Diagnosis and management of Major Depressive Disorder.

Dr Parag MoonSenior Resident,

Dept. of Neurology,GMC, Kota.

Major depressive disorder-one or more major depressive episodes (i.e. at least 2 weeks of depressed mood or loss of interest accompanied by at least 5 additional symptoms of depression).

Categorized into mild, moderate and severe.◦ Mild to moderate depression-depressive symptoms and some

functional impairment. ◦ Severe depression-additional agitation or psychomotor retardation

with marked somatic symptoms. Dysthymic disorder-at least 2 years of depressed mood for

more days than not, accompanied by additional symptoms that do not reach criteria for major depressive disorder.

Definition

1. Depressed mood most of day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).Children and adolescents-irritable mood.

2. Markedly diminished interest or pleasure in all, or almost all, activities most of day, nearly every day

3. Significant weight loss when not dieting or weight gain (e.g.,change of more than 5% of body weight in month), or decrease or increase in appetite nearly every day. Children- no expected weight gains.

4. Insomnia or hypersomnia nearly every day

5. Psychomotor agitation or retardation nearly every day.6. Fatigue or loss of energy nearly every day7. Feelings of worthlessness or excessive or inappropriate

guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)

8. Diminished ability to think or concentrate, or indecisiveness, nearly every day.

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without specific plan, or suicide attempt or specific plan for committing suicide

Not due to direct physiological effects of drug of abuse (Alcohol Intoxication or Cocaine Withdrawal),

Not due to side effects of medications or treatments (steroids) or to toxin exposure.

Not due to direct physiological effects of general medical condition (hypothyroidism)

Symptoms begin within 2 months of loss of loved one and do not persist beyond these 2 months- considered to result from Bereavement, unless associated with marked functional impairment or include morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

A) Reactive (neurotic) & endogenous depression: Reactive depression- symptoms in response to external

stressful stimuli C/F: anxiety, irritability, phobia & early insomnia, Endogenous depression- caused by factors within

individual which are independent of outside stimuli, more severity

C/F: Loss of appetite, weight loss, constipation, decreased libido, amenorrhea, early morning awakening (biological symptoms).

B) Primary & secondary: secondary because of H/O previous non affective psychiatric illness (schiz. , AN) or alcoholism, medical illness, or taking certain drugs (e.g.. Steroids)

No difference between them regarding prognosis & response to treatment

I) Classification based on etiology

A) Neurotic depressionB) Psychotic depression Cases of depression with so called biological symptoms

& severe forms come under Psychotic depression Milder forms come under neurotic depression

II) BASED ON SYMPTOMS

MOST useful classificationA) Unipolar (recurrent) Having depressive phases only Some of them may have manic episode later Manic episode might remain under diagnosedB) Bipolar- Both manic & depressive episode in cyclic pattern May have only manic episodes

III) BASED ON COURSE & TIME OF LIFE

C) Seasonal affective disorder-◦Repetitive depressive episodes at the same time of year◦Symptoms- hypersomnia, increased appetite, increased

craving for carbohydrates.◦Onset- in winter◦Recovery- in spring or summer◦Cause: might be shortening in the day light◦Treatment; exposure to bright artificial light during hours

of darknessD) Involutional depression:

◦Occurs at the time of involution of sex glands.◦Occurs around 45 years of age◦C/F: agitation, hypochondriacal symptoms

Fifth and fourth century B.C. persons with depressive disorders were described as having a distinct disease and that would eventually be named Melancholia

Hippocrates characterized all fears and despondencies, if they were prolonged, as symptoms of a disease process

Only 42% of patients with major depression diagnosed appropriately by their primary care physician (WHO)

By year 2020, major depression will be second only to ischemic heart disease in the amount of disability(WHO)

Background

Point prevalence- between 5% and 10% of people seen in primary care settings.

Women are affected twice as often as men. Fourth most important cause of disability worldwide Lifetime prevalence- 26% for women and 12% for men. 1.5 to 3 times with a first-degree biological relative. 84% had at least one comorbid condition, 61% had additional

psychiatric disorder and 58% comorbid medical illness Follows psychosocial stressor-death of a loved one, marital

separation, or Childbirth.

Incidence

A) Biological- monoaminergic theory(NE, DA, 5HT) (already dealt with)

B) Psychosocial◦ Recent stressful life events, ◦ Personality factors◦ Early environment- (maternal deprivation, relationship with

parents)◦ Learned helplessness

C) Cognitive theories depressive cognitions, negative thoughts,

negative view of self & regarding future.

ETIOLOGY OF DEPRESSION

Loss of interest or pleasure of some degree-nearly always present,

Less interested in hobbies, "not caring anymore," or not feeling any enjoyment in activities previously considered pleasurable.

Family members- social withdrawal or neglect of pleasurable avocations.

Reduction from previous levels of sexual interest or desire. Appetite-reduced, and many individuals feel that they have to

force Some may have increased appetite, crave specific foods. Significant loss or gain in weight.

Clinical features

Decreased energy, tiredness, and fatigue. Efficiency-reduced. Sense of worthlessness or guilt-unrealistic negative

evaluations of one's worth or guilty preoccupations or ruminations over minor past failings.

Report impaired ability to think, concentrate, or make decision.

Easily distracted or complain of memory difficulties.

Thoughts of death, suicidal ideation, or suicide attempts Belief that others would be better off if person were dead, to

transient but recurrent thoughts of committing suicide, to actual specific plans of how to commit suicide.

Transient (1- to 2-minute), recurrent (once or twice a week) thoughts.

Appearance: neglected dress & grooming Facial features: turning downwards of corners of mouth, vertical

furrowing of centre of brow, shoulders bent & head inclined forwards, direction of gaze downwards, gestural movements decreased

Sleep disturbance-insomnia Typically have middle insomnia (waking up during night and

having difficulty returning to sleep) or terminal insomnia (waking too early and being unable to return to sleep).

Initial insomnia (difficulty falling asleep). Oversleeping(hypersomnia)-prolonged sleep episodes at

night or increased daytime sleep. Psychomotor changes-agitation or retardation. Speech-decreased in volume, inflection, amount, or variety

of content, or muteness.

Sleep EEG abnormalities- 40%-60% of outpatients and in up to 90% of inpatients with MDD. 1) Sleep continuity disturbances, such as prolonged sleep latency, increased intermittent wakefulness, and early morning awakening2) Reduced non—rapid eye movement (NREM) stages 3 and 4 sleep (slow-wave sleep), with shift in slow-wave activity away from NREM period3) Decreased rapid eye movement (REM) latency (shortened duration of the first NREM period)4) Increased phasic REM activity (number of actual eye movements during REM)5) Increased duration of REM sleep early in night.

EEG

Chronic insomnia or fatigue Chronic pain Multiple or unexplained somatic complaints, “thick charts” Chronic medical illnesses (e.g., diabetes, arthritis) Acute cardiovascular events (myocardial infarction, stroke) Recent psychological or physical trauma Other psychiatric disorders Substance abuse disorders Family history of mood disorder

High risk for MDD.

Nations (Native American) Male Advanced age Single or living alone Prior suicide attempt Family history of suicide Family history of substance abuse Medical illness Psychosis Hopelessness

Risk Factors for Suicide

A) Pharmacotherapy- I) Antidepressants- TCA MAO inhibitors Newer antidepressant- SSRI, SNRI, SDRIII) Lithium III) Augmentation therapiesB) Psychosocial therapiesC) ECT

TREATMENT OF DEPRESSION

Characteristic three-ring nucleus Clinical effects

◦ Normalization of mood and resolution of neurovegetative symptoms

Biochemical effects◦ Inhibit monoamine uptake at nerve terminals◦ May potentiate action of drugs that cause neurotransmitter

release Temporal delay of weeks for clinical effects, although

biochemical effects are immediate

Tricyclic Antidepressants (TCAs)

Mechanism of action of TCAs“Tertiary” TCAs Inhibit 5-HT uptake

imipramine (weaker inhibition of NE uptake)amitriptyline

clomipramine

“Secondary” TCAs Inhibit NE uptakedesipramine (weaker inhibition of 5-HT uptake)nortriptyline

Dry mouth Constipation Dizziness Tachycardia Urinary retention Impaired sexual function Orthostatic hypotension Contraindications

◦ QTc greater than 450 msec ◦ Conditions worsened by muscarinic blockade (eg myasthenia gravis, BPH)◦ Pre-existing orthostatic hypotension◦ Seizure disorder

Side effect of TCAs

Irreversibly inhibit monoamine oxidase enzymes 2 isoforms

◦MAO-A (norepinephrine, serotonin, tyramine)◦MAO-B (dopamine)

Effective for major depression, panic disorder, social phobia Drug interactions and dietary restrictions limit use

Monoamine Oxidase Inhibitors (MAOIs)

Irreversible, non-selective MAOIs◦ phenelzine ◦ isocarboxazid◦ tranylcypromine

Selective MAO-B inhibitors◦ deprenyl (selegiline)◦ loses its specificity for MAO-B in antidepressant doses

Reversible monoamine oxidase inhibitors (RIMAs)◦ Moclobemide – not approved◦ Appears to be relatively free of food/drug interactions

Examples of MAOIs

Currently marketed medications◦ fluoxetine.◦ sertraline.◦ paroxetine◦ fluvoxamine◦ citalopram◦ escitalopram

Selectively inhibit 5-HT (not NE) uptake Differ from TCAs by having little affinity for muscarinic, as well

as many other neuroreceptors

Selective Serotonin Uptake Inhibitors(SSRIs)

Much higher therapeutic index than TCAs or MAO-I’s Much better tolerated in early therapy Equal or almost equal in efficacy to TCAs Side effects

◦ Nausea◦ Sexual dysfunction

Delayed ejaculation/anorgasmia◦ Anxiety◦ Insomnia

SSRI

Venlafaxine, Duloxetine: ◦ relatively devoid of antihistaminergic, anticholinergic, and

antiadrenergic properties◦ nonselective inhibitor of both NE and 5-HT uptake.

Adverse effects: ◦ GI ◦ Sexual dysfunction◦ Hypertension (venlafaxine)

Selective Norepinephrine-Serotonin Reuptake Inhibitors

Trazodone ◦ mixed 5-HT agonist/antagonist

1 antagonist H1 antagonist

Nefazodone ◦ 5 HT2 antagonist

Bupropion◦ Inhibits uptake of DA and NE◦ antismoking properties probably involves parent molecule◦ Lacks sexual side effects◦ Seizure risk

Other antidepressants

Mirtazapine◦2 antagonist◦5H2 and 5HT3 antagonist◦Net effect selective increase in 5HT1A function◦H1 antagonist

Advantages: sedation, no adverse sexual effects

Pharmacodynamic◦ Additive effects with alcohol and other sedating drugs◦ MAOI interactions

Pharmakokinetic ◦ Cytochrome P450-2D6 inhibition

Fluoxetine and paroxetine Increased levels of TCAs, antipsychotics, warfarin

◦ Cytochrome P450-3A4 inhibition Nefazodone and fluvoxamine Increased levels of terfenadine, astemizole, cisapride – can

cause fatal arrhythmias

Antidepressants and drug interactions

LITHIUM : useful in recurrent as well bipolar depression. Claimed to be useful in suicidal depression Dose range- 900- 1200 mg/day Can be used in resistant cases to augment therapy

A) Psychotherapies: Supportive psychotherapy Interpersonal psychotherapy

B) Cognitive therapies: to modify patient’s faulty ways of thinking about life situations

C) Behavioral therapies: Social skills training Problem solving skills

Identify automatic, maladaptive thoughts and distorted beliefs that lead to depressive moods.

Learn strategies to modify these beliefs and practice adaptive thinking patterns.

Use a systematic approach to reinforce positive coping behaviours.

8-12 sessions

Cognitive Behavioral Therapy (CBT)

Identify significant interpersonal/relationship issues that led to, or arose from, depression (unresolved grief, role disputes, role transitions, social isolation).

Focus on 1 or 2 of these issues, using problem-solving, dispute resolution, and social skills training.

12-16 sessions

Interpersonal Therapy (IPT)

A) Indication: Depression with suicidal ideation Depression with psychotic symptoms Resistant depression- not responding to various drug

combinations in full dosesB) Frequency & number of treatments: First 3 treatment on alternate day then twice a week 6-12 depending upon response

ECT

Mild to moderately severe MDD-psychotherapies are as effective as antidepressant medications.

Combined treatment with pharmacotherapy and psychotherapy-no more effective than either therapy alone.

Combined treatment-chronic or severe episodes, patients with co-morbidity, and patients not responding to monotherapy.(Level 1)

Recommend lifestyle management for all patients with depression.

Regular exercise Adequate housing Healthy regular meals Stress management strategies Sleep hygiene Engaging in at least one pleasurable activity a day Avoiding substance use Keeping a daily mood chart

Lifestyle – Self-Care

Assess and discuss self-management goals, challenges and progress. Provide patient education and self-management materials plus

community resources list. Review treatment plan and modify if no response to antidepressants

after 3-4 weeks At least three follow-up visits in first 12 weeks of antidepressant

treatment. At least one follow-up visit in first 12 weeks of referral for

psychotherapy Continued antidepressant treatment for 6 months after remission, at

least 2 years for those with risk factors.

Monitoring

Encourage adherence to continued treatment even and especially after remission.

Discuss relapse risk factors, symptoms and prevention. Discuss and plan gradual discontinuation of

antidepressants. Discuss need for social network of family, friends and

community.

SIGECAPS Mnemonic for Symptom Criteria for Major Depressive Episode

S – sleep disturbance (insomnia, hypersomnia) I – interest reduced (reduced pleasure or enjoyment) G – guilt and self-blame E – energy loss and fatigue C – concentration problems A – appetite changes (low appetite/weight loss or increased

appetite/weight gain) P – psychomotor changes (retardation, agitation) S – suicidal thoughts

Thank you

Practice guidelines for depressive disorders; American psychiatric association;Oct 2010

Diagnostic and statistical manual for mental diseases Fivth edition

Kaplan textbook of Psychiatry

References

A. Presence of one (or more) of the following symptoms. At least one of these must be 1,2 or 3:1. Delusions.2. Hallucinations.3. Disorganized speech (e.g., frequent derailment or incoherence).4. Grossly disorganized or catatonic behavior.B. Duration at least 1 day but less than 1 month, with eventual full return to premorbid level of functioning.C. Not better explained by major depressive or bipolar disorder with psychotic features or another psychotic disorder such as schizophrenia or catatonia and is not attributable to physiological effects of substance (drug of abuse, medication) or another medical condition.

Brief Psychotic Disorder

A)Two (or more) of the following, each present for a significant portion of time during 1-month period (or less if successfully treated). At least one of these must be (1), (2) or (3):1. Delusions.2. Hallucinations.3. Disorganized speech (e.g., frequent derailment or incoherence).4. Grossly disorganized or catatonic behavior.5. Negative symptoms (i.e., diminished emotional expression or avolition).

Schizophreniform Disorder

B. Episode of the disorder lasts at least 1 month but less than 6 months. C. Schizoaffective disorder and depressive or bipolar disorder with psychotic features ruled out because either

1 ) No major depressive or manic episodes have occurred concurrently with the active-phase symptoms2) If mood episodes have occurred during active-phase symptoms, they have been present for a minority of the total duration of the active and residual periods of the illness.

D. Disturbance is not attributable to the physiological effects of a substance (e.g., drug of abuse, a medication) or another medical condition.

A. Two (or more) , each present for significant portion of time during 1 -month period (or less if successfully treated) at least one of these must be (1 ), (2), or (3):1. Delusions.2. Hallucinations.3. Disorganized speech (e.g., frequent derailment or incoherence).4. Grossly disorganized or catatonic behavior.5. Negative symptoms (i.e., diminished emotional expression or avolition).B. Level of functioning in one or more major areas, such as work, interpersonal relations, or self-care, is markedly below level achieved prior to onset (failure to achieve expected level of interpersonal, academic, or occupational functioning).C. Continuous signs of the disturbance persist for at least 6 months which must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms)

Schizophrenia

D. Schizoaffective disorder and depressive or bipolar disorder with psychotic features ruled out because either 1 ) No major depressive or manic episodes occurred concurrently with active-phase symptoms, or 2) If mood episodes occurred during active-phase symptoms, they have been present for a minority of total duration of the active and residual periods of illness.E. Not attributable to physiological effects of substance (drug of abuse, a medication) or another medical condition.F. History of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms of schizophrenia, are also present for at least 1 month (or less if successfully treated).

A. Uninterrupted period of illness during which there is a major mood episode (major depressive or manic) concurrent with Criterion A of schizophrenia.

Note: Major depressive episode must include Criterion A1 : Depressed mood. B. Delusions or hallucinations for 2 or more weeks in the absence of a major

mood episode (depressive or manic) during the lifetime duration of the illness.

C. Symptoms that meet criteria for a major mood episode are present for the majority of the total duration of the active and residual portions of the illness.

D. Not attributable to effects of substance (drug of abuse, a medication) or another medical condition.

Schizoaffective Disorder

Manic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable

mood and abnormally and persistently increased goal-directed activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalization is necessary).

B. During the period of mood disturbance and increased energy or activity, three (or more) of the following symptoms (four if the mood is only irritable) are present to a significant degree and represent a noticeable change from usual behavior:1. Inflated self-esteem or grandiosity.2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep).3. More talkative than usual or pressure to keep talking.4. Flight of ideas or subjective experience that thoughts are racing.5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed.

Bipolar I Disorder

6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (i.e., purposeless non-goal-directed activity).7. Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments).

C. Mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

D. Not attributable to the physiological effects of a substance (drug of abuse, a medication, other treatment) or to another medical condition.

A. Distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and present most of the day, nearly every day.B. During period of mood disturbance and increased energy and activity, three (or more) of the following symptoms (four if the mood is only irritable) have persisted, represents a noticeable change from usual behavior, and have been present to a significant degree:

1. Inflated self-esteem or grandiosity.2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep).3. More talkative than usual or pressure to keep talking.4. Flight of ideas or subjective experience that thoughts are racing.5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed.

Hypomaniac Episode

6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation.7. Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments).

C. Episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic.D. Disturbance in mood and the change in functioning are observable by others.E. Episode is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization. If there are psychotic features, episode is, by definition, manic.F. Not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, other treatment).

A. Criteria have been met for at least one hypomanie episode and at least one major depressive episode.B. There has never been a manic episode.C. Occurrence of hypomania episode(s) and major depressive episode(s) is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder.D. Symptoms of depression or the unpredictability caused by frequent alternation between periods of depression and hypomania causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Bipolar II Disorder

A. Depressed mood for most of the day, for more days than not, as indicated by either subjective account or observation by others, for at least 2 years. Note: In children and adolescents-irritable and duration at least 1

year.B. Presence, while depressed, of two (or more) of the following:

1. Poor appetite or overeating.2. Insomnia or hypersomnia.3. Low energy or fatigue.4. Low self-esteem.5. Poor concentration or difficulty making decisions.6. Feelings of hopelessness.

Persistent Depressive Disorder (Dysthymia)

C. During 2-year period (1 year for children or adolescents), individual has never been without symptoms in Criteria A and B for more than 2 months at time.D. Criteria for a major depressive disorder may be continuously present for 2 years.E. There has never been a manic episode or a hypomanie episode, and criteria have never been met for cyclothymic disorder.F. Disturbance is not better explained by a persistent schizoaffective disorder, schizophrenia, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder.G. Not attributable to the physiological effects of a substance (drug of abuse, a medication) or another medical condition (e.g. hypothyroidism).H. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

A. Recurrent unexpected panic attacks. A panic attack is an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, and during which time four (or more) of the following symptoms occur;1. Palpitations, pounding heart, or accelerated heart rate.2. Sweating.3. Trembling or shaking.4. Sensations of shortness of breath or smothering.5. Feelings of choking.6. Chest pain or discomfort.7. Nausea or abdominal distress.8. Feeling dizzy, unsteady, light-headed, or faint.9. Chills or heat sensations.10. Paresthesias (numbness or tingling sensations).11. Derealization (feelings of unreality) or depersonalization (being detached from oneself).12. Fear of losing control or “going crazy.”13. Fear of dying

Panic Disorder

B. At least one of the attacks has been followed by 1 month (or more) of one or both of following:

1. Persistent concern or worry about additional panic attacks or their consequences (e.g., losing control, having a heart attack, “going crazy”).2. A significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks, such as avoidance of exercise or unfamiliar situations).

C. Not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g. hyperthyroidism, cardiopulmonary disorders).D. The disturbance is not better explained by another mental disorder

A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance).B. The individual finds it difficult to control the worry.C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past 6 months); Note: Only one item is required in children.

1. Restlessness or feeling keyed up or on edge.2. Being easily fatigued.3. Difficulty concentrating or mind going blank.4. Irritability.5. Muscle tension.6. Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep).

Generalized Anxiety Disorder

D. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.E. The disturbance is not attributable to the physiological effects of a substance (drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism).F. The disturbance is not better explained by another mental disorder

A. One or more symptoms of altered voluntary motor or sensory function.B. Clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions.C. The symptom or deficit is not better explained by another medical or mental disorder.D. The symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.

Conversion Disorder(Functional Neurological Symptom Disorder)