Ask the Expert: DepressionPresenter: Kenneth J. Herrmann, MD

NAMI Conference Spring 2014

Medical School at Chicago Medical School Internship, residency in general psychiatry,

fellowship in child and adolescent psychiatry at the University of Iowa

Formerly, Medical Director of Youth Services at the Mental Health Center of Dane Co.

Psychiatric Consultant, Psychiatric Services SC, www.psychsvcs.com/

Past Vice-President, Board of Directors NAMI WI Principal, My World Defense, A Healthcare

Security Company, http://myworlddefense.com/

Kenneth J Herrmann M.D.

Irritable/Depressed mood, diminished pleasure/interest

Weight changes of greater than 5% in one month

Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy, poor concentration Feelings of worthlessness, suicidal thoughts,

guilt

Diagnosis of Major Depressive Disorder

Genetic factors Personality and environmental factors Biochemical abnormalities

Etiology of Depression

Depression -Duration average of 7 1/2 months -44% in remission within 6 months of Dx -92% recovered by 1 ½ years -72% recurrence within five years

Prognosis - Adolescence

Depression: -2% of children in general population -7% depression in children admitted to Hospital -40% children in ped neuro clinics with headaches=depression -4.7% ages 14-16 (3.3% dysthymia) (as age increases female rates increase) -one in five adolescents by age 20 -Lifetime: Males 12% Females 25%

EPIDEMIOLOGY

Age at onset is decreasing Incidence is increasing

Trends for Affective Disorders

Substance Use Prematurity Family History Head Injury

Risk Factors For Mood Disorders

Hard to recruit for certain disorders FDA requirements for drug approval Funding Exclusion criteria Dropout rates Liability Time from idea to publication

Limitations of Current Research

Moderate to severe depression Fluoxetine alone or in combo with CBT 13 academic and community sites in the US 12-17 yrs old Combined > mono 42 week total study time Study start 7/98, completed 3/04

Arch. Gen. Psychiatry 10/07

The Treatment for Adolescents with Depression Study (TADS)

Thinking Outside the Box?

? Adequate information ? Diagnosis Increase in antidep. use / decrease in

suicides over 10 years prior to warning

FDA warnings and the Antidepressants

CONCLUSIONS: In both the United States and the Netherlands, SSRI prescriptions for children and adolescents decreased after U.S. and European regulatory

agencies issued warnings about a possible suicide risk with antidepressant use in pediatric patients, and these decreases were associated with increases in suicide rates in children and

adolescents.

Gibbons etal. Am J. Psychiatry 9/07

Diagnostic Accuracy is Most Important

Elevated, expansive or irritable mood Inflated self-esteem or grandiosity Decreased need for sleep More talkative (distractible) Flight of ideas or racing thoughts Increase in activity Foolish indulgencies

Mania/Bipolar Affective Disorder (BPAD)

Grandiosity Inappropriate sexual interest Psychotic symptoms “Ultrarapid” cycling

Characteristics of BPAD in Children

… you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble?

… you were so irritable that you shouted at people or started fights or arguments?

… you felt much more self-confident than usual?

… you got much less sleep than usual and found you didn’t really miss it?

… you were much more talkative or spoke much faster than usual?

… thoughts raced through your head or you couldn’t slowyour mind down?

Mood Disorder Questionnaire

Hirschfeld et al. Am J Psychiatry. 2000;157:1873-1875.

Has there ever been a period of time when you were not your usual self and…

… you were so easily distracted by things around you that you had trouble concentrating or staying on track?

… you had much more energy than usual?

… you were much more active or did many more thingsthan usual?

… you were much more social or outgoing than usual; for example, you telephoned friends in the middle of the night?

… you were much more interested in sex than usual?

… you did things that were unusual for you or that other people might have thought were excessive, foolish, or risky?

… spending money got you or your family into trouble?

Mood Disorder Questionnaire (cont’d)

Hirschfeld et al. Am J Psychiatry. 2000;157:1873-1875.

Depression

Adolescents 30% BPAD switch Irritability

Adults 10% switch Sadness

Depressive symptoms were predominant• Over the long term, patients with bipolar I

disorder spent nearly half of their time symptomatically ill

• Depression accounted for 31.9% of the time• Patients experienced manic symptoms 9.3%

of the time• Depression (but not mania) predicted greater

future illness burden

Judd et al. Arch Gen Psychiatry. 2002;59:530-537.

Long-term Frequency of Depressive Symptoms

(Percent of Follow-up Weeks)Patients with bipolar I disorder experienced mood symptoms nearly half of the time during a 12.8-year follow-up period.

Age of Onset(Pooled Data N=1,304)

Goodwin F, Jamison K. Manic Depression. New York: Oxford University Press; 1990.

Acute onset Hypersomnic retarded depression Psychosis Postpartum onset Family history Antidepressant Hypersomnia

Predictors of BPAD Outcome

Treatment for Depression

Cognitive Behavioral Therapy (CBT) Dialectical behavior therapy (DBT) Mindfulness

Non-Medical Txment of Depression

NEUROTRANSMITTER EFFECTS OF ANTIDEPRESSANTS

NE 5-HT DA

Bupropion SR

SSRIs

Venlafaxine

Nefazodone

Mirtazapine

Desipramine

Richelson. J Clin Psychiatry. 1994

Recent evidence suggests that neuronal plasticity plays an important role in the recovery from depression. Antidepressant drugs and electroconvulsive shock treatment increase the expression of several molecules, which are associated with neuronal plasticity, in particular the neurotrophin BDNF and its receptor TrkB. Furthermore, these treatments increase neurogenesis and synaptic numbers in several brain areas. Conversely, depression, at least in its severe form, is associated with reduced volumes of the hippocampus and prefrontal cortex and in at least some cases these neurodegenerative signs can be attenuated by successful treatment. Such observations suggest a central role for neuronal plasticity in depression and the antidepressant effect, and also implicate BDNF signaling as a mediator of this plasticity. The antidepressant fluoxetine can reactivate developmental-like neuronal plasticity in the adult visual cortex, which, under appropriate environmental guidance, leads to the rewiring of a developmentally dysfunctional neural network. These observations suggest that the simple form of the neurotrophic hypothesis of depression, namely, that deficient levels of neurotrophic support underlies mood disorders and increases in these neurotrophic factors to normal levels brings about mood recovery, may not sufficiently explain the complex process of recovery from depression. This review discusses recent data on the role of BDNF and its receptors in depression and the antidepressant response and suggests a model whereby the effects of antidepressant treatments could be explained by a reactivation of activity-dependent and BDNF-mediated cortical plasticity, which in turn leads to the adjustment of neuronal networks to better adapt to environmental challenges. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 2010

The role of BDNF and its receptors in depression and antidepressant drug action:

Reactivation of developmental plasticity

Bupropion Serotonin (re)-uptake inhibitors TCA’s (Tricyclic Antidepressant) Others: Nefazodone, Trazadone,

Mirtazapine, Venlafaxine, duloxetine MAOI’s (including Selegiline (Emsam patch))

ECT Trancranial Magnetic Stimulation (TMS)

Somatic Depression Treatment

Vilazodone (Viibryd): diarrhea, nausea or vomiting, and trouble sleeping, increases serotonin.

Vortioxetine (Brintellix): nausea, constipation, and vomiting, increases serotonin

Levomilnacacipran (Fetzima): nausea or vomiting, constipation, sweating, increased heart rate, erectile dysfunction, and palpitations, increases serotonin and norepinephrine.

Newer Antidepressants

Comorbidities: anxiety, subst. abuse, Compliance Formulary (preferred drug list) Medical legal Indication (“Off Label?”) Side Effects

Things to consider with meds

Treatment: Lamotrigine (Lamictal)

Positives:Once a day dosing

possibleNo Blood testsFew complaints of SE’s

NegativesLong time to get up to

good dose Rash ?

Neuroleptics (antipsychotics)

Mood Disorders (primarily BD)Schizophrenia/Schizoaffective

Some Sxs of PTSD

WBC monitoring Constipation Dizziness Sedation Miracle

Clozapine

Wgt neutral?, EPS, Nonsedating, Agitation

FDA approved ABILIFY® (aripiprazole) for the acute treatment of manic and mixed episodes, maintenance treatment of manic or mixed episodes, and as add-on treatment to lithium or valproate, associated with Bipolar I Disorder, with or without psychotic features, and schizophrenia in pediatric patients (10 to 17 years old). Refractoy Depression

Aripiprazole (Abilify)

Treatment: Risperidone (Risperdal)

Positives: No blood tests Once a day dosing Fast ShotgunFDA approved Risperdal

(risperidone) for the treatment of schizophrenia in adolescents, ages 13 to 17, and for the short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents ages 10 to 17.

Negatives:ProlactinSome reports of mania

induction Weight gainSedation NMSTardive dyskinesia Diabetes risk

Treatment: Olanzapine (Zyprexa)

Positives: No blood tests Once a day dosing Data FDA indication Fast Shotgun

Negatives:SedationWeight gain Diabetes risk

Wgt neutral Sedating vs activating Efficacy?

Ziprasidone (Geodon)

Midrange sedation Midrange wgt gain Diabetes risk Refractory Depression Bipolar Depression

Quetiapine (Seroquel)

Treatment: Lithium Positives:Low suicide ratesFDA approved 12yrs and

olderLong history of use Once a day dosingCheap

Negatives:Narrow therapeutic

windowFluid balance issuesMonitoring (thyroid &

kidney)AcneWeight

Lurasidone (Latuda): (Bipolar Depression)Once a day, with food, sedation and EPS

Asenapine (Saphris): Once a day, disolves in mouth-some find unpleasant taste

Iloperidone (Fanapt) Twice a day

The 3 Newest

SADS Hospice family members

Buproprion For Prevention of Depressive sx’s

ADHD: stimulants, bupropion, ?modafinil Anxiety: (OCD too) gabapentine, tiagabine,

SSRI, TCA Depression: ECT, additional mood stabilizer

(lamotrigine), antidepressant if we must Fatigue: modafinil, stimulants Insomnia: benzodiazepines, neuroleptics,

mirtazepine, trazadone Mania: mood stabilizer, neuroleptic

Combined therapy: symptoms/ co-occurring conditions

Neurotrophic Effects of Mood Stabilizers? MRI studies “…revealed that chronic lithium

significantly increases total grey mattervolume in the human brain of patients with manic-depressive illness.

Neuroprotective?“…lithium and valproate have recently been demonstrated to robustly increase the expression of the cytoprotective protein bcl-2 in the central nervous system.”

Husseini et. al.

The Good News

“Your doctor may use cytochrome P450 tests (CYP450 tests) to help determine how your body processes (metabolizes) a drug. Our bodies contain numerous P450 enzymes to process medications. Because of inherited (genetic) traits which cause variations in these enzymes, medications affect each person differently.”

From a Mouth Swab

Genetic Testing

Earlier Identification and Aggressive Txmnt Increase focus on primary and especially

secondary Prevention Neurotransmitter and enzyme specific

treatment. More delineation of “Normal” behavior and it’s

relationship to our genes. More Exploration of Combined Therapy Remission not just response

Future Trends Summary