Diagnosing and Treating Mood Disorders: The Science and Ethics

Chris Trimble, Leo Huizar, Fredah Kabbech, Megan Sieveke, Brandon Butler

Mood Disorders

Depression
Can refer to either:
A mood: a pervasive and sustained emotional response A clinical syndrome: a combination of emotional, cognitive and behavioral symptoms

How To Distinguish Depression From Normal Sadness

The mood change is pervasive across situations and persistent over time The mood change may occur in the absence of any precipitating events The depressed mood is accompanied by impaired ability to function in usual social and occupational roles The change in mood is accompanied by a cluster of additional signs and symptoms The nature or quality of the mood change may be different from that associated with normal sadness

Emotional Cognitive Somatic Behavioral

Four Types of Symptoms Associated With Mood Disorders

Emotional Symptoms
Depressed or dysphoric mood is the most common and obvious symptom of depression People who are depressed describe themselves as feeling utterly gloomy, dejected and despondent Manic patients experience euphoric like symptoms

Cognitive Symptoms
Involve changes in the way people think about themselves and their surroundings Depressed people may have trouble concentrating and are easily distracted Preoccupation with guilt and worthlessness Manic patients report sped up thoughts and ideas

Somatic Symptoms
Related to basic physiological or bodily functions Include fatigue, aches and pains, and serious changes in appetite or sleeping patterns

Behavioral Symptoms
Changes in the things that people do and the rate at which they do them Psychomotor retardation often accompanies the onset of depression Manic patients show energetic, provocative and flirtatious behavior

Diagnosing Mood Disorders

Defined in terms of episodes
discrete periods of time in which the persons behavior is dominated by either a depressed or manic mood

Major Depressive Episode

Five or more of the following symptoms must have been present during the same two week period and represent a change from previous functioning At least one of the symptoms is either
Depressed mood Loss of interest or pleasure

Major Depressive Episode Symptoms

Depressed mood most of the day, nearly every day Diminished pleasure in all, or almost all activities Significant weight loss (without dieting) or weight gain Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness or guilt Diminished ability to think or concentrate Recurrent thoughts of death or suicidal ideation

Manic Episode
A distinct period of abnormally and persistently elevated, or expansive mood, lasting at least one week During the period of mood disturbance, three of more of the following symptoms have persisted and have been present to a significant degree

Manic Episode Symptoms

Inflated self esteem or grandiosity Decreased need for sleep More talkative than usual Flight of ideas
Distractibility (drawn to unimportant stimuli) Increase in goal directed activity Excessive involvement in pleasurable activities that have a high potential for painful consequences

Mood Disorders
Two primary types:
Unipolar mood disorder: the person experiences only episodes of depression Bipolar mood disorder: the person experiences episodes of mania as well as depression

Types of Mood Disorders and Frequency

Types of Mood Disorders

Unipolar Mood Disorders
Major Depressive Disorder Dysthymic Disorder

Bipolar Mood Disorders

Bipolar I Disorder Bipolar II Disorder Cyclothymic Disorder

Subtypes

Major Depressive Disorder

One or more major depressive episodes No manic or unequivocal hypomanic episodes Lifetime prevalence of 15% Major Depressive Disorder 15% suicide mortality VA 1991 Study
Major Depressive Disorder mortality 38.7% 13% no psychiatric monitoring

Major Depressive Disorder

Course is variable
Some having episodes years apart, clusters of episodes, and some with frequent episodes throughout life Only about 20% have chronic episodes

After the first episode, 50%- 60% chance of a second , and a 5%-10% chance of a manic episode (i.e. developing bipolar I disorder) After second episode, 70% chance of a third After third episode, 90% chance of a fourth The greater number of previous episodes is an important risk factor for recurrence

Major Depressive Disorder

By definition, Major Depressive Disorder cannot be due to:
Physical illness, alcohol, medication, or street drug use. Normal bereavement. Bipolar Disorder 7Mood-incongruent psychosis (e.g., Schizoaffective Disorder, Schizophrenia, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified).

Major Depressive Disorder Co-occurring Disorders

Substance Abuse Anxiety
80 to 90% of individuals with Major Depressive Disorder also have anxiety symptoms (e.g., anxiety, obsessive preoccupations, panic attacks, phobias, and excessive health concerns).

Cancer, COPD (Chronic Obstructive Pulmonary Disease), Pain, eating disorders Causation:
Meds: steroids Diseases: hypothyroidism

Dysthymic Disorder
Depressed mood for at least two years Never without at least two of the following symptoms for more than two months
Poor appetite or overeating, insomnia or hypersomnia, low energy, low self esteem, poor concentration, feelings of hopelessness

Dysthymic Disorder
No major depressive episode during the first two years Lifetime risk of 3%

Bipolar I Disorder
One or more manic episodes Lifetime risk of 1%

These positron emission tomography scans of the brain of a person with bipolar disorder show the individual shifting from depression, top row, to mania, middle row, and back to depression, bottom row, over the course of 10 days.

Bipolar II Disorder
One or more major depressive episodes At least one hypomanic episode
A hypomanic episode is a less severe version of a manic episode.

No manic episodes

Subtypes of Mood Disorders

Melancholia: describes a particularly severe type of depression Psychotic features: when hallucinations or delusions were present during the most recent episode Rapid cycling: the person experiences at least 4 episodes within a 12 month period

Subtypes of Mood Disorders

Postpartum Onset: when episodes begin within 4 weeks after childbirth Seasonal affective disorder: when the onset of episodes is regularly associated with changes in seasons

Prevalence of Mood Disorders

Depression accounts for more than 10 percent of all disabilities in the US Younger generations are experiencing higher rates of depression, and those who become depressed are doing so at an earlier age Depression affects 1314 million people each year

Prevalence of Mood Disorders

Ratio of unipolar to bipolar is at least 5:1 Lifetime prevalence of all mood disorders is 8%, ranked third behind substance abuse disorders and anxiety disorders

Gender Differences
Women are two or three times more vulnerable to depression than men
Sex hormones, stressful life events, childhood adversity, etc May be more likely to seek treatment May be more likely to be labeled as depressed

No differences seen in bipolar disorders

Children Statistics
Up to 2.5% of children in the US suffer from depression Up to 8.3% of adolescents in the US suffer from depression Girls entering puberty are twice as likely to experience depression as boys

Types of Causes

Environmental Factors Psychological Factors Biological Factors

Environmental Factors: Stress

Levels of stress may vary from person to person. Depressive episodes can make a person more vulnerable to further episodes, so small amounts of stress can activate depression
Learner Helplessness- after experiencing chronic or repeated stressful events, people can learn to feel helpless

Environmental Factors: Substance Abuse

Depression that is a result of drug abuse, medication, or toxin exposure Associated with use and withdrawl from: alcohol, amphetamine, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedaitves, hypnotics and anxiolytics Exposure or habitual use of chemicals can alter brain structure and function resulting in depression

Environmental Factors: Childhood Difficulties

Depression can develop in children who have experienced a traumatic event including but not limited to:
Death of family member or friend Natural disaster Divorce Loss of parents job, home, etc...

Many of these children are emotionally damaged or lack emotional development and often have difficulties adjusting Traumatic Event may affect the development of the Limibic System

Depression In Disease
Estimated 1/3 people with chronic disease have depression. Alzheimers
Boston Study
14% had history of depression

HIV
1/3 estimated to have depression

Continued
The rate for depression occurring with medical illness*:
Heart attack: 40-65% Coronary artery disease (without heart attack): 18-20% Parkinson's disease: 40% Multiple sclerosis: 40% Stroke: 10-27% Cancer: 25% Diabetes: 25%

*Reviewed by the doctors at The Cleveland Clinic Department of Psychiatry and Psychology.

Psychological Factors
Cognitive Vulnerability
People responding differently to the same negative experience involving loss, failure and disappointment

https://www.depressionadvances.com/animation/brainAnimations.html

HYPOTHYROIDISM COMMON SYMPTOMS

Delayed reflexes Cardiac failure Cold intolerance Brittle hair Dry skin Depressed mood Apathy Weight gain Fatigue Impaired concentration Thoughts of suicide Delusions Decreased appetite

DEPRESSION
Weight changes Appetite problems Sleep problems

Biological Factors
Neurotransmitters and Neurons
The signal enters the neuron through the dendrite and proceeds through the cell body to the axon where it is switched from a electric signal to a chemical one Theses chemical signals are called neurotransmitters
Neurotransmitters can fit into many receptors, but receptor sites can only receive specific transmitters Upon release the transmitter is broken down by mono amine oxidase (MAO) or its taken back in by the neuron that released it, called reuptake

Biological Factors
Of the 30 or so known neurotransmitters, depression effects Serotonin, Norepinephrine, and Dopamine Depression has been linked to both low and elevated Norepinephrine concentrations.

Biological Factors: Serotonin

The permissive hypothesis of serotonin function postulates that the deficit in central serotonergic neurotransmission permits the expression of bipolar disorder but is not sufficient to cause it.
According to this theory, both the manic and the depressive phases of bipolar illness are characterized by low central serotonin function but differ in high versus low norepinephrine activity.

Biological Factors: Norepinephrine

The catecholamine hypothesis of affective disorders proposes that some forms of depression are associated with a deficiency of catecholamine activity (particularly norepinephrine) at functionally important andrengeric receptor sites in the brain, whereas mania is associated with a relative excess.

Biological Factors: Dopamine

Evidence is substantial that enhanced dopamine activity may play a primary role in psychotic depression.

Biological Factors: Hormones

About one half of all depressed persons have a high level of the hormone cortisol in their blood A person with a depressive mood disorder may not have their hypothalamus regulating the cortisol production in the adrenal gland correctly Normal cortisol levels peak at 8:00a.m. and 4:00p.m. for non depressed person, while a person with depression may have the hormone released at a constant level

Biological Factors: Genetics

There is a 1.5 to 3% greater chance for a person to develop a depressive disorder if a parent or sibling has it as well
50% of those with bipolar disorder have a parent with history of clinical depression 25% of children of a parent who is bipolar develop a depressive disorder 50-75% of children of two parents with bipolar disorder develop a depressive disorder

Biological Factors: Twin Studies

If one twin develops depression there is a 76% chance that the other twin will develop a disorder as well
When raised apart the percentage is 67% Because this number is not closer to 100%, there is indication that other factors are also responsible

Fraternal twins have a 19% chance of developing a depressive disorder if the other develops one

Bipolar Causes
Relation to Person w/Bipolar 2nd degree relative Sibling Fraternal Twin One Parent Both Parents Identical Twin Risk of Developing Bipolar 1% 3-7% 15-25% 15-30% 50-75% 70%

Causes of Depression
Depression has been linked to size/function in the temporal and frontal lobes and the cingulate gyrus. However, it is unclear as to whether the depression causes the abnormalities or the depression is a result of the abnormalities.

Treatment of Mood Disorders

Treatments:
Unipolar Mood Disorders
Cognitive Behavioral Therapy Antidepressant Medication

Bipolar Mood Disorders

Lithium Anticonvulsant Medication Psychotherapy

Others
Electroconvulsive Therapy Vagus Nerve Stimulation Transcranial Magnetic Stimulation

Cognitive Behavioral Therapy

CBT combines both cognitive therapy and behavioral therapy
Cognitive Therapy teaches a person how certain thinking patterns are causing their symptoms-by giving them a distorted picture of what's going on in their life, and making them feel anxious, depressed or angry for no good reason, or provoking them into ill-chosen actions.

Cognitive Behavioral Therapy

Behavioral Therapy helps patients weaken the connections between troublesome situations and their habitual reactions to them. It also teaches them how to calm their mind and body, so they can feel better, think more clearly, and make better decisions

Cognitive Behavioral Therapy

Identification of Skill Deficits:
Help patient to identify deficits so that they can learn better ways to manage life

Evaluation of Life-Experiences
Help patient develop realistic expectations about life, and help distinguish between what the patient needs and what they want

Self-talk
Help patient identify negative self-talk, teach them how to combat these thoughts and to replace them with positive thought

Cognitive Behavioral Therapy

Automatic thoughts
Help patient identify negative automatic thoughts and ways to replace these thoughts with positive ones

Irrational ideas and Beliefs

Teach patient how to identify their irrational thoughts and how to differentiate between irrational and rational thought

Overgeneralizing and Catastrophizing

Help patient identify and change negative overgeneralizations

Cognitive Behavioral Therapy

Cognitive Distortions
Help patient determine what evaluations are distortions by providing objective feedback of their evaluations of the world

Pessimistic Thinking
Help patient develop more optimistic view of world

Treatment: Antidepressants
Four types of drugs are used in the treatment of depression and other associated mood disorders:
Tricyclic antidepressants Monoamine Oxidase Inhibitor Selective Serotonin Reuptake Inhibitors Serotonin Norepinephrine Reuptake Inhibitors

Tricyclic Antidepressants
From 1960s until late 1980s, tricyclic antidepressants represented the major pharmaceutical treatment for depression They still provide the surest antidepressant response for moderately to severe depression

Tricyclic Antidepressants
TCAs work by increasing the concentration of norepinephrine and serotonin in certain regions of the CNS TCAs impede the reuptake of norepindephrine and serotonin They are safe and effective for up to 80% of patients

Tricyclic Antidepressants
There are two broad chemical classes:
Tertiary Amines
They have a greater effect in boosting serotonin than norepinephrine.
amitriptyline, imipramine, trimipramine and doxepin

Secondary Amines
Greater increase of norepinephrine levels
nortriptyline, desipramine, and protriptyline

Monoamine Oxidase Inhibitors

MAOIs treat depression by inhibiting the effect of monoamine oxidase which causes the concentrations of serotonin, norepinephrine and dopamine to increase Most doctors will not prescribe MAOIs unless a patient is not responding to other antidepressants

Monoamine Oxidase Inhibitors

Definitely Effective
Atypical Depression Major Depression Dysthymia Melancholia Panic Disorder Bulimia Atypical facial pain Anergic Depression Treatment-resistant depression Parkinsons Disease

Other Possible Uses

Obsessivecomplusive Disorder Narcolepsy Headache Chronic pain syndrome Generalized anxiety disorder

Selective Serotonin Reuptake Inhibitors

SSRIs work by inhibiting the reuptake of serotonin into the neuron that made it Includes fluoxetine and paroxetine

Serotonin Norepinephrine Reuptake Inhibitors

This class of drugs is most recent addition to the family of antidepressants and has a structure and chemical profile that distinguishes them both tricyclic antidepressants and SSRIs. Work by increasing levels of Serotonin and Norepinephrine by inhibiting their re-absorption back into the cell.

Venlafaxine
Venlafaxine inhibits serotonin and norepinephrine reuptake without significant effects on muscarinic, cholinergic, histaminic, or alphaandrenergic receptors. Therefore, venlafaxine activity is similar to tricyclics and SSRIs but has a less adverse side-effect profile.

Bupropin
Bupropin is the newest drug for treating depression, although the exact neurochemical mechanism is not known
Does not inhibit monoamine oxidase or inihibit the reuptake serotonin and norepinephrine Does inhibit the reuptake of dopamine to some extent

It is a stimulant type drug that is used in the treatment of major depression.

Treatments: Antidepressants
50-65% of people given an antidepressant show much improvement over 3 months, compared to 25-30% of people given a placebo.
Indicates that although drug is effective, antidepressants, like most medicines, may have some benefits due to placebo affect

Treatments: Antidepressants
Medication must be used every day or at every time prescribed. If not taken correctly treatment will not be effective and may have adverse effects. Antidepressants will usually take 1-2 weeks work, however some may take up to six weeks

Treatments: Antidepressants
On the basis of clinical research and experience, the consensus is that most people can be taken off their antidepressants after six to eight months of clinical response without doing worse than patients continuing on the drug

Bipolar Treatments
Psychiatric Management Acute Treatment Maintenance Treatment

Psychiatric Management
At this time, there is no cure for bipolar disorder; however, treatment can decrease the associated morbidity and mortality.

Bipolar Treatments: Lithium

Lithium is prescribed to people with bipolar disorder to even out the highs and lows. Because bipolar disorder requires long term treatment, a patient may have to take Lithium for many years, often in combination with other antidepressants

Bipolar Treatments: Lithium

Lithium interferes with the synthesis and reuptake of chemical messengers by which nerves communicate with each other (neurotransmitters). Lithium also affects the concentrations of tryptophan and serotonin in the brain. Lithium's effects usually begin within one week of starting treatment, and the full effect is seen by 2 to 3 weeks.

Bipolar Treatment: Anticonvulsants

Often prescribed to patients who do not respond to lithium Include carbamazepine (Tegretol) or valproic acid (Depakene) More than 50% respond positively to these drugs Reduce the frequency and severity of relapse

Treatments: Electroconvulsive Therapy

Patient is put to sleep and temporarily paralyzed, so that their muscles do not contract and cause injuries like fractures. An electric current is then run through the brain to initiate a seizure. ECT is sometimes the most effective, rapid method of treating severe major depressive disorder (MDD).
for patients with poor response to medications, poor tolerance of usual antidepressants, severe vegetative symptoms, or psychotic features

Treatment: Vagus Nerve Stimulation

VNS stimulates the limbic system, a group of related structures that affect mood, motivation, sleep, appetite, alertness and other factors commonly altered by depression. VNS is delivered to the left cervical vagus nerve by the NeuroCybernetic Prosthesis (NCP) System which is implanted just under the skin in the left chest area.
Delivers a pre-programmed, intermittent electrical pulse to cervical vagus nerve 24 hours a day

Transcranial Magnetic Stimulation

TMS is a procedure in which the electrical activity in the brain is influenced by a magnetic pulse. This procedure can be used to alter function of certain areas of the brain, especially those involved in depression

Side Effects of Treatments

Side Effects: Tricyclics

Initially: they cause blurred vision Constipation Light-headedness when standing or sitting up suddenly Dry mouth Difficulty urinating Feelings of confusion Cognitive Dysfunction
A small percentage of people will have other side effects such as:
sweating, a racing heartbeat, low blood pressure, allergic skin reactions or sensitivity to the sun.

Side effects usually disappear once therapeutic effects if medication take hold

Side Effects: Tricyclics

More serious side effects, although rare, can be aggravation of narrow angle glaucoma and seizures Some tricyclic side effects relate to the fact that these medications have similar effects on other neurotransmitters in the CNS, notably histamine and acetylcholine

Drug Interactions: Tricyclics

Drug
MAOIs Norepinephrine pressure arrhyhmias Phenothiazines Barbiturates metabolism Cimetidine heterocyclics Haloperidol Methylphanidate heterocyclics

Interaction
Stroke, hypertension Large increase in blood and incidence of Psychosis, agitation Increase heteocyclic Blocks metabolism of Can block metabolism of heterocyclics Blocks metabolisms of

Side Effects: MAIOs

The side effects of MAOIs are generally more severe or frequent than for other antidepressants

Side Effects: MAIOs

Drowsiness Constipation Nausea Diarrhea Stomach upset Fatigue Dry mouth Dizziness Low blood pressure Lightheadedness, especially when getting up from a lying or sitting position Decreased urine output Decreased sexual function Sleep disturbances Muscle twitching Weight gain Blurred vision Headache Increased appetite Restlessness Shakiness Trembling Weakness Increased sweating

Drug Interactions: MAOIs

Because of the extensive inhibition of monoamine oxidase by MAOIs enzymes raises the potential for a number of drug interactions.
Many of these interaction occur with overthe-counter medications

Drug Interactions: MAOIs

Drug
Other MAOIS TCAs, Carbamazepine, Cyclobenzaprine SSRIs Stimulants (dextromamphetamine); Busirone Meperidine Dextromethorphan Direct Sympathomimetics Indirect Sympathomimetics Oral Hypoglycemics (insulin) Fenfluramine, L-Tryptophan

Interaction
Increase risk for side effect; covulsions Hypertension; convulsions Serotonin Syndrome Increased blood pressure Potentially fatal interaction Brief psychosis Increased blood pressure Hypertensive crisis possible May worsen hypoglycemia Serotonin Syndrome possible

Food Interactions: MAOIs

Food Restrictions MAOIs inhibit Avoid: monoamine oxidase in Cheese, overripe aged gut that is responsible fruit, fava beans, sausage, salami, sherry, for the break down of liquors, sauerkraut, tyramine. A build up of monosodium glutamate, pickled fish, brewers tyramine can lead to a yeast, beef and chicken sudden increase in liver, fermented products, red wine blood pressure and a Used in moderation chance of heart attack Coffee, chocolate, or stroke. colas, tea, soy sauce,
beer, other wines

Side Effects: SSRIs

loss of appetite, weight loss increased appetite, weight gain allergic reactions dry mouth irritability / anxiety sleeplessness drowsiness headache shaking dizziness fits / convulsions disturbance of sexual function (but this is also a feature of depression) sweating bruising manic or hypomanic behaviour

shaking dizziness fits / convulsions disturbance of sexual function (but this is also a feature of depression) sweating bruising manic or hypomanic behaviour abnormal movements low sodium level suicidal ideas abnormal movements low sodium level suicidal ideas

Drug Interactions: SSRIs

Although the potential for interaction does exist, SSRIs are not associated with many of the interactions are seen with other antidepressants
Paroxetine and fluvoxamine have been associated with increased bleeding when given with wafarin Does not effect Lithium levels

Suicide and SSRIs

There is evidence that the use of antidepressants, especially SSRIs, can cause an increase in suicidal thoughts, however it does not show an increase in cases.
A severely depressed patient, or those with bipolar syndrome in a low phase, usually only have the energy to focus on their low. As the medication begins to take affect they will have an increase in energy and suicidal thoughts as they transition from their low or depressed episode. It is this time when the patient is still in a depressed state of mind, that they are able to think more about and idealize suicide because oh their higher energy level.

Side Effects: SNRIs

Nausea and vomiting Dizziness Insomnia Sleepiness Abnormal dreams Constipation Sweating Dry mouth

Yawning Tremor Gas Anxiety Agitation Abnormal vision Headache Sexual dysfunction

Side Effects: Bupropin

28% of patients will lose five pounds or more 0.04% of patients will experience seizures
Common: Agitation, constipation, diarrhea, dizziness, dry mouth, headache, increased perspiration, insomnia, nausea, vomiting Rare: Acne, blurred vision, chest pains, chill, coordination problems, confusion, decrease in white blood cell count, fainting, fever,hair color change

Withdrawls: SNRIs
Stopping treatment with SNRIs, especially when done suddenly, can cause withdrawal-like symptoms:
nausea, vomiting, anxiety, diarrhea, agitation, confusion, headaches, nightmares, coordination changes, or skin-tingling or shock-like sensations Sometimes referred to as discontinuation syndrome

Side Effects: Electroconvulsive Therapy

Anxiety or nervousness Gastrointestinal distress (nausea and diarrhea) Headache Insomnia Rash Slight weight loss Sexual impotence in men (about 10%) Lose of interest in sex for both men and women; inability to achieve orgasm

The Chris Pittman Case

In 2001, the 12 year boy shot and killed his grandparents while being under the influence of Zoloft, a popular antidepressant for the previous couple of days

The Chris Pittman Case

Defense attorneys argued that Chris suffered adverse reactions to the drug including akathisia (a neurological reaction characterized by extreme internal restlessness, which has been associated with suicide and violence), emotional blunting, mania and psychosis with testimonies by Chriss aunt and sister

The Chris Pittman Case

Former FDA scientist Dr. Richard Kapit, who had approved Zoloft for human clinical trials even testified in Chriss defense stating that some antidepressants can alter the behavior of people under 18, causing mania and even suicide Chris was charged and sentenced as an adult on February 15, 2005, and is now serving 30 years in prison

Ethics

Ethics
Ethical issue arises over a depressed patients ability to make decisions concerning treatment. An elderly patient that has been diagnosed with depression has recently become gravely ill, requiring dialysis.

Ethics
If you are not given an effective dosage of antidepressant medication, suicide rates increase. Is the hit-or-miss method of treatment with medication ethical? Untreated Depression has a high risk of suicide that accompanies the disorder

Ethics
54% of patients with bipolar disorder are misdiagnosed as having depression Misdiagnoses and treatment of patients with bipolar disorder as having a unipolar disorder can magnify the patients symptoms
Many antidepressants can cause a patient with bipolar disorder to have exaggerated and prolonged highs and lows

Should we be quick to treat Depression with medication when misdiagnosis can have serious consequences.

References
Downing-Orr, Kristina. Rethinking Depression - Why Current Treatments Fail. 1st ed. New York: Plenum Press, 1998. Higgins, Edmund S. "Is Depression a Neurochemical or Neurodegenerative?." Current Psychiatry 3.9 (2004): 39-40. Kline, Nathan S., M.D., Factors in Depression, Rockland State Hospital, Raven Press Books, Inc., 1974 Lazarus, Jeremy A. "Ethics in Split Treatment." Psychiatric Annals 31.10 (2001): 611-614. Oltmanns, Thomas F., Case studies in Abnormal Psychology, 3rd, John Wiley and Sons, Inc., 1991 Oltmanns, Thomas F., and Robert E. Emery. Abnormal Psychology. 5th ed. Upper Saddle River: Prentice Hall, 2004. Schatzberg, Alan F., and Charles B. Nemeroff. Textbook of Psychopharmacology. 2nd ed. Washington: American Psychiatric Press Inc., 1998. Spitzer, Robert L., Psychopathology, A case book, Columbia University, McGraw-Hill, Inc., 1993 Diagnostic and Statistical Manual of Mental Disorders. IV txt revision ed. Washington: American Psychiatric Association, 2000. "Depression Caused by Chronic Illness." Web MD. July 2005. WebMD Inc.. 02 Apr. 2006 <http://www.webmd.com/content/article/45/1663_51215.htm>. "Neurotransmitter Animation." Depression Advances. 2006. Eli Lilly and Company. 05 Apr. 2006 <https://www.depressionadvances.com/animation/brainAnimations.html>.