Mood Disorders

“I did not experience depression until I had pretty much solved my problems. I had come to terms with my mother’s death three years earlier, was publishing my first novel, was getting along with my family, had emerged intact from a powerful two-year relationship, had bought a beautiful new house, was writing well. It was when life finally was in order that depression came slinking in and spoiled everything. I’d felt acutely that there was no excuse for it under the circumstances, despite perennial existential crises, the forgotten sorrows of a distant childhood, slight wrongs done to people now dead, the truth that I am not Tolstoy, the absence in this world of perfect love, and those impulses of greed and uncharitableness which lie too close to the heart- that sort of thing. But now, as I ran through this inventory, I believed that my depression was not only a rational state but also an incurable one. I kept redating the beginning of the depression: since my breakup with my girlfriend, the past October; since my mother’s death; since the beginning of her two year illness; since puberty; since birth. Soon I couldn’t remember what pleasurable moods had been like. I was not surprised later when I came across research showing that the particular kind of depression I had undergone (major depression)has a higher morbidity rate than heart disease or any cancer.”

Andrew Solomon from Anatomy of Melancholy

Diagnosis of Mood Disorders

Diagnosis of Mood Disorders requires assessment of the patient’s present state and a setting of the present into the context of past history. The patient may suffer from an episode of major depression, mania, hypomania, or a mixed manic-depressive state in the present. The patient’s past history may include episodes of these states. The patient’s past baseline symptoms and functioning must be described, and may show evidence of return to baseline functioning or not. Present episodes, past episodes, and baseline symptoms/function are put together in a time line to arrive at the specific Mood Disorder Diagnosis. Major Depressive Disorder may be single episode or recurrent (the most common type). Bipolar Illness requires only 1 Manic Episode for initial diagnosis. Patients often have past episodes of hypomania, depression and mixed states.

Major Depressive Episode

(Note that this is not a diagnosis- it is a building block)

The core feature of a depressive episode is either depressed mood or loss of interest or pleasure that has lasted for at least two weeks. Patients feel depressed most of the time or have periods when they feel better; experience markedly less interest or pleasure in all or almost all daily activities; lose or gain weight; have trouble sleeping or sleep too much nearly every day; feel agitated or slowed down nearly every day; feel fatigued; have feelings of worthlessness or excessive guilt; note a decreased ability to concentrate or indecisiveness; and have recurrent thoughts of death. The symptoms represent a change in functioning, and functioning is impaired.

DSM-IV Criteria for Major Depressive Disorder (adapted)

•Presence of an episode of Major Depression (if only 1 episode, the disorder is classified as Single Episode).

•The Major Depressive Episode is not better accounted for by Schizoaffective Disorder and not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder NOS.

•There has never been a Manic Episode, Mixed Episode, or Hypomanic Episode.

Epidemiology of Major Depression (1)

• National Comorbidity Study– lifetime prevalence of depressive disorders in

women is 21-24%; and men is 12-15%– in any one year, 13% women and 8% men depressed

• From 50-70% of patients who have one episode of major depression will have at least one subsequent episode of depression and about 12% will have subsequent manic episodes. Risk of relapse is greatest shortly after remission of depressive symptoms.

• A minimum of 20 weeks of medication treatment is considered necessary to decrease the chance of relapse.

Epidemiology of Major Depression (2)

• The longer a patient has remained well, the lower the risk of relapse. Increased risk is associated with chronic depression lasting two years duration and a history of at least three previous affective episodes.

• Major depression occurs in all socioeconomic groups and ages.

• Relatives of depressed patients (unipolar) have 2-5X risk of major depression compared to controls. No increase in risk of bipolar illness.

Depression Case (1)Lauren is a 27 year old divorced white female graduate student who came for psychiatric evaluation because, “I think there is something wrong with me”. She had a 6 month history of problems including: difficulty falling asleep, trouble staying asleep, early morning awakening, a feeling of no energy, decreased concentration, crying spells, irritability, social withdrawal, and occasional feelings of hopeless but no thoughts of wanting to die. She felt badly about herself, ashamed of her “weakness” . She was caught up in beliefs that she was a failure and “not worth anyone’s time”. Things had been going well in her Ph.D. program in Molecular Biology until a few months ago when her inability to concentrate became severe. At that time, she found that she could not read for more than 15 minutes, she forgot what she read, she couldn’t concentrate on analyzing her data without getting frustrated and giving up, and she couldn’t write- something she had previously felt came easily to her. She began to stay home more, which worried her friends. One of them told her that he was worried about her as she didn’t seem “like herself”. Lauren appreciated his concern, but was very embarrassed about seeming to be inadequate.

Depression Case (2)

Lauren married her high school sweetheart when she was 21. She decided to end the relationship after 5 years because of his increasingly significant use of alcohol and total unwillingness to address his problem. Lauren decided to start psychotherapy at age 24 when her husband’s denigration of her became severe and emotionally painful, yet she felt “stuck”. She did not feel as bad then as she does now, but did have notable trouble with sleep, energy level, concentration, crying, and irritability. She believes her psychotherapy was very helpful in allowing her to see her situation more clearly and figure out why she had so much difficulty doing what was best for herself. Prior to this bad period, she had 2 other times in her life when she felt depressed, at ages 16 and 18. These periods were brief, lasting no more than a month or two and consisted mainly of feeling sad and tired. She described herself as, “I have always felt insecure around other people. I don’t really think I measure up”.

Depression Case (3)

After finishing high school, Lauren attended an excellent state university and graduated with Honors. She decided to continue on in a graduate program because she enjoyed molecular biology and thought a Ph.D. would give her many job options. She had three close friends and described herself as someone who had always valued her relationships with others. Her relationship with her parents and 2 younger siblings was warm and supportive. Lauren had called her parents and talked with them prior to making the psychiatric appointment. They were interested, concerned, and wanted to do whatever they could to help her. There were 3 family members on her mother’s side of the family who had been depressed, including her aunt. Her father’s father drank too much when he was in his 20s and 30s, but stopped after he almost lost his job. Lauren has been healthy and has no history of head injury, seizure disorder, or toxic exposure. She has no other medical complaints.

Mental Status EvaluationLauren was dressed in blue jeans and a casual shirt. She looked tired and apprehensive, but made good eye contact with the examiner. She sat quietly in the chair throughout the interview. Her speech was soft and occasionally halting, but fluent. Lauren described her mood as “down” and “blah”. Her affect was sad, although she did not cry during the interview. She had a preserved sense of humor. She denied having significant anxiety, except when she worried about not being able to continue in her graduate program. Her thinking was goal-directed, and did show negativity in thoughts about herself. She felt like a failure and was ashamed that she could not just “snap out of this”. There was no evidence of hallucinations or delusions. She was oriented to person, place and time. Her cognitive functions were intact grossly, although she complained of having difficulty concentrating. Further cognitive testing was not done as the patient did well in the interview. She evidenced excellent judgement, and had some insight into her problem, stating, “I think I am depressed, but even if this is something else, I need to get some help.”

Questions and Discussion Points (1)

• What psychiatric problem is Lauren experiencing? • Present episode of Major Depression• DSM-IV Diagnosis: Major depression, Mild-moderate, Recurrent.

• What symptoms is Lauren experiencing? • 6 month history of problems• difficulty falling asleep• trouble staying asleep• early morning awakening• a feeling of no energy• decreased concentration• crying spells, irritability• low self-esteem and self-denigration• shame• social withdrawal• occasional feelings of hopelessness but no thoughts of wanting to

die.

Questions and Discussion Points (2)

• What is Lauren’s past history?• Past episode of depression at age 24, probably Minor

Depressive Episode, treated with psychotherapy• Brief periods of depressive symptoms during adolescence.• Baseline insecurity, initial poor choice of mate probably

secondary to low self-esteem and expectation of denigration from self and others.

• Good interpersonal and work-related functioning.• Family support.

• What is Lauren’s Family History?• Many maternal family members with depression.• Paternal history of alcohol dependence. (One type of family

history pattern for patients with depressive disorders is depression in female relatives and alcohol and drug problems in male relatives.)

Treatment

Lauren was treated with nortriptyline (a tricyclic antidepressant- this was prior to the introduction of fluoxetine, the first selective serotonin reuptake inhibitor) and monthly psychotherapy. She had a full remission of biological symptoms within 3 months on 100 mg of nortriptyline at bedtime. Lauren was able to discuss shame, issues of low self-esteem, and uncomfortable feelings about her sexuality that she had been unable to talk about previously. Therapy focused on understanding and altering her perceptions about herself and her relationships, her interpersonal inhibitions, and new ways of looking at herself and relationships. She started dating within 6 months and had a very satisfying and happy relationship for the first time in years. At 2 years after initiation of treatment, she was stable, free of depressive symptoms, had finished her Ph.D., and was engaged to be married.

* While traumatic or stressful events can lead to symptoms of mood disorder, this is typically treated as a separate, usually transient “adjustment disorder with depressed mood.”

* There are theories that some (or much) depression may arise in situations with poor social support, chronic stress, negative personal or occupational situations, etc.

* As with schizophrenia, theories of the brain mechanisms underlying mood disorders have been driven by the mechanisms of action of effective drugs.

Proposed Brain Mechanisms Underlying Mood Disorders (1)

*Post-mortem studies of subjects with major depressive disorder (MDD) by Rajkowska and colleagues (1999, 2000) have found a decrease in neuron density and neuronal atrophy in the dorsolateral prefrontal cortex. This was accompanied by a

decrease in glial density.

*Imaging studies (Drevets and Raichle, 1998; Drevets, 2000) have found decreases in cerebral blood flow and metabolism in this cortical area in depressed patients.

*The abnormalities in blood flow and metabolism appear to be state dependent, reversing during symptom remission (Bench et al., 1995; Mayberg et al., 1999), and in some but not all studies reversing with antidepressant therapy (Baxter et al., 1999;

Drevets et al., 1999).

Proposed Brain Mechanisms Underlying Mood Disorders (2)

Proposed Brain Mechanisms Underlying Mood Disorders (3)

• Postmortem studies of brains from subjects with MDD have also found decreases in neuronal number in the orbital prefrontal cortex (Rajkowska et al., 1999; Rajkowska, 2000).

• Imaging studies indicate an increase in blood flow and cerebral metabolism in the orbital prefrontal cortex in MDD and anxiety disorders (Baxter et al., 1987; Biver et al., 1994; Cohen et al., 1992; Drevets et al., 1992, 1995; Ebert et al., 1991), and this is reversed with antidepressant therapy (Drevets et al., 1992; Nobler et al., 1994; Brody et al., 1999, Drevets 1999; Mayberg et al., 1999).

Proposed Brain Mechanisms Underlying Mood Disorders

*One of the most common biological abnormalities in patients with major depression is hyperactivity of the hypothalamic-pituitary-adrenal axis, the stress response system.

*Dexamethasone, a synthetic adrenal corticosteroid, normally suppresses pituitary adrenocorticotropic hormone (ACTH) release for 24 hours.

*In depressed patients this suppression is often less pronounced or less prolonged.

*There is also evidence for elevated levels of thyrotropin-releasing hormone (TRH) and other thyroid abnormalities in depression.

Proposed Hormonal Mechanisms Underlying Mood Disorders

• One of the most common biological abnormalities in patients with major depression is hyperactivity of the hypothalamic-pituitary-adrenal axis, the stress response system.

• Dexamethasone, a synthetic adrenal corticosteroid, normally suppresses pituitary adrenocorticotropic hormone (ACTH) release for 24 hours.

• In depressed patients this suppression is often less pronounced or less prolonged.

• There is also evidence for elevated levels of thyrotropin-releasing hormone (TRH) and other thyroid abnormalities in depression.

Drug-based Theories of Mood Disorders I

* The initial treatments that were effective in treating many cases of depression had in common raising the levels of catecholamines (norepinephrine and dopamine) at the synapse (MAO inhibitors, reuptake blockers-- “tricyclic antidepressants).

* These led to the Norepinephrine and Catecholamine (includes Dopamine) hypotheses of mood disorders. Reduced catecholamine availability at the synapse caused depressive disorders

* These pharmacological phenomena take effect almost immediately, yet treatment may last 2 weeks or more before significant symptom remission occurs.

Drug-based Theories of Mood Disorders II

* More recently, serotonin has been implicated in mood disorders.

* Brain serotonin is low in many depressed patients and reduced levels of the serotonin metabolic breakdown product (5-HIAA) are common in cerebrospinal fluid. This is common among suicidal depressives.

* Selective serotonin reuptake inhibitors (?????) are effective in restoring mood.

Drug-based Theories of Mood Disorders II

* More recently, serotonin has been implicated in mood disorders.

* Brain serotonin is low in many depressed patients and reduced levels of the serotonin metabolic breakdown product (5-HIAA) are common in cerebrospinal fluid. This is common among suicidal depressives.

* Selective serotonin reuptake inhibitors (Prozac) are effective in restoring mood.

* But why do SSRIs take so long to work? Adaptive plastic change in receptors?

Questions and Discussion Points

• What kinds of medications are used in the treatment of depression?

•Antidepressant medications.•Mood stabilizing medications (for patients

with bipolar depression and unipolar depression that does not fully respond to antidepressants alone).

•Antipsychotic medications (for patients with depression and psychosis).

Questions and Discussion Points• What are the features of a medication that would help with these problems?

• Improve sleep architecture.• Improve mood.• Diminish anxiety• Decrease the biological component of psychological symptoms such

as low self-esteem, self-denigration, negative thinking, and shame.• Increase available serotonin and norepinephrine

– SSRIs use reuptake inhibition– TCAs use reuptake inhibition– MAOIs inhibit degradation– Mirtazepine uses 2 interesting mechanisms

» autoreceptor blockade increasing adrenergic outflow from the presynaptic neuron

» heteroceptor antagonism (an inhibitory serotonin receptor that resides on an adrenergic nerve terminal) leading to increased serotonin output

Questions and Discussion Points

• What are the side effects of antidepressants?

•5-HT2 : anxiety, insomnia, sexual dysfunction

•5-HT3 (brainstem and gut): nausea, GI distress

•H1 antagonism: sedation, weight gain, potentiation of CNS depressants

•Muscarinic (cholinergic) antagonism: dry mouth, constipation, urinary retention, blurry vision, tachycardia, cognitive impairment

•alpha-1-adrenergic receptor antagonism: orthostatic hypotension, dizziness, reflex tachycardia, impaired ejaculation, priapism.

Questions and Discussion Points

• What are some of the problems that patients face when deciding to take medication?

• Lack of acceptance of mental disorders as diseases- the perception that mental illness is willful and psychologically driven. In the case of mood disorders, the states of mind seem very “normal” the patient.

• Inability to face the illness or a desire to run away and pretend that the illness will go away on its own.

• Lack of support from important others like family or mate.• Realistic problems like job loss and social rejection.• General fear of mind-altering medications (which may be

quite irrational as the individual may not fear the use of alcohol, cigarettes, marijuana, or cocaine).

• Unhappiness with side effects of medication.• Discomfort with the physician or other members of the

treatment team.

Questions and Discussion Points

• How can these problems be minimized?• Education of the patient about his/her disease; the probable

course and risks if untreated, and the probable course and benefits/risks if medication is used.

• Develop an understanding of the patient’s point of view about his/her disease, symptoms, hopes for the future, fears.

• Identify the patient’s strengths and help the patient mobilize all his/her individual and social resources. Involve the family when this is helpful.

• Acknowledge the possible risks of medication treatment and assure the patient that he/she will be followed carefully.

• Encourage open communication between patient and physician.

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