Posted by: faithful | July 29, 2000

emory lectures 2

Table of Contents

Mood Disorders – Introduction

Monoamines in Depression

Depression in Medical Practice

Hormonal Abnormalities in Depression

Pharmacotherapy of Mood Disorders

Optional: Additional Thoughts: A Diagnostic Overview

Before launching into a detailed description of each mood disorder, it is important to step back and remember that patients unfortunately do not read textbooks (or the DSM-IV). Although they may come to us prediagnosed, many don’t, and of those who are, the diagnosis can of course be incorrect. So each evaluation requires a systematic approach.

Patients rarely fall into the pure culture, cookie-cutter categorical diagnoses found in psychiatric textbooks. Instead, they present with a cluster of symptoms (what they report) and signs (what you observe) often in the context of a complicated history (psychosocial problems, substance abuse, personality disorders, and medical disease, for example) and it is our job as clinicians to find which diagnostic pattern best describes the pattern we are observing. This is not some dry intellectual or philosophical exercise, nor is it exclusively the realm of the mental health worker. Since diagnosis drives treatment, the correct intervention can literally make the difference between life and death in some situations, and certainly between severe pathology and health in most others. More depression is treated by primary care physicians than by psychiatrists (most, unfortunately, goes unrecognized and untreated). In most situations, our initial diagnosis is a working hypothesis and the results of the treatment itself become part of the refinement of the diagnosis (response to lithium, for example, or failure to respond to antipsychotic medication alone).

To do this, we need a general approach, a simplifying schema that helps us organize our thinking. Here is one approach that I find helpful: I like to think of psychiatric diagnoses as falling into 1 (or more) of 3 broad categories:

    1. Affective (mood) disorders
      1. , e.g., major depression, bipolar disorder, characterized by primary derangements of mood plus or minus secondary psychotic features.
  • Psychotic disorders
      1. , e.g., schizophrenia, characterized by derangements in reality-testing, perception, or cognition (hence the often-used term, “thought disorder”)
  • Organic
    1. , e.g. substance abuse/dependence, delirium, personality changes secondary to a head trauma.

Sorting out which of these 3 categories the episode falls into is half the battle. Some episodes straddle categories, e.g., schizoaffective disorder (both mood and psychotic disorder) or cocaine dependence in a schizophrenic (dual diagnosis, both substance abuse and psychotic disorder).

      • Psychiatric diagnosis cannot be made based on a single, cross-sectional mental status exam. To illustrate what one must also consider, I will compare schizophrenia to bipolar disorder. The clinician must also consider:
      • longitudinal course:
        • schizophrenia:
          • usually premorbid lower functioning;
          • as children maybe odd, clumsy, socially isolated;
          • 6 months of symptoms reflective of chronicity of illness
          • probably represents several illnesses lumped together
        • bipolar disorder:
          • often excellent premorbid functioning;
          • tend to be socially outgoing, high achievement (multiple goal-oriented activities); make excellent salesmen (and medical students);
          • episodic with intervening periods of high functioning
        • family history
        • family history of affective disorder (major depression or bipolar disorder) positively correlated with bipolar disorder; family history of schizophrenia negatively correlated with bipolar disorder disorder:
        • caveats:
          • schizophrenia grossly overdiagnosed in the 1970s in the United States;
          • schizophrenia may be over diagnosed in African Americans;
          • bottom line: take past diagnoses with a grain of salt; try to get description of behavior, not just the label
  • +/- biological markers
    • ; few currently available. The Dexamethasone Suppression Test maybe helpful in diagnosing major depression, as might a good somnogram (sleep study).

Bipolar Disorder

(also known as “manic depression”)

Bipolar disorder is a severe, debilitating mood disorder characterized by periods of expansive, irritable, or grandiose moods, usually followed by an episode of major depression, then an intervening period of normalcy lasting several months or years until the next relapse. Of psychiatric diagnoses, bipolar disorder has the highest suicide rate. During the prodome leading to mania (so-called hypomania), a person may be extremely productive, with multiple goal-oriented activities, high energy, diminished need for sleep, and rapid thinking and talking (most medical students would love to be in this state chronically!). However, hypomania is a trajectory leading to mania, often with severe agitation, delusions of grandiosity or persecution, disorganization of thought and behavior, and overt psychosis (auditory hallucinations, visual hallucinations, or other perceptual disturbances). Cross-sectionally, bipolar disorder is indistinguishable from schizophrenia, as much as psychiatric folklore would have you believe (studies show clinicians conducting a “blind” cross sectional exam of a bipolar disorder v. a schizophrenic patient make the correct diagnosis only about 50% of the time.

Bipolar I Disorder diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)):

    • “clinical course … characterized by the occurrence of one or more Manic Episodes or Mixed Episodes… Often individuals have also had one more more Major Depressive Episodes” (pp. 350-1)
    • recurrent – 90% have recurrence
    • interval between episodes tends to decrease with time
    • 60-70% associated with major depressive episodes immediately before or after
    • Rapid Cycling: 4 or more mood episodes within a year (Major Depressive, Manic, Mixed, or Hypomanic) = 5-15% of Bipolar I Disorder
    • prevalence: 0.4% – 1.6%
    • strongly familial: 4-24% prevalence among first-degree relatives
    • Criteria for Manic Episode:
    • Distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary).
    • During the … mood disturbance, 3 (or more) of the following have persisted:
      • Inflated self-esteem or grandiosity
      • Decreased need for sleep
      • More talkative than usual or pressure to keep talking
      • flight of ideas or … racing thoughts
      • distractibility
      • increase in goal-directed activity or psychomotor agitation
      • excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., … buying sprees, sexual indiscretions, or foolish business investments).
    • Not a Mixed Episode
    • Sufficiently severe to cause –
      • marked impairment in occupational functioning or in usual social activities or relationships… or
      • hospitalization … or
      • psychotic features
    • The symptom are not due to … a substance … or general medical condition (DSM-IV, p. 332)

For the sake of comparison, here are the criteria for schizophrenia:

Diagnostic Criteria for Schizophrenia (per DSM-IV):

2 or more criteria over a 1 month period (or less if treated):

    • Delusions = fixed, false, idiosyncratic belief
    • Hallucinations = perceptual disturbance, e.g., vision, hearing voices
    • disorganized speech
    • grossly disorganized or catatonic behavior
    • negative symptoms, e.g. affective flattening or avolition

social or occupational dysfunction


<= 1 month = Acute Psychotic Disorder

1-6 months = Schizophreniform disorder

>= 6 months = Schizophrenia

NOT accounted for by:

Mood disorder: affective symptoms -> psychosis; psychosis never present in the absence of mood symptoms;

Schizoaffective disorder: affective symptom + psychosis AND psychotic symptoms in the absence of mood symptoms.

Substance abuse or withdrawal.

Pervasive developmental disorder

Bipolar disorder disorder, manic episode, v. Schizophrenia, summarized:

Bipolar Disorder Schizophrenia
Mood Congruence of Delusions +++ +/-
Bizarreness of Delusions + ++++
Interpersonal Engagement +++++
Euphoric Often Rare
Multiple goal-oriented activities Common especially early in episode (hypomania) Not characteristic
Downward Drift +/- ++++
Premorbid functioning Excellent Odd or unusual, more socially withdrawn
Effect on Examiner Infectious Euphoria Disconnect
Return to Normalcy Between Episodes The rule The exception; patients may have negative or residual symptoms


The primary objective in bipolar disorder is to determine what phase of the illness the patient is in, then intervene appropriately. If the patient is hypomanic or manic, mood stabilizers must be initiated or adjusted to treat the underlying disorder. (Many hypomanic patients will see little reason for treatment, but if this is not their first episode, they may remember past episoders and realize they are on a trajectory.)

Mania or hypomania is treated with “mood stabilizers” formally known as thymoleptics. The most common include lithium, valproic acid, and carbamazepine. All 3 have randomized, controlled studies demonstrating their efficacy over placebo. They take from 10 days to 2 weeks to start to work, so should be initiated as soon as possible in the suspected manic patient. Acutely, mania can respond to benzodiazepines such as lorazepam or clonazepam.

Psychotic symptoms, if present, may require initiation of a neuroleptic (antipsychotic) medication, such as haloperidol, or one of the newer agents such as Risperidone or olanzapine (see below). Mania itself is notoriously treatment resistant to neuroleptics (antipsychotics), however, but frank psychotic symptoms may respond (such as auditory hallucinations or delusions).

Agitation and insomnia both can respond well to benzodiazepines. Avoid antipsychotic medications in the non-psychotic agitated patient; benzodiazepines are almost always preferable.

Depression, if present, may respond to antidepressant medication or electroconvulsive therapy. Caution: beginning an antidepressant can trigger a manic episode, so the standard of care is to initiate the mood stabilizer first in a depressed bipolar patient, then the antidepressant once the patient is stable. ** Note that for this reason, in any depressed patient, you should inquire about a history of mania. **

Antihistamines may also be helpful as hypnotics (to help the patient sleep) or for the agitated patient who for whatever reason should not be treated with benzodiazepines (such as the substance-abusing patient where you wish to minimize the risk of relapse).

It is conceivable that a patient maybe started on a mood stabilizer, such as lithium, an antidepressant such as Prozac, a benzodiazepine such as lorazepam, and an antipsychotic such as Risperidone all at the same time (although initiation of the fluoxetine could probably wait until stabilization of the mania).

(antipsychotics are sometimes referred to as neuroleptics).

Mood Stabilizers


Carbamazepine (Tegretol)

Valproic Acid (Depakote)

Also referred to as thymoleptics (antipsychotics are sometimes referred to as neuroleptics).


    • the oldest, not necessarily the best
    • mechanism of action unknown; inhibits adenyl cyclase may stabilize the membranes of excitatory neurons in the CNS, inhibiting their discharge
    • may also act via blocking cells’ ability to restore normal levels of PIP2 (phosphatidylinositol biophosphate), which is usually cleaved to stimulate intracellular calcium release -> cellular activation and a cascade of other effects
    • may also inhibit transmembrane cation pumps (Na+, K+, Ca++)
    • may inhibit tryptophan uptake by serotonergic neurons

Efficacy: quite good; 30-80% of manics will respond acutely, per pure drug studies, but in clinical practice, 50% is closer to reality

    • note: lithium is no more efficacious than the anticonvulsants (Depakote and Tegretol primarily) in treating acute mania overall
    • but maybe more effective in treating “classical” bipolar disorder
    • less effective in rapid cycling, atypical
    • maybe good in combination with e.g., Tegretol, in decreasing relapse rates

Side effects: multiple

  • bloating and weight gain
  • fatigue
  • cognitive clouding
  • narrow therapeutic index; may lead to encephalopathy if concentration increases too much
  • acne
  • hypothyroidism
  • renal toxicity – polyuria/polydypsia may result from damage to the distal tubules
  • cardiac toxicity – similar to hypokalemia; depresses sinus node’s pacemaking ability
  • Teratogenicity: particularly in first trimester associated with Ebstein’s anomaly (as high as 3% of those exposed in utero)

Therapeutic level: .8-1 for maintenance; 1-1.2 for acute mania

Tegretol (carbamazepine)

Efficacy: equal to lithium; maybe more effective in atypical or treatment refractory cases, or cases with personality overlay.

side effects:

    • Sedation, ataxia, dizziness
    • hepatotoxicity
    • bone marrow suppression (extremely rare)
    • rash

Therapeutic blood level: 8-12

Depakote (valproic acid)

Efficacy: equal to lithium; maybe more effective in atypical or treatment refractory cases, or cases with personality overlay.

– may have more rapid onset (10 days v. 2 weeks)

side effects:

    • Sedation, ataxia, dizziness
    • Hepatotoxicity
    • rash

Therapeutic blood level: 50-100




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