Affective%20Disorders

1
Affective Disorders
2
Depression

• found throughout history
• unipolar or major depression
• bipolar or manic depression

3
Symptoms of depression

• must be evident daily or almost every day for at
  least 2 weeks
• often comorbid with anxiety

4
Depression

• Depression
• over 10 with 5 (11,000,000) suffering from a
  depressive episode in any given year
• untreated - 25 - 30 will attempt or commit
  suicide
• 2X greater prevalence in women than men
• estimated only 50 receive specific treatment
• increased rate of and suicide attempts

5
(No Transcript)
6
How do we treat depression?

• Pharmacologically
• drugs have been available for 40 years

7
Pharmacological Txt for Depression

• antidepressants typically require 10 30 days to
  start working full effect may take 6 weeks and
  in many cases improvement can continue over
  several months
• what takes so long?
• 2 lines of thought
• role of upregulation and downregulation of
  receptors
• effects on intracellular processes such as 2nd
  messengers and their functions in the neuron

8
one result of activation of 2nd messenger system

• an intracellular target of 2nd messenger system
  is called cAMP response element binding protein
  (or cREB)
• CREB increases in the hippocampus with chronic
  antidepressant medication

9
What does CREB do?

• cREB activates genes that control the production
  of BDNF a neurotrophin
• neurotrophins promote neural health, growth, etc

10
neurogenic theory of depression

• two of the functions of 2nd messengers is
• 1)protect neurons from damage due to injury or
  damage
• 2) promote and maintain health and stability of
  newly formed neurons

11
(No Transcript)
12
(No Transcript)
13
So how do we treat depression?

• Pharmacologically
• drugs have been available for 40 years
• Traditional Antidepressants
• 1. tricyclic antidepressants

14
Tricyclic antidepressants

• Blocks reuptake of NE and 5HT
• blocks histamine receptors
• block ACh receptors
• widely used
• fairly significant side effects
• mainly because they block ACh receptors
• blurred vision, dry mouth, urinary retention,
  irregular heart rate, constipation, sexual
  dysfunction,
• effects on other NT
• sedation, weight gain

15

• tricyclics estimated to be effective in 60 -
  70 of moderately to severely depressed
  individuals

16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
So how do we treat depression?

• Pharmacologically
• drugs have been available for 40 years
• Traditional Antidepressants
• 1. tricyclic antidepressants
• 2. MAO inhibitors- MAO
• - enzyme that breaks down excess DA, NE, 5HT

20
MAO inhibitors (irreversible)

• phenelzine (Nardil)
• Isocarboxazid (Marplan)
• tranylcypromine (Parnate)
• 2003 nonselective MAOI selegiline (Eldapril)
• transdermal skin patch

21
MAO inhibitors

• mechanism of action
• reversible inhibitors of MAO A NE/5HT
• moclobemide (Aurorix) not in U.S. not
  particularly effective
• MAO B inhibitors - DA
• selegiline (Deprenyl- used at low doses for PD)

22

• proved as effective (if not more so) than
  traditional tricyclics or SSRIs particuarly for
  unresponsive depression
• not used as first level txt due to risk (or
  perceived risk) of adverse side effects

23
Limitations of MAO inhibitors

• Alters the metabolism of amino acid tyramine

24
Limitations of MAO inhibitors

• Alters the metabolism of amino acid tyramine
• foods high in tyramine include aged cheeses,
  wine, smoked fish, yeast products

25
Limitations of MAO inhibitors

• Alters the metabolism of amino acid tyramine
• foods high in tyramine include aged cheeses,
  wine, smoked fish, yeast products
• consumption of these can result in a hypertensive
  crisis
• severe headaches, heart palpitations. Flushing,
  nausea, vomiting, stroke

26
Limitations of MAO inhibitors

• Alters the metabolism of amino acid tyramine
• foods high in tyramine include aged cheeses,
  wine, smoked fish, yeast products
• consumption of these can result in a hypertensive
  crisis
• severe headaches, heart palpitations. Flushing,
  nausea, vomiting, stroke
• very long 1/2 life (2 weeks)

27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30
2nd generation antidepressants

• from late 1970s - mid 1980s- looked for agents
  that could overcome some of the of TCA
• slow onset, limited efficacy, side effect
  profile,etc
• amoxapine (Asendin)
• primarily SNRI (but also blocks DA)
• Trazodone (Desyrel)
• doesnt block NE or 5HT
• less anti ACh quicker action?
• 5HT agonist (5HT2)

31

• Buproprion (Wellbutrin, Zyban)
• antidepressant, anticraving (for nicotine
  dependence)
• antidepressant effect much like the SSRIs but
  with less nausea, diarrhea, somnolence and sexual
  dysfunction
• selectively inhibits DA, NE reuptake

32
SSRIs

• Fluoxetine (Prozac) - first introduced in US in
  1988
• SSRIs have a more favorable side effect profile
  than earlier antidepressants
• relatively safe (esp in OD situations)
• some controversy...

33
SSRIs

• 6 SSRIs
• fluoxetine (Prozac)
• paroxetine (Paxil)
• sertraline (Zoloft)
• fluvoxamine (Luvox)
• citalopram (Celexa)
• escitalopram (Lexapro)

34
How do SSRIs work?

• Block reuptake of 5HT
• selective serotonin reuptake inhibitor
• single action antidepressant

35
(No Transcript)
36
5HT withdrawal syndrome

• occurs in 60 of people who discontinue
  experience withdrawal
• onset usually within a few days and persists for
  3 4 weeks (fluoxetine even longer due to its ½
  life)

37
Symptoms of withdrawal

• disequilibriam (dizziness, vertigo, ataxia)
• GI distress
• Flulike symptoms (fatigue, lethargy, chills)
• sensory disturbances
• sleep disturbances

38
5HT syndrome

• most often seen when individual takes 2 or more
  drugs that increase 5HT activity
• ex. SSRIs, MAOIs, TCA
• incidence rare
• more than 80 resolve
• no specific criterion for diagnosis
• can be mild or potentially lethal

39
(No Transcript)
40
dual action antidepressants

• may be more effective at treating somatic
  symptoms associated with depression
• ex. pain
• older tca with dual actions
• new antidepressants with dual actions

41
Examples of dual-action antidepressants

• Nefazodone (Serzone)
• strongest pharmacological action is 5HT2 blockade
• also inhibits reuptake of NE and 5HT
• black box warning liver failure

42
StarD study

• sequenced treatment alternatives to relieve
  depression

43
Current problems that still exist with
pharmacotherapy of depression

• Some patients do not respond well to first
  treatment
• most take 3 - 4 weeks to exert significant
  therapeutic effects

44
Some current issues
45
Bipolar disorder

• Incidence 1
• population-based epidemiologic studies found
  age-corrected lifetime risks ranging from 0.3
  percent to 1.5 percent, with risks to men and
  women in 10 countries as divergent as Lebanon and
  Korea.
• Less favorable profile than for depressive
  disorders
• Most come to the attention of docs
• Age of onset
• Wide range with average 30

46

• Bipolar disorder patients have a relatively high
  rate of nonadherence to pharmacotherapy,
  estimated at 3245 of treated patients (Rothbaum
  Astin, 2000).
• Approximately 25-50 of individuals with bipolar
  attempt suicide, and 11 actually commit suicide.
  

47
Heritability of Bipolar I

• 50 percent bipolar I disorder patients have at
  least one parent with a mood disorder, most often
  major depressive disorder.
• mode of inheritance - complex and likely involves
  multiple interacting genes.
• If one parent has bipolar I disorder, 25 percent
  chance that a mood disorder
• if both parents have bipolar I disorder, there is
  a 50 to 75 percent chance that their child has a
  mood disorder.

48
Encephalitis lethargica
49
drugs that can produce manic states

• amphetamine
• cocaine
• corticosteroids
• hallucinogens
• l-dopa
• pcp
• methylphenidate

50
What is the aim for drugs for treating bipolar

• stabilize acute mania, mixed and depressive
  symptoms
• dont induce mood alterations
• prevent future relapses

51
Pharmacotherapy for Bipolar

• Until the last 10 15 years lithium only
  approved drug for treating bipolar
• now number of drugs referred to as Mood
  stabilizers

52
Treatments for Bipolar

• Lithium
• Anticonvulsants
• Atypical antipsychotics

53
Lithium History

• Lithium (Duralith, Eskalith, Lithobid)
• Metal isolated in 1818
• Introduced into medicine in 1840 for txt of
  bladder stones and gout
• lithium bromide - 1873- used to treat manic
  episodes although thought was that bromide was
  active ingredient
• 1886 - prophylactic and short term effects of
  lithium for txt depression
• Late 1880's - early 1900's - general public so
  enthusiastic endorsing taking of waters

54

• 1940's - lithium chloride used as replacement
  for NaCl
• 1949 - lithium caused lethargy when injected in
  animals -
• 1950's - 1960's - did FDA trials demonstrating
  short-term prophylactic efficacy of lithium for
  bipolar 1 disorder
• 1970's - reintroduced to treat mania
• 2003 - Evidence suggests that lithium, unlike any
  other mood stabilizer, may have a specific
  antisuicide effect

55
Lithium

• pharmacokinetics
• kidneys excrete 95
• sweat 4-5
• pharmacodynamics
• good question!!!!!
• modulation of the levels of several genes maybe?

56

• ethnic differences
• AA with similar plasma levels as Caucasians had
  on average 60 higher intracellular levels
• many AA respond better with lower plasma Li
  levels and lower side effects
• does not produce dependence or withdrawal
• Frequency of bipolar relapses in 2 years
• In 20 40 of patients on lithium
• In 65 90 of patients without lithium
• Suicidal attempts rose 22-fold, and fatalities
  increased 14-fold, within the first year after
  discontinuing the lithium.

57
Side effect profile for Li

• Side Effects
• Gastric distress nausea, decreased appetite,
  vomiting, diarrhea
• Weight gain - poorly understood effect of lithium
  on carbohydrate metabolism
• (in long-term therapy 30 become obese)
• tremor - recognized in 4th edition of DSM IV -
  usually noticed in hands and fingers
• cognitive effects , - dysphoria, lack of
  spontaneity, slowed reaction times, impaired
  memory
• potential teratogenicity

58

• renal polyuria with 2ndary polydipsia -
  urinary output can be up to 3 liters/day (for
  most of us it is 1 - 2) due to antagonism of
  ADH Most serious renal adverse effects - renal
  failure
• thyroid effects - causes generally benign and
  often transient dimunition in concentrations of
  circulating thyroid hormones
• cardiac - can result in sinus dysrhythmias
• dermatological effects - various kinds of acne,
  possible worsening of psoriasis risk of
  tetracycline alopecia-
• lithium toxicity and overdose
• antipsychotics TI 100 TCAs/MAOI TI 10
• Lithium 3

59
What are the signs of lithium toxicity?

• Doses are adjusted to achieve plasma
  concentrations of 0.6 to 1.2 mM Li (lower end of
  the range for maintenance therapy and elderly
  patients) on samples taken 12 hours after the
  preceding dose.
• Overdosage - usually with plasma concentrations
  over 1.5 to 1.8mM Li
• keep in mind individual differences
• Symptoms Shaking and trembling, confusion,
  slurred speech, nausea and vomiting, diarrhea,
  abdominal pain, unsteadiness on the feet, coma,
  seizures

60

• At plasma levels of 1.5 to 2.0 mEq/l - most
  reactions involve GI tract with nausea, vomiting,
  diarrhea and abdominal pain
• Neurological side effects commonly seen at this
  dose include slight tremor, lethargy, impaired
  concentration, dizziness, slurred speech, ataxia,
  muscle weakness and nystagmus
• once get above 2.0 mEq/l - more severe side
  effects
• above 2.5 mEq/l - can cause stupor, coma, renal
  failure, cardiac arrythmias and death

61
Treatment for Li toxicity

• no antidote to lithium usually add sodium
  containing fluids immediately if toxic signs are
  severe, may use hemodialysis, gastric lavage,
  diuretic, antiepileptic, etc

62
maintainance therapy

• - although li prevents manic and depressive
  episodes lt 50 achieve complete relief
• Recommendations
• maintain bipolar patient on Li for 9 12 months
  after manic episode

63
anticonvulsants

• introduced in 1990s to treat bipolar
• possible mechanism?
• Kindling - electrophysiological process in which
  repeated sub-threshold stimulation of a neuron
  eventually generates an action potential
• kindling in temporal lobes?
• carbamazepine reduces kindling (in animal models)

64
anticonvulsants that have been used or are being
considered to treat bipolar

• carbamazepine (Tegretol), divalproex (Depakote),
  gabapentin (Neurontin) and lamotrigine
  (Lamictal), valproic acid (Depakene)

65

• valproate (Depakote) approved in 1995
• also reduces kindling, has anticonvulsant effects
  and GABAergic effects
• Most serious side - liver toxicity and failure
• Persons taking more than one type of
  anticonvulsant seem to be at higher risk.
• Most common side effects with valproic acid
  therapy are nausea, vomiting and indigestion
  abdominal pain, constipation or diarrhea
• Both loss of appetite with weight loss and
  appetite stimulation with weight gain have been
  reported.

66
carbemazepine

• carbamazepine (Tegretol)
• altered effectiveness of birth control pills
• rarer side effects - clumsiness, double vision,
  edema (excess of fluid in tissue or body cavity),
  skin rash, and cardiovascular complications.

67
carbemazepines onset of action

• lt 1 day seizures
• 6 12 days mania
• gt 30 days aggression not caused by mania
• full effect
• within hours for epilepsy
• 2 weeks for mania
• 2 3 weeks for depression

68
Potential interactions for carbemazepine

• grapefruit juice, influenza vaccine, isoniazid
  (treats tb), cimetidine (heartburn), erythromycin
  (antibiotics), and phenelzine (MAOI) increase
  plasma levels
• Phenytoin (anticonvulsant), alprazolam,
  clonazepam, primidone (anticonvulsant), and
  phenobarbital decrease both CBZ level and levels
  of interacting agents
• fluoxetine increases levels
• decreases levels of imipramine, phenothiazines,
  haloperidol, theophylline, thyroid hormones,
  ritonavir, saquinavir, contraceptives,
  risperidone, thiothixene, cyclosporine,
  corticosteroids, doxycycline, trazodone, doxepin,
  and amitriptyline
• can reduce its own level by "autoinduction"
  coadministration with lithium increases toxicity
  of both CBZ and the interacting agents
• coadministration with clozapine further increases
  bone marrow toxicity and resulting
  agranulocytosis

69
Atypical antipsychotics

• risperidone (Risperdal) more antidepressant
  than antimanic
• clozapine may be more antimanic than
  antidepressant
• olanzapine (Zyprexa) useful for both acute
  mania and (now available in combination with
  fluoxetine) as Symbyax
• quetiapine (Seroquel)
• ziprasidone (Geodon)
• aripiprazole (Abilify)

70
(No Transcript)
71
(No Transcript)