Mood DisordersChildren and Adolescents

Waqar Waheed, MD FRCPC, DABPN

Department of Psychiatry

University of Calgary

Impact• Impaired relationships• Poor school performance• Substance use • Legal problems• Suicide

Mood Disorders: Depressive

• Major Depressive Disorder

• Dysthymic Disorder

• Depressive Disorder Not Otherwise Specified

StatisticsStatistics

1 in 250 pre-schoolers, 1 in 40 children,

1 in 12 adolescents suffers from depression

(Birmaher et al 1996a)

Etiology• The single most predictive factor

associated with risk of developing MDD is…

• High family loading, heritability for MDD is 40 %

• Craddock et al 2005

Etiology

• Biological Factors

• Genetic Factors

• Psychological Factors

• Social Factors

Biological Factors

• Subnormal Growth Hormone Secretion (Ryan et al 1994)

• Subnormal Thyroid Hormone Secretion (Dorn et al 1996)

• Dysregulation of the Hypothalamic-Pituitary-Adrenal axis-Conflicting data (Birmaher et al 1996, Pfeiffer et al 1991)

• Neurotransmitters– Norepinephrine/Serotonin Dysregulation

(Ryan et al 1990)

• MRI Findings-Decreased frontal lobe volume and increased ventricular volume (Steingard et al 1996)

Genetic Factors

Concordance rates for depression are at least double in monozygotic twins

(McGuffin and Katz 1989) than in dizygotic twins (Carlson and Abbott 1995)

Lifetime risk for Major Depression in children of depressed patients ranges from 15% (Orvaschel et al 1988) to 45% (Hammen et al 1990)

Neuronal serotonin presynaptic reuptake site

• People who have homozygosity or heterozygosity for the less functional allele for this site are most likely to develop MDD when exposed to recurrent negative life events

• Caspi et al 2003, Kendler et al 2005

Psychological Factors

• Cognitive Behavioral Model–Research in children and adolescents supports the validity and clinical utility of this model (Brent et al 1997)

Social Factors

• Less Than 100% Twin Concordance

• Positive correlation of life events with the onset of depression in children

Major Depressive Disorder

• Either 1. Depressed or Irritable

Mood or 2. Anhedonia

• Failure to make expected weight gains

Dysthymic Disorder

Depressed or Irritable Mood for at least one year

“Double Depression”• Dysthymia has been theorized to

be a “gateway” to recurrent mood disorders

• Children usually have their first episode of Major Depressive Disorder 2-3 years after the onset of Dysthymia(Kovacs et al 1994)

Clinical Presentation

The expression of depressive symptoms varies according to age

Pre-School Children

• appear sad and slowed• limited verbal communication (Kashani and Carlson, 1987)

1.

mood congruent auditory hallucinations

somatic complaints

(E.B. Weller et al 2004a)

Adolescents• Delusions

• Pervasive anhedonia

Co-Morbidities

• Up to 50% have two or more comorbidities

• Anxiety Disorders

• Disruptive Behavior Disorders

• ADHD

• Substance Use Disorders(Presenting symptom in 20% of depressed adolescents, Weller and Weller 2004)

Mood Disorders: Bipolar

• Bipolar I Disorder• Bipolar II Disorder• Cyclothymic Disorder• Bipolar Disorder Not Otherwise Specified

Mood Disorders: Bipolar• Diagnostic (DSM-IV TR) Criteria are

identical to those for adults

• Less common than Depressive Disorders in this age group (Lifetime Prevalence 1%)

(Levinsohn et al 1995)

• 2 out of every 3 patients with Bipolar Disorder initially present with a Major Depressive Disorder

Diagnostic Controversy

• Use of the A/I phenotype

• Wash U cardinal symptoms

• Biederman group approach

• CBCL phenotype

A/I Phenotype

• Also present in– ODD/CD– Autistic Disorder– ADHD– MDD

Wash U Phenptype

• Requires elation and/or grandiosity as cardinal symptoms

Biederman group phenotype

• Broad, there is no construct of cardinal symptom(s)

CBCL Bipolar Phenotype

• Includes hyperactivity and suicidal ideation/behaviors

Proposed definitions of episodes and cycling

phenomena

Episode

• Onset to offset of manic episode using DSM-IV TR criteria

Ultra-rapid cycling

• Mood “switches” every few days during an episode

Ultradian Cycling

• Mood “switches” multiple times daily during an episode

• In 78-99% of children with Bipolar I (in 20 % of adult patient)

Clinical Presentation

The expression of manic symptoms varies in children according to their age

Pre-School Children

• Explosive/unmanageable temper tantrums

• Sexualized behaviors

• Nightmares with violent themes(Popper 1984)

School Age Children

• “Atypical" manic episodes among prepubertal children

• Chronic, non-episodic, rapid cycling pattern

(Geller and Luby 1997)

Adolescents

• Irritable/labile mood is MORE common than elevated/expansive mood

• Psychotic features are MORE common than in adults(Ballenger et al 1992, McElroy et al 1997)

Differential Diagnosis of Bipolar Disorder

Differential Diagnosis of Bipolar Disorder

• ADHD

• Disruptive Behavior Disorders (ODD/CD)

Suspect the presence of Bipolar Disorder in a child vs. ADHD if: • The ADHD symptoms appeared later in

life (e.g., at age 10 years old or older)

• The symptoms of ADHD appeared abruptly in an otherwise healthy child

• The ADHD symptoms were responding to stimulants and now are not

• The ADHD symptoms come and go and tend to occur with mood changes

Bipolar Disorder vs. ADHD

• A child with ADHD has recurrent severe mood swings, temper outbursts, or rages.

• A child with ADHD has hallucinations and/or delusions.

• A child with ADHD has a strong family history of bipolar disorder in his or her family,

BIPOLAR DISORDER VS. DISRUPTIVE BEHAVIOR DISORDER

• If a child has “off and on” oppositional or conduct symptoms or these symptoms only appear when the child has mood problems,

• If a child has severe behavior problems that are not responding to treatment,

• If a child has behavior problems and a family history of BP disorder,

• If a child has behavior problems and is having hallucinations and delusions.

BIPOLAR DISORDER VS. DISRUPTIVE BEHAVIOR DISORDER

Cyclothymia

In children and adolescents, the minimum duration of symptoms is 1 year

Co-Morbidities• Occurrence of co-morbid

disorders with bipolar disorders is close to 100% (Kessler et al 2001)

–ADHD

–Disruptive Behavior Disorders

–Anxiety Disorders

–Substance use Disorders

Assessment• Clinical interviews of identified

patient, family and school teacher

Rating Scales

•Children's Depression Inventory (CDI)

•Children's Depression Rating Scale (CDRS)

•Hamilton Depression Rating Scale (HAM-D)

•Young Mania Rating Scale-Parent Version (P-YMRS)

Lab Tests

• Thyroid Function Tests

• Urine Drug Screen

• Pregnancy Test

Dexamethasone Suppression Test

• Positive initial DST status in major depression does not add significantly to the likelihood of antidepressant response

• Negative test (Cortisol suppressed in response to Dex) is not an indication for withholding antidepressant treatment

• No relationship to suicidality

Other Investigations

•MRI Head Not indicated in the absence of

focal neurological signs.

EEG/Sleep Study

• To assess for seizure disorder if there is clinical suspicion

Prognosis

• Greater symptom severity and the presence of co-morbidity are predictors of a poorer prognosis

•The mean duration of a untreated Major Depressive Episode is 9 months

•For untreated Dysthymic Disorder, the mean duration is 4 years

• 18 month rate of recurrence for patients noncompliant with successful medication treatment is 90 (38% in med-comlian%

Treatment Modalities

•Setting

•Psychotherapy

•Medications

Other Modalities

• ECT• Light Therapy• Transcranial Deep Brain Stimulation

• Vagal Nerve Stimulation

Psychotherapy

• Supportive Therapy

• Cognitive-Behavioral Therapy

• Interpersonal Psychotherapy

Cognitive-Behavioral Therapy

• CBT is based on the cognitive triad; negative thoughts about the self, the world, and the future

Supportive Psychotherapy

• Maintain/improve self-esteem• Minimize/prevent symptom

recurrence• Maximize patient’s adaptive

capacities• The most widely practiced form

of individual

Interpersonal Psychotherapy

IPT aims to intervene specifically in social functioning with consequent benefits in symptom experience. (for 12 and older)

IPT-A

• Patient's social functioning problems are conceptualized as one or more of four areas

• Interpersonal Disputes (relationship conflict)

• Role Transitions (puberty, new school, new family)

• Grief (death of a loved one)

• Interpersonal Deficits (social/communication skills)

Other Forms of Therapy

•Group Therapy

•Family Therapy

•Play Therapy

MEDICATION MANAGEMENT OFDEPRESSIVE DISORDERS

SSRI treatment

• Fluoxetine - FDA approved for depression in children and adolescents

• Escitalopram - FDA approved for depression in adolescents

• Recent meta-analysis indicates a NNT of 6 for fluoxetine, 10 for other SSRI’s in adolescent depression (Bridge et al 2007)

Other treatments• There is evidence for the use of venlafaxine

(Emslie et al 2007) and bupropion in the treatment of adolescent depression (Daviss 2008).

• TCA’s have been shown to be of benefit in child and adolescent depression (Hazell et al 2006) but their use continues to be limited by the a/e, toxicity profiles.

SSRI’s and Suicidality

• Two meta-analyses (Bridge et al 2007, Hammad et al 2006) found an increase of 1 to 3 spontaneously reported suicidal adverse events per 100 youth treated with SSRIs

• The adverse event included increases in suicidal ideation (majority) and attempts at suicide (less commonly) with no completed suicides

SSRI’s and Suicidality

• The NNH was 112• Given the NNT of 10, nearly 11 times the

number of adolescents would respond favorably than might spontaneously report suicidality

• Suicide rates went up following a decline in the use of SSRIs due to the black box warning (Gibbons et al 2006, 2007; Libby et al 2007)

Other adverse effects

• GI• Headache• Insomnia/hypersomnia• Jitteriness/tremulousness• Decreased sexual drive• “Behavioral activation” (8%) usually within 7-10

days, mgmt is to switch med• Onset of mania (2-3%) usually in 2-3 weeks, switch

med, consider mood stabilizer

Side Effects

Indications

• Mild depressive illness supportive psychotherapy

• For moderate to severe depressive illnesses (having more than the minimal number of diagnostic criteria) or non-responders to brief supportive therapy consider SSRI, CBT/IPT or a combination.

Dosing

• Prozac usually 10 mg x 1 week then 20 mg, re-evaluate in 4-6 weeks, if no response, change to 30-40 mg

• Escitalopram, similar except at half the dosages

Psychotic Depression

• Augment SSRI with an antipsychotic until psychosis stable, then taper and discontinue the antipsychotic while maintaining antidepressant med

•Should be continued for at least 6 months after complete symptom remission

Treatment-resistant depression

• Treatment-resistant depression is defined as failure of at least two adequate antidepressant drug trials of at least 8–10 weeks' duration, each at a therapeutic dose and serum level (if available) without even mild improvement

(American Academy of Child and Adolescent Psychiatry 2004; Ghaziuddin et al. 1996; Kutcher and Robertson 1995; Walter and Rey 1997).

TRD• Optimization (extending the initial medication trial

and/or adjusting the dose; adding CBT or IPT)-usually used if there has been partial response

• Switching to another agent in the same or a different class of medications, augmentation, or a combination (e.g., lithium, triidothyronine) (Hughes et al. 2007) – usually used if no response or unable to tolerate

• No studies have validated these practices in children.

TRD

• Finally, the use of somatic therapies that have not been well studied in children, such as transcranial magnetic stimulation, or more intensive somatic therapies for depressed teens, such as ECT, should be considered

Light Therapy Typically used for the treatment of

Seasonal Affective Disorder

and of delayed sleep phase disorder (DSPD)

• 20-30 minutes each morning during the fall, winter and early spring months

• Symptom relief within one to two weeks of regular use

Electro-Convulsive Therapy

• May be used for adolescents

• The principal adverse effect of ECT is anterograde and retrograde memory impairment

• Used for refractory depression/mania or psychotic depression

Transcranial Magnetic Stimulation

• TMS is a procedure in which electrical activity in the brain is influenced by a pulsed magnetic field

Types of TMS• Single-pulse TMS (diagnostic and research applications) • Paired-pulse TMS (used to evaluate cortical excitability)

• Repetitive TMS (rTMS) has been used in therapeutic applications because it is capable of producing rapid bursts of pulses lasting approximately 60 seconds – An advantage of the rTMS procedure in the

clinical setting is that no anesthesia is needed.

(Curra et al. 2002; Quintana 2005)

rTMS: Research in adolescent depression

• Adjunctive rTMS treatment in a prospective open label study in 8 adolescents demonstrated benefit (Wall et al 2011)

• Two small case series (totaling nine subjects) have reported on the use of rTMS in adolescent depression (Loo et al. 2006; Walter et al. 2001).

rTMS Adverse Effects

• Tension headaches reported in one patient were the only adverse effects noted from the rTMS procedure

(Walter et al. 2001)

• Neuropsychological testing revealed no cognitive side effects after the course of rTMS was completed (Loo et al. 2006).

Deep Brain Stimulation

• Deep brain stimulation (DBS) is a neurosurgical procedure

• Stimulation electrodes are chronically implanted into specific areas of the brain

• An implanted, externally programmable pacemaker delivers high-frequency electrical pulses.

• The site of electrode placement differs depending on the disorder to be treated.

DBS• DBS is currently approved for generalized

dystonia in children 7 years and older. Its place in psychiatry is presently unclear.

• DBS is considered an experimental procedure in children and adolescents with psychiatric disorders.

•

Vagal Nerve Stimulation

• In July 2005, the VNS Therapy System was approved by the FDA for depression patients who have run out of treatment options

• No studies to date in use for children/adolescents with mood disorders

MEDICATION MANAGEMENT OFBIPOLAR DISORDERS

Medications: Bipolar Disorders

• Lithium Carbonate (2 RCTs)

• Valproic Acid (2 RCTs)

• Carbamazepine (open label)

• Atypical Antipsychotic Medications (1 RCT for R, O, S, A and Z)

General Considerations

• FDA approved medications

–Risperidone/Aripiprazole (10+ yo)

–Lithium Co3 (12+ yo)

–Olanzapine (13+ yo)

• Blood levels are monitored for Lithium, Valproic acid and Carbamazepine

• Onset of action usually within the first week of treatment

(most RCTs were 3 weeks in duration)

Pharmacogenetics of CBZ

• CBZ places individuals with HLA B*1502 allele at high risk of SJ Syndrome– These patients may continue if identified

1-2 months after initiation of treatment.

– Absence of allele does not preclude risk of SJ Syndrome

Side Effects

Monitoring• In addition to clinical evaluation, lab

tests are usually recommended periodically to assess for:–Blood Levels of Medication–Bone Marrow Function–Liver/Pancreas Function–Thyroid Function–Kidney Function/Electrolyte levels–ECG

Types of Antipsychotic Medications

Mechanism of Action

• Both types of antipsychotics block Dopamine receptors

• The defining feature of the “atypical” antipsychotics is that they also block Serotonin receptors.

Common Side Effects• Sedation• Weight Gain• EPS (parkinsonism, akathisia, dystonia)-

managed with anticholinergic meds• Metabolic Syndrome

–Dyslipidemia–Impaired glucose tolerance–BP elevation/ Central adiposity

Uncommon Side Effects

• Neuroleptic Malignant Syndrome

• Heat Stroke

• Tardive dyskinesia

• Seizures

• Heart Rhythm disturbance

Monitoring

• In addition to clinical evaluation (including weight and blood pressure assessment), lab tests used for monitoring including:–Fasting blood sugar–Cholesterol levels–Liver functions–Electrocardiogram

Abuse Potential

• Although not as common as with medications such as Ritalin, Dexedrine or benzodiazepines, the antipsychotic medication Seroquel (street name “Qwell”, “Susie Q”) has been increasingly identified as a substance of abuse

(Pinta et al 2007, Waheed et al 2005, Wirshing et al 2004)

Treatment Resistant Bipolar Disorder

• For bipolar disorder, failure of at least one antipsychotic–mood stabilizer/antidepressant combination treatment trial of at least 6 weeks' duration without even mild improvement is considered evidence for treatment refractoriness

• (American Academy of Child and Adolescent Psychiatry 2004; Kutcher and Robertson 1995; Walter et al. 1999).

Treatment for Bipolar Depression

• Lithium CO3

• Lamotrigine

• They have both demonstrated benefit either as monotherapy or as adjunctive treatment in open label studies

Questions/Comments?

Waqar.Waheed@albertahealthservices.ca