Disclosures FEARS AND TEARS: TREATING ANXIETY AND DEPRESSION IN PRIMARY CARE I have no financial interests I WILL be talking about non FDA approved uses of medications for anxiety and depression in children and adolescents Elizabeth Reeve MD HealthPartners Medical Group Questions Elizabeth.A.Reeve@HealthPartners.com Goals and objectives A Developmental Approach Review symptoms and presentation of anxiety and depression Develop an understanding of when to refer for therapy, when to start medications, and when to do both Be comfortable with prescribing 2 different, bupropion, and venlafaxine Risks for depression and anxiety start BEFORE conception Genetics of parents Genes that increase risk for depression Genes that code for drug metabolism, receptor and transporter differences Risks in utero Epigenetics The study of heritable changes in gene function that do not involve change in the genetic code itself Felt to be due to environmental stress Toxic exposures Alcohol Childhood Early life adversity 1
Serotonin Transporter and Receptor Differences Serotonin transporter (SERT or 5-HTT) is also know as the sodium dependent serotonin transporter The protein involved is coded by the SLC6A4 gene The transport of serotonin by the SERT protein terminates the action of serotonin and recycles it A repeat polymorphism in the promoter of this gene may impact serotonin transport The short form polymorphism may predict a decrease in the response to serontonergic acting antidepressants and may increase the risk of depression when exposed to adverse events Serotonin Transporter and Receptor Differences Rs6295 (HTR1A) a single nucleotide polymorphism (SNP) C and G variations C allele has been found in some cases to be associated with a better response to antidepressants G allele may incur an increased risk for depression CC genotype has also been associated with an increase change of love (SNPedia) To Make it More Confusing Other concepts and characteristics impact risk Resilience Optimism Humor Cognitive flexibility Exposure to positive role models Involvement with religion Attachment Temperament Strange Situation Procedure (Ainsworth) Studies using this paradigm have shown that preschool children of mothers with anxiety are more likely to be insecurely attached Insecurely attached preschoolers had more anxiety disorders later in childhood and adolescence. Caspi et al. (1995) Longitudinal study of 800 children over a twelve year period Boys who were confident and eager to explore new situations at age five had lower rates of anxiety Girls who were passive and shy at ages 3-5 years had higher rates of anxiety 2
Consequences of Maternal Depression Prenatal Inadequate prenatal care, poor nutrition, higher preterm birth, low birth weight, pre-eclampsia and spontaneous abortion Infant Anger and protective style of coping, passivity, withdrawal, dysregulated attention and arousal, lower cognitive performance Toddler Passive noncompliance, less mature expression of autonomy, internalizing and externalizing problems, lower interaction, less creative play and lower cognitive performance School age Impaired adaptive functioning, internalizing and externalizing problems, affective disorders, anxiety disorders and conduct disorders, attention deficit/hyperactivity disorder and lower IQ scores Adolescent Affective disorders (depression), anxiety disorders, phobias, panic disorders, conduct disorders, substance abuse and alcohol dependence, attention deficit/hyperactivity disorder and learning disorders Why are these Factors so Important? Helps to understand that the road to each person s depression or anxiety is different This may explain some of the lack of predictability to medical treatment and why antidepressants have such a variable response Normal Anxiety Developmental stages with increased anxiety Stranger anxiety Separation Boogie man Perfectionism Rules Looks/Body image/grooming Common fears Normal Depression Sadness Loss, grief, disappointment Loneliness Overwhelmed Situational stress New school, friends, significant others Onset of symptoms Depression starts as a change in the level of functioning Some depression becomes chronic but not most You are not born depressed Consider temperament, and environmental stress The onset of anxiety is usually more insidious Generalized anxiety, Social anxiety, OCD PTSD and Panic disorder may be more abrupt 3
Level of functioning Mild, moderate, severe Assess change based on the individuals previous level of functioning, based on objective data Consider a wide range of activities: friendships, academics, sports, clubs, family life, spiritual life The lower the baseline function the harder it is to measure change Always consider the presence of a precipitating stress Always get collaborative data Mild: symptoms are not obvious to others, and are discovered only on interview Moderate: symptoms are visible to others and cause dysfunction in at least one area of life Severe: symptoms are obvious to others and impair multiple spheres of life How Do Anxious Children Present? If severely disordered may be obvious Rituals may be obvious in OCD School refusal Mutism More subtle symptoms: Frequent trips to the nurse Missed days of school Poor socialization Below expected academic performance Symptoms of anxiety in childhood Separation anxiety Temper tantrums on separation, calling/texting when apart, need to know schedules Generalized anxiety Worry, reassurance seeking, physical symptoms Social anxiety Avoidance of groups, avoids public restrooms, won't talk to strangers (ask for help, pay in a store, order food in a restaurant), avoids performance, may not eat in public OCD Reassurance seeking, washing, counting, checking, control, need for sameness How do Depressed Children Present Young children may not be able to express feelings of sadness Will be irritable, difficult to soothe, poor with transitions, clingy, developmental regression School age children may have increased somatic issues Sleeping, appetite, aches and pains, changes in bowel and bladder function Middle school children may have more academic impact, drop out of activities Adolescents Changes in peer group, avoidance of family, acting out DSM Depression Must have depressed mood or loss of interest or pleasure Must have four more symptoms Must ALL be present for two weeks Must cause functional impairment Anxiety Must have excessive worry or anxiety most days for 6 months Must include worry in more than one event or activity Must be associated with a sense of lack of control Must have at least three associated symptoms Edginess, fatigue, poor concentration, irritability, muscle tension, sleep issues Must cause impairment 4
DSM Generalized Anxiety Disorder Social Anxiety Disorder Panic Disorder Separation Anxiety Disorder School Avoidance Obsessive Compulsive Disorder Selective Mutism PTSD Major Depression Disruptive Mood Dysregulation Disorder Persistent Depressive Disorder Cams study: Child/adol Anxiety Multimodal Study Randomized control trial with 488 7-17 year old subjects GAD, Social phobia, Separation Anxiety CBT, sertraline, both, placebo Combined therapies had higher rates of remission Both CBT and med group had higher rates of remission than placebo In subjects who responded at 12 weeks the response was maintained at 24 and 36 weeks Treatment of Adolescent Depression: TADS Randomized controlled trial in 13 academic sites 327 subjects between the ages of 12-17 Compared fluoxetine, CBT, and fluoxetine with CBT CBT alone was less effective than combined treatment or fluoxetine and not significantly more effective than placebo at week 12 Combined treatment increased the speed of the response, quality of life, remission and overall safety, primarily by preventing treatment emergent suicidality CBT benefit caught up with fluoxetine at week 18 All treatments were equally effective at 80% rate by week 36 The longer the treatment in TADS the more persistent the benefits over one year of naturalistic follow-up Literature Literature Strawn, JAACAP, October 2016 Meta-analysis of randomized placebo controlled trials of and SNRI s 1612 children and adolescents GAD, Social anxiety, Separation anxiety SNRI s and had a moderate effect size in reducing anxiety symptoms No difference in efficacy Strawn et al., JAACAP 4/2015 Randomized Placebo controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder 7-17 years old, GAD, 30-120 mg duloxetine 135 medication group, 135 placebo Medication gourd was statistically significantly improved 5
Pearls For You So you Made the Diagnosis The first line treatment for both mild to moderate depression or anxiety is appropriate therapy The degree of functional impairment is the best measure of severity of symptoms treat both anxiety and depression equally well Treatment with medications must be at an adequate dose for an adequate length of time If the symptoms are mild to moderate start with therapy Educate the patient about the disorder, therapy resources and the expected timeline for improvement Have a follow-up in 4-6 weeks to ensure they have started therapy. Ask specific questions about the relationship with the therapist, the process of therapy, the goals of therapy Does the patient feel better? Practical Treatment Advice ELEMENTS OF COGNITIVE BEHAVIORAL THERAPY Primary medications /SNRI s Buspirone (GAD only) Secondary options Benzodiazepines Tricyclics How to Choose a Medication Medication decisions are first line All have same potential efficacy Choose based on side effect profile Individuals may have an idiosyncratic benefit to one SSRI and not another This may be influenced by metabolism differences Consider second choice dependent on diagnosis as well as safety and side effects of medication Depression Choose SSRI number one If no benefit switch to SSRI number two Must be from a different cytochrome P450 class If no benefit after two try buproprion If partial benefit and dose is maximized augment SSRI with buproprion If still no benefit change to venlafaxine Refer Anxiety Choose SSRI number one Switch to SSRI number two DO NOT USE BUPROPRION Switch to venlafaxine Consider buspar in generalized anxiety Consider clomipramine if OCD Avoid benzodiazepines Refer 6
Metabolism Considerations Fluoxetine (Prozac): 2.5 mg-80 mg Paroxetine (Paxil): 2.5 mg-60 mg Sertraline (Zoloft): 12.5 mg-200 mg Fluvoxamine (Luvox) 25 mg-300 mg Citalopram (Celexa) 10 mg-60 mg Escitalopram (Lexapro) 5 mg-30 mg Fluoxetine and paroxetine P450 2D6 Citalopram/escitalopram P450 C19 Sertraline P450 C9, C19, 2D6, 3A4 Venlafaxine P450 2D6, 3A4 Duloxetine P450 2D6, 1A2 Common side effects Akathisia (restlessness) Insomnia Nausea/Diarrhea Headache Sedation (not usual) Weight gain (minimal) Sexual dysfunction (60%) Half-life Fluvoxamine ~ 18-24 hours Sertraline and Paroxetine ~ 24 hours Citalopram ~ 33 hours Fluoxetine ~ 2-3 days Norfluoxetine ~7-8 days SSRI withdrawal Paroxetine probably the worst Does not happen with fluoxetine Characterized by flu-like syndrome Fever, shaking, fatigue, sweating, nausea, diarrhea Usually starts within 24-36 hours and resolves within 2-3 days, although may last longer Treat by restarting medication and slowing down the taper 7
Serotonin syndrome Can happen with any SSRI, as well as other me serotonergic effect such as venlafaxine, clomipramine, fenfluramine Rapid onset Symptoms related to flood of extracellular 5HT May be frightening for the patient trembling, shivering, fever, chills, clonus, hyperreflexia, may seem ataxic Treat with support and 5HT blockers cyproheptadine and chlorpromazine Buspirone Good for generalized anxiety but not for other forms of anxiety Needs twice daily and sometimes three times daily dosing making compliance with an adolescent problematic Common side effects: nausea, headache, mild fatigue Easy to taper off if ineffective Typical dose 20-60 mg in divided doses Bupropion Venlafaxine Can be used alone or to augment a partial responder to an SSRI Most common side effects Headache, decreased appetite, agitation/activation Start with Buproprion XL 150 mg, increase to 300 mg after two weeks if no benefit Can be started and stopped abruptly with little risk of problems Contraindicated if seizure disorder is present or very high risk for seizures Common side effects: sedation, sexual dysfunction, restlessness, insomnia, weight gain MUST be slowly tapered if discontinuing Start with XR formulation at 75 mg. If there is a history of significant sensitivity to consider starting at 37.5 mg XR Usual dose is 150-225 mg General medication issues All take 4-6 weeks for full benefit Do NOT continue medications if there is not clear objective evidence of benefit Treat depression for 9-12 months if medications are beneficial Treatment of anxiety is of variable length depending on the benefit from adjunctive therapy and individual circumstances Call your friendly mental health colleague for hand holding advice when needed 8