Two principle types of affective disorder Major depression Unipolar disorder Bipolar disorder

1. Two principle types of affective disorder • Major depression • Unipolar disorder • Bipolar disorder • Sometimes referred to as manic-depressive disorder

2. Major Depression • We all have experienced the essential feelings associated with depression • Feel down and listless • Lack energy to do things • If the result of a life event such as death of a loved one, loss of job, or breakup of a relationship • Considered reactive depression • Does not constitute mental illness unless the symptoms last longer than normal or are abnormally intense • However, clinical depression is different from these normal reactions to life events.

3. Major Depression • In clinical depression the mood disorder is severe. • A more intense emotional reaction • Lasts longer • Individual withdraws from life and social interactions • Anhedonia • inability to experience pleasure in anything • Often stop eating, bathing, caring for themselves • May remain in bed for prolonged periods • suicidal thoughts and/or attempts • One estimate is that 7-15% of depressed individuals commit suicide • Compared to 1-1.5% of general population

5. Most episodes of unipolar depression will improve in 6-9 months. • However, the episodes usually recur throughout life • Increasing in frequency and intensity • Stress is often associated with the first episode of depression • Later episodes can occur in the absence of significant stressors

6. About 3-4% of men experience unipolar depression • About 5-9% of women • Mean onset of unipolar depression is about 27 years • Diagnosis of depression has been on the rise, and occurring earlier in life • Americans born before 1905 • 1% developed depression by age 75 • Americans born since 1955 • 6% developed depression by age 24

7. Bipolar disorder • Depressive and manic phases alternate. • We have already discussed depressive symptoms • The primary symptom of mania is elation • Sometimes they can be irritable, impatient, or belligerent • Their thoughts are and ideas are racing • Everyone else is so slow • Approximately 1% of the population is diagnosed with bipolar depression • No gender differences • Onset is between 20-30 years of age • Episodes continue throughout lifetime

9. Mental illness and creativity • A high proportion of creative individuals in the arts and sciences have experienced bipolar disorder • Some find the manic phases to be very productive times • Is creativity linked to mental illness?

10. Box 16.1 Mood Disorders and Creativity

11. Biological risk factors • Scientists agree that psychiatric disorders develop as a result of an interaction of genes and environmental events. • Role of heredity • Adoption studies • Twin studies • Linkage studies

12. Role of heredity • Adoption studies • Individuals diagnosed with an affective disorder who were adopted at an early age • If the disorder has a heritable component one would expect that the adopted individual would have more biological relatives with the same disorder, rather that being like the adopted family • Better evidence comes from twin studies • Compare the concordance rate for monozygotic (100% shared genes) to dizygotic (50% shared genes). • Dizygotic is sometimes also referred to as fraternal

13. Role of heredity • Overall (any mood disorder) concordance rate is 65% for identical and about 20% for fraternal. • Note that severe depression has a higher heritability effect than less severe depression. • Also note that the heritability effect for Bipolar disorder is very large. • 80% vs. 16% • Keep in mind that even fraternal twins are showing heritability effects • General population depression = about 5-6%  goes up to 20 some % • General population bipolar = about 1%  goes up to 16%

14. Role of heredity • Linkage studies look for similarities in gene location on chromosomes in families that have a history of a disorder • No single dominant gene for affective disorder is known

15. Role of stress • There is a lot of evidence that anxiety and depression are closely related • People diagnosed with depression are often experiencing anxiety • It has also been shown that intense environmental stress and anxiety often precede episodes of depression • Especially early in the disorder • Altered patterns of stress hormones are frequently found in depressed patients

16. Stress • Identical life stressors can be perceived very differently by individuals • Some cope well • Others succumb more easily • It is likely that genetics plays a role in how we respond physically and behaviorally to daily traumas and stress • Neuroscientists have focused on the hypothalamic-pituitary-adrenal (HPA) axis as an important area of the nervous system involved in stress response and etiology of depression

17. HPA axis • When we are stressed the hypothalamus releases CRF (corticotropin releasing factor). • This is in response to NTs such as NE, ACh, and GABA • CRF causes the anterior pituitary gland to release ACTH (adrenocorticotropic hormone) into the blood stream • ACTH causes the adrenal glands (atop the kidneys) to increase the release of cortisol as well as other glucocorticoids • These substances all play a role in the stress response • Sympathetic reaction. • Normally increasing cortisol levels feedback to the brain and the HPA to shut down.

18. 16.3 The HPA axis

19. HPA • One consistent finding in depressed individuals is abnormal secretion of cortisol. • Many depressed patients have elevated cortisol levels • This is the result of greater-than-normal release of ACTH

20. HPA • Depressed patients often have enlarged pituitary and adrenal glands • However, this enlargement is likely due to the increased activity that is asked of the glands, rather than the original abnormality • The hypersecretion is likely due to abnormal regulation of CRF by the hypothalamus • Studies have shown higher-than-normal CRF levels in the CSF (cerebrospinal fluid). • Also increased numbers of CRF-producing cells have been found in the hypothalamus • Postmortem • It has also been shown that antidepressant drugs and electroconvulsive therapy reduce CRF levels in depressed patients

21. Circadian secretion of cortisol • Another consistent finding in depressed patients is an abnormal circadian rhythm of cortisol secretion • Notice the higher than normal levels, but also flatter release function for depressed patients • May reflect a general abnormality in the biological clock • Disrupted sleep and temperature patterns are also common

22. Dextramethasone challenge • Depressed individuals also tend to fail to dextramethasone challenge. • Dextramethasone is a synthetic glucocorticoid • Should act as a negative-feedback stimulus • Suppress hypothalamic release of CRF • Suppress pituitary release of ACTH • Which should decrease cortisol levels • Depressed patients that don’t respond to dextramethasone challenge • more likely to relapse

23. Consequences of altered glucocorticoid levels • Normal release of glucocorticoids is useful in preparing an organism for stress • When the levels are persistently elevated several systems begin to show pathological changes • Damage to immune system • Disrupts organ function • neuronal atrophy in hippocampus • Leading to cognitive impairment • imbalances in the serotonin system • Correlated with anxiety • hormonal changes • Associated with depression

24. Altered biological rhythms • Not just cortisol • Altered sleep rhythms are very common in depression • Normal sleep cycle has 4 stages of non-REM sleep • lasting about 70-100 minutes • Followed by 10-15 minutes of REM sleep • You cycle through these stages 4 or 5 times per night

26. Depressed individuals have distinct abnormalities in their sleep rhythm • 1) long period before sleep onset • 2) significant decrease in time spent in slow-wave sleep • 3) onset of REM sleep occurs much earlier after onset of sleep finally begins • Can sometime occur immediately after falling asleep • 4) REM sleep is significantly increased during the first third of sleep. • 5) normally REM periods tend to increase as the night progresses, but depressed individuals do not show this pattern • 6) When ocular movement is measured depressed individuals show more frequent and vigorous eye movements. • Which suggests more intense dreaming.

27. 16.5 Altered sleep architecture in depression (Part 1)

28. 16.5 Altered sleep architecture in depression (Part 2)

29. These alterations in sleep patterns are similar to what happens when someone required to alter their sleep pattern by 12 hours • Sometimes circadian rhythms seem desynchronized • Sleep awake cycle • Temp cycle • Hormone cycle • Has led to novel treatment • Sleep deprivation therapy.

30. Box 16.2 Sleep Deprivation Therapy (Part 1)

31. Box 16.2 Sleep Deprivation Therapy (Part 2)

32. Animal models of depression • No perfect model • Animals don’t have feelings of worthlessness and guilt • Animals models can mimic certain aspects of depression • Reduction in motor activity • Changes in neuroendocrine response • Cognitive changes • Changes in eating and sleeping

33. Reserpine induced sedation • Reserpine blocks VMAT (vesicular monoamine transporter) • Causes DA and NE levels to drop to very low levels • Remember the reserpine rabbits (ch. 5). • Causes extreme sedation • Clinically viable antidepressants antagonize the effects of reserpine • so it is effective for testing monoamine based medications • Not useful for novel approaches that don’t involve the monoamine system

34. Behavioral despair or forced swim test • Rats become immobile after learning they cannot escape • Immobility is thought to reflect a lowered mood • Resigned to fate • Similar to learned helplessness • Depressed humans often express they feel hopeless and that nothing they do has an effect • Antidepressants reduce the amount of time spent freezing

35. Maternal separation • Induce stress at an early age by separating young rats from their mothers for brief periods of time during the first few weeks of life • This model has shown that early stress can alter corticotropin releasing factor function • May predispose individuals to clinical depression later in life • Known as the stress-diathesis model of depression • Stress (early stress experiences) • Diathesis (genetic predisposition)

36. Stress-diathesis model • They propose that the genetic character of depression is expressed by • lowered monoamine levels in the brain • increased reactivity of the HPA axis to stress • These factors create a lowered threshold for depression • Negative early life experiences may lower the threshold even further • Nemeroff et al. showed that maternal separation rats (during first 3 weeks of life) showed elevated stress responses later in life • Elevated ACTH and cortisol levels • Increased CRF in the brain • Increased CRF gene expression • Serotonin reuptake blockers reversed these effects • Not yet understood how 5-HT reuptake blockade modifies CRF activity

37. Therapies for affective disorders • There are several drug classes that are effective antidepressants • All treatment methods require chronic administration. • Significant change can occur in 1-3 weeks, but maximum effectiveness may not be achieved for 4-6 weeks • Suggests that the clinical effect must depend on compensatory changes that take time to develop

38. MAO-Is • Monoamine oxidase inhibitors • MAO-Is • Oldest antidepressants • Iproniazid used in 1950s to treat tuberculosis • It was noted that it had significant mood elevating effects • Can have severe and dangerous side effects • With appropriate dietary restrictions MAO-Is can be safe • Tend to work well with patients that don’t respond to other treatments and don’t want ECT • Also effective for anxiety and eating disorders (bulimia and anorexia nervosa). • Common MAO-Is • Phenelzine (Nardil) • tranylcypromine (Parnate) • Isocarboxazid (Marplan)

39. Mechanism of action for MAO-Is • Monoamine oxidase is an enzyme that breaks down monamines (NE, DA, and 5-HT) • Inhibition of MAO increases the amount of monamines for release into the synapse • It is likely receptor density changes, or changes in second messenger function that leads to relief • The NT changes would occur almost immediately • However complete effects can take weeks to develop

40. Side effects of MAO-Is • Hypertension • Insomnia • Overeating • MAO-Is inhibit MAO in the liver • MAO is responsible for deaminating tyramine • Tyramine is a by-product of fermentation in many foods • If these foods aren’t avoided than higher-than-normal NE levels can occur • Leading to dramatic increases in blood pressure • Headache, nausea, sweating, vomiting • Possible stroke • MAO-Is also inhibit other liver enzymes (cytochrome P-450) • Thus the effects of alcohol and other drugs can be intensified and prolonged.

42. Tricyclic antidepressants • Named because the drugs all have a characteristic three-ring structure • Imipramine is the prototypical tricyclic antidepressant • Originally developed as an antipsychotic it was not very effective, but found to have mood elevating effects

43. Tricyclic antidepressants: mechanism of action • Act by binding to the presynaptic transporter proteins. • Inhibit reuptake • Prolongs the duration of the NTs in the synapse • Eventually cause pre- and postsynaptic changes • Many tricyclics inhibit the reuptake of NE and 5-HT • Some are more effective at inhibiting one or the other • Doesn’t seem to influence the drugs effectiveness • Does determine side effects

44. Tricyclic antidepressants: side effects • Most TCAs also block choline, histamine, and α-adrenergic receptors • Which influences side effects • Histamine receptor blockade can cause sedation and fatigue • Cholinergic receptor blockade can cause drymouth, constipation, urinary retention, dizziness, confusion, blurred vision, and impaired memory • α-adrenergic receptor blockade along with increased synaptic NE can lead to hypotension, tachycardia, and arrhythmia • Particularly problematic for elderly patients with cardiac disorders • Low therapeutic index • 10 times the normal dose can cause fatalities • Particularly problematic given that these drugs are being supplied to patients that are potentially suicidal

45. Second-generation antidepressants • These drugs are an attempt to provide faster onset of action with fewer side effects. • They were designed to more selective in their action. • Avoiding anticholinergic and cardiovascular effects of previous drugs • Turns out that none of the drugs are more effective nor do they have a faster onset • The biggest difference is the nature of their side effects

46. Selective serotonin reuptake inhibitors (SSRIs) • Drugs in this class include • Fluoxetine (Prozac) • Sertraline (Zoloft) • Paroxetine (Paxil) • They are useful to treat depression but have also been used to treat anxiety disorders, obesity, and alcoholism • The SSRIs are safer than other antidepressants • The SSRIs are more selective than TCAs in enhancing serotonin function. • Block 5-HT transporter more than noradrenergic transporter • Takes several weeks to see full effects

47. Side effects of SSRIs • Do not affect NE, ACh, or histamine • Thus SSRIs do not produce sedation, cardiovascular toxicity, or anticholinergic side effects • However there are side effects related to the increased serotonin activity • Anxiety • Restlessness • Movement disorders • Muscle rigidity • Nausea • Headache • Insomnia • Sexual dysfunction (occurs in 40-70% of patients) • A major reason that patients terminate treatment • Especially young males

48. Side effects of SSRIs • SSRIs are generally safer than than TCAs and MAOIs • Can have life-threatening effects when combined with other serotonergic agonists, or drugs that interfere with the metabolism of SSRIs • Referred to as serotonin syndrome • Severe agitation • Disorientation and confusion • Ataxia • Muscle spasms • Exaggerated autonomic activity • Fever • Shivering • Chills • Diarrhea • Hypertension • Increased heart rate

49. SSRIs and dependence • Also can cause physical dependence • About 60% of patients experience withdrawal when treatment is terminated • Can last for several weeks • Dizziness • Ataxia • Nausea • Vomiting • Diarrhea • Fatigue • Chills sensory disturbances • Insomnia • Vivid dreams • Anxiety • Irritability

50. Third generation antidepressants • The newer versions of antidepressants have returned to affecting both the NE and 5-HT system • Mirtzapine (remeron) • Causes increased release of NE and 5-HT at the synapse • There are also SNRIs (serotonin norepinephrine reuptake inhibitors) • Duloxetine (cymbalta) • Venlafaxine (Effexor) • Third generation antidepressants resemble tricyclics but with fewer side effects