INTRODUCTIONINTRODUCTION

• Depression afflicts approximately 5% of the population, 1-2% with bipolar disorder.

• Suicide from depression is 25-30% of depressed population.

• Depression 2-3 X higher in women.

• 70% of patients have response to drugs.

• There is major depression and secondary mood disorders

““BREAKING OUT OF THE BREAKING OUT OF THE BOX”BOX”

• Results from a recent national survey

• Myths– 54% believe depression is a weakness not an illness.

– 62% believe depression is not a health problem.

– >50% believe depression is “normal” and will not seek treatment.

MAJOR DEPRESSIVE DISORDERMAJOR DEPRESSIVE DISORDER

Genetic factors influence risk of illness and sensitivity to environmental factorsA family history of depression is a risk factor for

developing depression

Neural circuits implicated:limbic structures: cingulate cortex, hippocampus,

anterior thalamusreward structures: nucleus accumbens, amygdala,

ventral tegmentum, prefrontal cortexhypothalamus and anterior temporal cortex

Depression: a multifactorial brain disorder

• Symptoms reflect abnormal functioning in many parts of the brain:– sleep disturbances to brainstem and hypothalamus

– appetite and energy to various hypothalamic areas

– anhedonia or mania to limbic structures

– anxiety to amygdala

– alterations in thought content to cortex

• Abnormal overactivation of the HPA in half of those with major depression: likely also a hypersecretion of CRF with increased CRF in CSF.

• Long-term exposure to glucocorticoids can damage hippocampal neurons and suppress new neurons postnatally

CLINICAL SYMPTOMS OF CLINICAL SYMPTOMS OF DEPRESSIONDEPRESSION

• loss of pleasure (anhedonia)

• loss of energy• social withdrawal

psychomotor retardation or agitation

• insomnia• loss of appetite• decreased hygiene

• crying spells• difficulty concentrating• indecisiveness• sad thoughts/thoughts

of suicide• hopelessness• helplessness• guilt/shame

BIOLOGY OF DEPRESSIONBIOLOGY OF DEPRESSION

• the “amine hypothesis” based on pharmacological studies stated depression resulted from a lack of biogenic amines (eg. -methyl-p-tyrosine; reserpine; antidepressants themselves).

• current theory favors the notion of a dysregulation of both NE and 5-HT leading to alterations in NE and 5-HT receptors.

• antidepressants re-regulate receptor sensitivity.

• drug-induced re-regulation of the receptors takes weeks (downregulation of some).

The Five Steps of Neurotransmission—Sites of Drug Action

SEROTONIN-A KEY PLAYERSEROTONIN-A KEY PLAYER Serotonin has widespread distribution and density of innervation in

CNS (mood, memory, pleasure, aggression, hypothalamic control)

Alterations of serotonin in depressed drug-free patients: The reduction point of view

decreased 5-HT levels in CSF increased amounts of 5-HT2 receptors in brain and platelets reduced levels of plasma tryptophan blunted neuroendocrine responses to the serotonin releasing drug

fenfluramine efficacy of SSRI’s in treating depression loss of SSRI efficacy with tryptophan depletion Increased presynaptic alpha-2 noradrenergic receptor

sensitivity=greater reduction in 5-HT release

SEROTONIN--A KEY PLAYERSEROTONIN--A KEY PLAYER

The overactive point of view

In some depressives CSF 5-HT is elevatedApprox. 30% of depressed patients do not respond to SSRIsDepletion of 5-HT by inhibition of tryptophan hydroxylase

(TH) alleviates depressive symptoms in some patientsTianeptine, a 5-HT reuptake enhancer that works opposite

to SSRIs, is a marketed antidepressantA selective TH inhibitor shows activity in an animal model of

depressionThe activation of TH by stress can be blocked by Prozac

MAJOR ANTIDEPRESSANT MAJOR ANTIDEPRESSANT DRUG CLASSESDRUG CLASSES

• tricyclics

• SSRI’s

• SNRI’s

• MAOI’s

• other cyclics

PHARMACOLOGYPHARMACOLOGY

• ALL tricyclics block the reuptake of both NE and 5-HT.

• SSRI’s block 5-HT reuptake.

• SNRI’s block NE reuptake.

• other cyclics have mixed effects on NE and 5-HT reuptake.

• MAOI’s prevent metabolism of the neurotransmitters (elevation of synaptic levels).

REGULATION OF SEROTONIN REGULATION OF SEROTONIN NEUROTRANSMISSIONNEUROTRANSMISSION

POSSIBLE MECHANISMSPOSSIBLE MECHANISMS

• All antidepressants downregulate -adrenergic receptors; -2 receptors and presynaptic 5-HT-1a/b

• Antidepressants decrease number of amine transporters• Long-term treatment with SSRI causes 6-fold increase in 5-HT

release• Postsynaptic 5-HT-1a receptor does not desensitize in some brain

structures (eg. Hippocampus)• Antidepressants increase formation of new synapses by increasing

BDNF (BDNF increases 5-HT fiber sprouting)• In raphe nucleus SSRIs first decrease firing but over weeks

increase firing with an increase in 5-HT release• Increase response to 5-HT in prefrontal cortex

.

CLINICAL PHARMACOLOGY OF CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTSANTIDEPRESSANTS

• Indications: depression, panic and phobias, OCD, enuresis, anorexia nervosa, bulimia

• Drug Choice: past response, tolerance to side effects, drug-drug interactions

• Treatment: 1-6 months; recent report suggests changing if no improvement by 4 weeks

• Note: All antidepressants now carry a “black box” warning that they may lead to suicidal thoughts/behavior

SIDE EFFECTS OF TCA’sSIDE EFFECTS OF TCA’s

• antimuscarinic effects• postural hypotension• tachycardia, arrhythmias• sedation• weight gain• jittery feeling• sexual dysfunction (ejaculatory)

TCA TOXICITIESTCA TOXICITIES

• a commonly used drug for suicide (less common with increased use of SSRIs)

• lowers threshold for convulsions

• cardiac arrhythmias

• cardiac conduction defects

SIDE EFFECTS OF SSRI’sSIDE EFFECTS OF SSRI’s

• nausea, GI disturbances• headache• nervousness• insomnia• some sedation• anorgasmia/impotence• possible fatal interaction with MAOI’s

SEROTONIN SYNDROMESEROTONIN SYNDROME

• A potentially fatal interaction when SSRI’s and MAOI’s are combined

• Symptoms: • autonomic instability (labile HR/BP)• hyperthermia• rigidity and myoclonus• confusion,delirium• seizures• coma

SIDE EFFECTS OF MAOI’sSIDE EFFECTS OF MAOI’s

• “Wine-cheese” interaction• antimuscarinic effects—but unusual compared to

TCAs• sedation• irritability/insomnia• weight gain• anorgasmia/impotence• postural hypotension

““WINE-CHEESE EFFECT”WINE-CHEESE EFFECT”

• MAOI’s enhance any indirectly acting sympathomimetic.

• tyramine in certain foods is not metabolized in presence of MAOI and potentiates catecholamine release.

• ingredients in OTC cold preps can also lead to markedly enhanced sympathomimetic effects.

SYMPTOMS OF MANIASYMPTOMS OF MANIA

• increased energy (buying, phoning, sex)

• increased gregariousness

• pressured speech, talkativeness

• decreased sleep• drunkenness• combative, dangerous

behavior

• distractibility• racing thoughts• impulsive actions and

decisions• elevated mood• euphoria• grandiosity• irritability/hostility

(easily angered)

MANIA—too much neurotransmission?

Increased production of inositol phosphate (IP-3) which increases intracellular Ca2+ signalling

Increased DAG which:

activates PKC which phosphorylates a number of substrates including myristoylated alanine rich C kinase (MARCK)

MARCK activates nuclear transcription factors and modulates genes that increase neuromodulatory peptide hormones and alters cell signalling which:

changes neurotransmitter synthesisneuronal excitabiltiysynaptic plasticityneuronal cell loss (prefrontal cortex?)

LITHIUMLITHIUM

• a monovalent ion that can enter neurons but is not readily removed.

• major mechanism is the reduction of neuronal PI second messenger resulting in reduced response of neurons to ACh and NE

• may actually enhance 5-HT

CLINICAL PHARMACOLOGYCLINICAL PHARMACOLOGY

• primary therapy for mania

• a narrow therapeutic window (0.8-1.2 meq/L; some guides say 0.6-1.4 meq/L)

• absolutely necessary to monitor serum level (trough level approx. 5 days after initial dose)

• solely eliminated by kidney, therefore assess patient’s kidney function

ADVERSE EFFECTSADVERSE EFFECTS

• tremor• decreased thyroid function• polydipsia/polyuria• edema• ECG changes (depression of T-wave)• excreted in breast milk

Other MedicationsOther Medications

• Anticonvulsants: carbamazepine and valproic acid for rapid cyclers

• Olanzepine approved for treatment of mania

• St. John’s Wort: questionable efficacy, but high potential for drug-drug interactions

STRESS & ANTIDEPRESSANTS

Limbic hypothalamic-pituitary-adrenal axis [LHPA] regulates arousal, sleep, appetite, capacity to experience & enjoy pleasure, and mood

In depression the LHPA is overactive--an effect mediated by neurotransmitters

Adrenal glucocorticoids and mineralcorticoids interact with 5-HT receptors in brain during conditions of chronic stress

Corticoid receptor function is impaired in MDD patients

TREATING DEPRESSION

Interpersonal and cognitive therapy are effective

Pharmacotherapy plays important role, but still a high incidence of non-responders

Shortcomings in developing new ADhigh rate of response to placebosinadequate duration of treatmentoutcome measures too insensitive to

measure differences between active and inactive treatments

STRESS & ANTIDEPRESSANTS

TCA’s can prevent overactivity of the LHPA caused by chronic unpredictable stress

TCA’s reverse stress-induced downregulation of 5-HT-1A in hippocampus and upregulation of 5-HT-2A in cortex

SSRIs do not prevent stress-induced elevation of activity in LHPA

This could explain why some patients with severe depression exhibit “treatment resistance

STRESS & ANTIDEPRESSANTS Mineralcorticoid & glucocorticoid receptors are lower in

hippocampus and prefrontal cortex in suicide victims with a history of depression

Hypercortisolemia may damage hippocampal (HPC) neurons postmortems of depressed patients finds smaller left HPC volume suicide victims with history of depression also have fewer 5-HT-1As

in HPC

5-HT-1A & 2A receptors are associated with the neurobiology of mood PET imaging studies find widespread reductions in 5-HT-1A

receptors

Antidepressants (AD) upregulate (sensitize) 5-HT-1A receptors in hippocampus but down-regulate 5-HT2A’s elsewhere.

STRESS & ANTIDEPRESSANTS

Patients with melancholia, a severe form of depression, tend to have high cortisol levels and are more effectively treated with TCAs than SSRIs

Patients with major depression, and resistant to AD treatments, have been reported to improve after receiving steroid suppression agents (eg. Ketoconazole)

CRF receptor antagonists which decrease the release of steroids are being developed as AD

DEPRESSION: UNANSWERED QUESTIONS

What are the suspectibility genes and their environmental modifiers?

What are the pathophysiologies of the neural systems underlying this complex disorder?

How do we understand the therapeutic mechanisms underlying the currently available pharmacological and ECT approaches?

How do we improve our success rate in treating MDD?

PHARMACOGENOMICS

Pharmacogenomics: genetic differences that relate to medication response differenceslong (L) form and short (S) form

polymorphisms for 5-HT transporter gene promotor site have been found

the “L” form is associated with more transporter being expressed

the “S” form is associated with greater psychopathology

PHARMACOGENOMICS--CONT’D

102 patients homozygous for short (S/S) allele demonstrate a worse antidepressant response to fluxoamine than those with L?S or L/L

51 patients with homozygous L/L allele improve with Prozac in sooner than those with L/S or S/S

Allelic variations in 5-HT-1A or -2 receptors suspected of role in efficacy of antidepressant medications

SEROTONIN-A KEY PLAYERSEROTONIN-A KEY PLAYER

Efficacy of SSRI’s in treating depression

Loss of SSRI efficacy with tryptophan depletion