BPD

• Affective dysregulation symptoms – mood lability, intense anger, rejection sensitivity, depressive “mood crashes” • Impulsive-behavioral dyscontrol symptoms – Impulsive aggression, self-mutilation, or self-damaging behaviors • Cognitive-perceptual symptoms – Suspiciousness, paranoid ideation, illusions, derealization, depersonalization

Oldham, JM et al. Practice Guidelines for the Treatment of Patients with Borderline Personality Disorder, American Psychiatric Association, 2001. www.psychiatry.org AUDIENCE QUESTION

Imagine that you are seeing a patient who is struggling with borderline personality disorder (BPD) and you have decided to start a medication. Before going over the risks and benefits of a specific medication choice, how would you educate the patient about medications in general to treat BPD? CLINICAL PEARLS: MEDICATIONS AND BPD

• Prescribe psychotherapy. • There is no magic pill! Establish expectations and be realistic • Often use medications to treat co-occurring disorders. What else is going on with the patient? • Prescribe medications to target a particular symptom of BPD rather than the entire diagnosis. • Remember principles about treating women of child-bearing years. Is the patient pregnant? Planning to become pregnant? Using contraception? • Avoid polypharmacy. Is the patient on a medication that is not working? • Goal is diminish symptom severity and optimize function. What are the patient’s goals for treatment? • Treat for as short of a time as possible. CASE STUDY

• Female Veteran Smith is admitted into an intensive inpatient trauma treatment program. In addition to targeting PTSD symptoms related to her history of military sexual trauma, she reports affective symptoms while in treatment: – Intense periods of depressed mood that can last for a few hours to days – Difficulty trusting others and feeling easily hurt by others – Rage and anger to even small slights or misunderstandings

What would you prescribe? ANTIDEPRESSANTS AND AFFECTIVE DYSREGULATION

• 2001: American Psychiatric Association (APA) Practice Guidelines supported selective serotonin reuptake inhibitors (SSRI) or venlafaxine • Multiple reviews since 2001 have shown a limited role due to modest therapeutic effects for SSRIs • Current clinical practice: often still prescribed for comorbid anxiety and mood disorders

Lieb et al., (2010) Cochrane Database Syst Rev,: (6) CD005653 AUDIENCE POLL

What is the percentage of patients with Borderline Personality Disorder who also have co-occurring Bipolar I or II disorder? – 5% – 15% – 25% – 50%

Gunderson, JG et al. J Clin Psychiatry 2014; 75:829-834. MOOD STABILIZERS

Medication Effects

Carbamazepine Potential improvement in impulsivity

Divalproex Improvement in interpersonal sensitivity, irritability, and aggression

Lamotrigine Improvements in anger, affective instability, impulsivity.

Lithium Improvement in affective instability, and possible overall functioning

Topiramate Improvement in anger, anxiety, interpersonal dysfunction and self-reported quality of life.

Ripoll, L. (2013) Dialogues Clin Neurosci. 15: 213-224 CONFLICTING DATA WITH LAMOTRIGINE

 Earlier data: BPD symptoms without Bipolar diagnosis improve with lamotrigine particularly in terms of affective lability and impulsivity items on rating scales • 2018 randomized controlled trial with lamotrigine showed that it was not clinically effective after 52 weeks

Preston et al. (2004). J Affect Disorders. 79(1-3): 297-303. Reich et al. (2009). Int Clin Psychopharmacol. 24 (5) 270-5. Crawford et al (2018). Am J Psychiatry. 175 (8): 756-764. MOOD STABILIZERS AND POTENTIAL TERATOGENIC EFFECTS

• As of 2015, updated FDA drug labeling requirements will replaced A, B, C, D, X system (FDA’s Pregnancy and Lactation Labeling Final Rule) • Points to remember: – High dose folic acid supplementation for mood stabilizers associated with neural tube defects – Baseline risk in general population of major congenital malformations is 1-3%. Most mood stabilizers don’t cause birth defects. – Discuss contraception choices (consider method of contraception and compliance issues, drug-drug interactions)

www.fda.gov; Kennedy, MH. (2017) Ment Health Clin. 7(6): 255-261.; Petersen, I. (2017). Clin Epidemiol. 9:95-103. AUDIENCE POLL

Which group of medication is generally avoided in treating patients with BPD? – Typical antipsychotics – Benzodiazepines – Opiate antagonists BENZODIAZEPINES

• No solid evidence for efficacy • Can risk worsening disinhibition • Concern for withdrawal symptoms upon discontinuation • Recommended against in the treatment of PTSD

Clinicians Guide to Medications for PTSD http://www.ptsd.va.gov OPIATE ANTAGONISTS

• Numerous case reports and trials of naltrexone and naloxone for self-injurious behaviors and dissociative symptoms in personality and developmental disorders • 2012 placebo-controlled trial failed to show statistical significance with dissociative symptoms

Bohus et al. (1999). J Clin Psychiatry. 60(9): 598-603; Roth et al. (1996). J Clin Psychiatry. 57 (6): 233-237; Saper et al. (2000). Headache. 40 (9), 765.; Schmahl C. Int Clin Psychopharmacol. 2012; 27: 61-68. ATYPICAL ANTIPSYCHOTICS

• Have been open and double-blind studies best studied agents for BPD (typicals and atypicals) • Use lowest doses possible • Improves – Anxiety – Affective symptoms – Anger/ aggression – Cognitive disorganization – Self-injurious behavior OLANZAPINE

• In trial of olanzapine + DBT versus placebo + DBT medication group showed more rapid decrease in irritability and aggression scores • 12 week randomized, double-blind, placebo- controlled study showed low dose olanzapine (5-10 mg) showed clinically modest advantage over placebo for borderline psychopathology and faster time to response versus placebo

Linehan et al. (2008). J Clin Psychiatry. 69 (6), 999-1005. Zanarini et al. (2011). J Clin Psychiatry. 72 (10): 1353-62. ARIPIPRAZOLE

• 2007 study looked at efficacy of 15 mg aripiprazole daily after 18 months of treatment relatively effective for long term treatment of BPD with broad benefits (impulsivity, aggression, affective instability, self-injury)

Nickel et al., Psychopharmacology, 2007 May; 191 (4): 1023-6 How long to treat? REMISSION VERSUS RECOVERY FOR BPD

• Remission= not meeting criteria for BPD

Remission + • Recovery= ≥1 emotionally sustaining relationship with a close friend or life partner/spouse + and be able to work (including working as a house person) or go to school on full-time basis

Zanarini MC., Am J Psychiatry. 2012; 169 (5): 476-8 TIMELINE OF SPECIFIC BPD SYMPTOMS

• Remit more quickly: impulsive behavior, self-injury, and aggression • Remit more slowly: interpersonal affective symptoms (intolerance of aloneness and conflicting feelings about dependency) • 39% of patients with BPD met criteria for “excellent” recovery at 20 year follow-up

Ripoll, L. (2013)Dialogues Clin Neurosci. 15: 213-224. Zanarini, MC., (2018) Psychiatry Res. 262: 40-45