Set-2

The 5-HT Theory of Depression

-5-HT neurotransmission is involved in the regulation of:Eating, Sleep, Mood & Limbic system activity -Therefore decreased 5-HT levels in brain areas that regulate mood are responsible for clinical depression

Physiological Effects of Anxiety

-Autonomic system = sympathetic activation Behavior = fear, fight or flight -Endocrine - direct activation lot of these effects are related to the adrenal glands via activation of the adrenal cortex via the HPA axis, and by activation of the adrenal medulla by sympathetic innervation -Cardiovascular = increased HR, palpitations; GI = increased motility -Immune system is inhibited by cortisol secretion

"Atypical' Antidepressants:

-ECT,Light therapy, Meditation, A "real job"

GABA

-GABA is the most prevalent inhibitory neurotransmitter -GABAergic neurotransmission is inhibitory to the NE, DA, 5-HT, and cholinergic systems

TCA and Other Noradrenergic Reuptake Inhibitors: Cellular Effects

-Autoreceptor (a2) activation reduces amount of NE made by decreasing TH levels (via decreased cAMP activity)

SNRIs

-Block both serotonin and norepinephrine reuptake -Overall effect is to increase 5-HT and NE in synaptic terminals and increase receptor activation. However, main effectiveness is seen after receptor adaptations

MOA for treating drug-resistant depression:

-Causes 'burst' of glutamate release in the prefrontal cortex. this thought to be due to blockade of GABA-ergic signaling -Increased PFC glutamate stimulates synapse formation

Suspected Serotonergic Anomalies in Depression are

-Decreased 5-HT neurotransmission in the dorsolateral prefrontal cortex -Increased 5-HT activity in the amygdala and ventral prefrontal cortex -Inefficient serotonergic control of circadian rhythms

Other adaptive changes to tricyclic antidepressants are thought to include

-Decreases in GABA-B receptor levels -Decreases in NMDA receptor levels -Normalization of glucocorticoid release and glucocorticoid sensitivity

The HPA Axis in Depression

-HPA axis function is upregulated in during derpression -Normal functions of HPA negative feedback loops are disrupted -Adrenal hypertrophy can occur. this indicates that cortisol is being overproduced -Thymus hypotrophy can occur

Physiological effects of Epinephrine and Norepinephrine

-Increased rate and force of contraction of the heart muscle -Constriction of blood vessels -Dilation of bronchioles Stimulation of lipolysis in fat cells -Increased metabolic rate Dilation of the pupils -Inhibition of certain "non-essential" processes

Tricyclic Antidepressant MOA N.B; Alpha-1 receptor activation is coupled to Gq (increase in inositol phosphate, DAG, etc...)

-Long-term tricyclic antidepressants use ultimately results in adaptation to the drug such that... -The initial blockade of NE reuptake by tricyclic agents initiates a series of neuronal alterations -Over weeks, a-1 adrenergic receptors become more sensitive to NE stimulation. This is (obviously) a receptor responsiveness adaptation -Over time, both NE and 5-HT neurotransmission are thought to increase due to the effects of tricyclics

Main Classes of Antidepressants

-Monoamine oxidase inhibitors (MAOIs) -Tricyclic antidepressants (TCAs) -Selective serotonin re-uptake inhibitors -Mixed serotonin/norepinephrine reputake inhibitors -Norepinephrine/dopamine reuptake inhibitors (NDRIs) -Noradrenergic and specific serotonergic antidepressants (NaSSa) -Serotonin 2A antagonists/Serotonin reuptake inhibitors (SARI) -Atypical antidepressants

Serotonin and Norepinephrine Reuptake Inhibitors

-More selectively block 5-HT and NE re-uptake than TCAs -Different SNRIs have different abilities to block 5-HT and/or NE reuptake S -Effexor is an example of an SNRI

Atypical antidepressants

-Nefazadone -Bupropion -Buspar

Circadian Rhythms in Depression

-Neurally-controlled circadian rhythmicity is often dysfunctional in depressed patients -There is a major 5-HT pathway from the raphe nuclei to the SCN that may be dysfunctional during depression -Circadian rhythms appear shortened during depressive episodes

TCA Mechanism of Action Prevents reuptake by blocking transporters on the presynaptic neuron Selectivity ratio - for instance desipramine relatively NE-selective, chlorimipramine relatively 5-HT selective Onset of action is delayed because effectiveness is possibly due to down regulation of presynaptic 5-HT and/or alpha2 receptors, which leads to compensatory effects that are thought to be the reason these drugs work (ie increases in NE and 5HT release and alterations in gene transcription, etc)

-Prevent reuptake of norepinephrine and 5-HT -Selectivity ratio varies widely -Onset of action is delayed for 7-14 days

Ketamine as an Antidepressant

-Relatively safe drug typically used for anesthesia. Also a drug of abuse -Is an NMDA receptor antagonist-Ligand gated ion channel gates for cations -Also used to treat chronic pain-NMDA receptor activation involved in spinal cord, brain pain signaling -Treatments are two-hour i.v. sessions. Up to six treatments are all that are required

Selective Serotonin Reuptake Inhibitors (SSRI's) Mechanism of Action

-Selectively inhibit reuptake of 5-HT -Induce compensatory changes in the 5-HT NT system, including desensitization of autoreceptors -Induce compensatory changes in gene transcription -Compensatory changes in gene transcription include alterations in BDNF, trkB, CREB which most likely lead to therapeutic effects

Serotonin's Role in Anxiety Areas where 5-HT sends projections: Hypothalamus, cortex, etc...

-Serotonergic neurons send projections to areas known to modulate anxiety reactions -Serotonin plays a key role in depression - increased anxiety is often associated with depression Serotonin plays a modulatory role on the actions of other transmitters/hormones such as NE and CRF

5-HT1a Receptor Agonists; Buspirone Stimulation of the 5-HT1a receptor by serotonin causes decreased firing of the neurons. Over time (weeks), these receptors become desensitized to 5-HT1a agonists. Knockout mice missing the 5-HT1a receptor show anxiety-like effects.

-The 5-HT1a receptor is located on 5-HT neurons in the midbrain dorsal raphe and elsewhere in the brain Can be both presynaptic (autoreceptor) and postsynaptic Coupled to Gi and... Activation results in the opening of an inwardly rectifying K+ conductance, causing neuronal hyperpolarization

The greater the enhancement of 5-HT neurotransmission via antidepressants

-The better the clinical results -i.e agents that selectively increase NE neural transmission are often effective in treating depression

5-HT2a Receptor Antagonists Neocortex = complex thought processing N.B; the mechanism of action resulting in anti-anxiety and anti-depressant effects are complicated

-Trazadone and nefazdone are examples 5-HT2a receptors are located in the neocortex -Found post-synaptically -GPCR coupled to Gq, so... -Binding of 5-HT2a antagonists to the 5-HT2a receptor blocks activation of the phospholipase C second messenger system -In addition to antagonizing 5-HT2a receptors, trazadone and nefazodone inhibit reuptake of serotonin

Tricyclic Antidepressants

-Tricyclic antidepressant agents inhibit norepinephrine reuptake -Also usually inhibit serotonin reuptake to some degree -Do not block DA transport/reuptake -Some antagonistic action on alpha-adrenergic receptors (results in 'side effect' of sedation) -Also have anti- histamine and muscarinic effects

Noradrenergic and Specific Serotonin Reuptake Antidepressants (NaSSAs)

-mirtazapine increase the synaptic concentrations of NE and 5-HT -Antagonize a-2 adrenergic autoreceptors AND a-2 receptors on 5-HT neurons (a-2 receptors are coupled to Gi) -Also block 5-HT2 and 5-HT3 receptors -Net effect is to increase NE and 5-HT secretion -Overall, NaSSa's increase NE neurotransmission and cause... Increased 5-HT neurotransmission, followed by... Long-term neuronal adjustments All of this is mainly due to blockade of negative NE feedback loops and... Blockade of 5-HT neuron inhibition

Major MAOIs

1. Phenelzine (Nardil)-Irreversible, non-competitive 2. Tranylcypromine (Parnate) -Irreversible, non-competitive 3. Selegiline (Eldepryl)-Targets only MAO-B at lower doses 4. Meclobromide -MAO-A selective, competitive 5. Clorgyline- MAO-A selective, competitive

The Reticular Activating System in Depression

1. decreasing locus coeruleus activity dec, leads to decreased activation of "wakefulness" 2. Decreased Raphae activity also leads to decreased activation of "sleep" pathways - The net result is Dysfunctional activity AND sleep onset patterns 3. Prolonged high levels of cortisol alters 5-HT and NE neurotransmission -One possible effect of this is abnormally increased 5-HT secretion in the amygdala and hippocampus

Anxiolytics Benzos bind the GABA receptor Barbiturates also bind the GABA receptor 5HT1a = buspirone 5HT receptor targets for anxiolytics, as well as beta blockers and Alpha 2 adrenergic agonists: clonidine TCAs include fluvoxamine, used for obsessive/compulsive disorder Ziprasidone has a high affinity for 5HT1a receptors Alcohols - EtOH, chloral hydrate Astressin is a CRF receptor antagonist Cannabinoids are thought to be involved in the modulation of GABA- ergic and glutamatergic transmission

-GABAergic (benzodiazepines) -SSRIs, SNRIs -5-HT1A receptor agonists -5-HT2A, 2c, 3 receptor -antagonists -Adrenergic agents: Beta- blockers and Alpha-2 adrenergic receptor agonists -TCAs MAO Inhibitors -Antihistamine agents Antipsychotics (ziprasidone) -Alcohols -Newer drugs: Astressin/CRF antagonists Cannabinoid receptor agonists

Nefazadone

-Nefazadone enhances 5-HT neurotransmission by blocking 5-HT reuptake, NE reuptake -Antagonizes 5-HT2 receptors -Also antagonizes a-1 adrenergic receptors, potentially causing postural hypotension Nefazadone metabolites have similar effects as the parent drug

Buspirone is used for GAD "Side Effects" include tachycardia, palpitations, nervousness, GI distress

A 5-HT1a receptor partial agonist Anxiolytic effect takes several weeks to develop Has a relatively high margin of safety, few "side effects" No rebound anxiety or withdrawal when discontinued The metabolite 1-PP is an a-2 adrenergic receptor antagonist

Scopolamine as an Antidepressant

Also given i.v. Muscarinic receptor antagonist "Which" muscarinic receptor not known in terms of antidepressant activity In the PFC, muscarinic receptors found presyanptically on glutamate neurons Causes similar synaptic, molecular changes as ketamine

Additive medications that are used to enhance the effect of antidepressants include

Atypical antipsychotics, bupropion and thyroid hormone

Why does EtOH require such a high dose to cause it's anxiolytic effects?

Because of it's initial effect, which is disinhibition (increasing activity, activating the stress axis, etc).

Drug-Drug Interactions with BZDs BDZ's have additive effects with other CNS depressants (narcotics), alcohol => have a greatly reduced margin of safety. BDZs reduce the effect of antiepileptic drugs. Combination of anxiolytic drugs should be avoided. SSRI's and oral contraceptives decrease metabolism of BDZs. Concurrent use with ODC antihistaminic and anticholinergic drugs can cause over-sedation

CNS depressants Antiepileptic drugs Other anxiolytic drugs SSRIs and oral contraceptives Antihistamines Anticholinergics

SSRIs Used To Treat Anxiety Disorders

Citolopram, Fluoxetine, Fluvoxamine, Paroxetine and Sertraline

Major depressive disorder are

unipolar

SSRIs Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Venlafaxine (Effexor)

work by selectively blocking 5-HT reuptake transporters both immediately and chronically The reasons for the long-term efficacy of these drugs is thought to be related to their long-term actions on 5-HT1a receptors These (often) autoreceptors are thought to desensitize more to 5-HT, allowing for increased 5-HT neurotransmission

Tertiary Amine Tricyclic Antidepressants

Amitryptiline (Elavil), Clomipramine (Anafanil), Doxepin (Adapin), Imiprimine (Tofranil), Trimipramine (Surmontil)

Secondary Amine Tricyclic Antidepressants

Amoxapine (Asendin), Desipramine (Norpramin), Maprotiline (Pamelor), Protriptyline (Vivactil)

Serotonergic Antidepressants MOA

An increase in synaptic 5-HT levels as initial response. In response Receptors (particularily 5-HT1a autoreceptors) downregulate. Over time, some form of homeostasis is thought to be established, which includes overall raised levels of 5-HT in specific brain areas (cortex, raphe nuclei)

Alpha-2 Adrenergic Receptor Agonists (Clonidine)

Antihypertensive Used in the treatment of panic attacks Useful in suppressing anxiety in withdrawal from nicotine, and opioid analgesics Withdrawal after long-term use may lead to hypertensive crisis

Anxiety

Anxiety is a response to a danger or threat (the "fight or flight response") The purpose of anxiety is to preserve the organism. Nearly every organism shows anxiety-like behavior. Without anxiety or fear, organisms would perish - example: knockout mouse - no CRF receptors, no fear of birds, etc... 'Real' cause of anxiety - getting repeatedly shocked by a stun gun Perceived - the floating rat

Dose-Response Curve for GABAergic Drugs

Barbs are the least 'safe', as small increases in dosage cause larger changes in response Benzos are relatively much safer -Why does EtOH require such a high dose to cause it's anxiolytic effects

Alpha-2 Adrenergic Receptor Agonists: Mechanism of Action

Bind to a-2 adrenergic receptors on presynaptic (and postsynaptic) neurons Cause a decrease in cAMP Inhibit NE secretion

Barbiturates Mechanism of Action

Bind to barbiturate receptor site on GABA-a receptors Increase the duration of GABA-gated channel openings At high concentrations may bind the GABA binding site on GABA receptors Less selective than Bzds: because it Depress actions of excitatory neurotransmitters and Exert non-synaptic membrane effects

"Side Effects" of Benzodiazpines CNS depression: drowsiness, excess sedation, impaired coordination, nausea and vomiting, confusion Memory loss is associated with CNS depression Withdrawal syndrome can result in convulsions and death

CNS depression, Memory loss, Dependence, Serious withdrawal syndrome

Neurotransmitters Involved in Anxiety

CRF,Urocortins,Norepine,hrine, 5-HT, GABA, Dopamine

SNRI MOA

Depression is associated with reduced levels of the monoamines in the brain, such as 5-HT. The selective 5-HT and noradrenaline re-uptake inhibitors (SNRIs) are thought to restore the levels of 5-HT and noradrenaline in the synaptic cleft by binding at their re-uptake transporters preventing the re-uptake and subsequent degradation of 5-HT and noradrenaline. This re-uptake blockade leads to the accumulation of monoamines in the synaptic cleft and the concentration returns to within the normal range. This action of SNRIs is though to contribute to the alleviation of the symptoms of depression. In the presence of the SNRIs, small amounts of 5-HT and noradrenaline continue to be degraded in the synaptic cleft.

SSRI MOA

Depression is associated with reduced levels of the monoamines in the brain, such as 5-HT. The selective 5-HT re-uptake inhibitors (SSRIs) are thought to restore the levels of 5-HT in the synaptic cleft by binding at the 5-HT re-uptake transporter preventing the re-uptake and subsequent degradation of 5-HT. This re-uptake blockade leads to the accumulation of 5-HT in the synaptic cleft and the concentration of 5-HT returns to within the normal range. This action of SSRIs is though to contribute to the alleviation of the symptoms of depression. In the presence of the SSRI, small amounts of 5-HT continue to be degraded in the synaptic cleft.

NE Reuptake Inhibitor MOA

Depression is associated with reduced levels of the monoamines in the brain, such as noradrenaline. The selective noradrenaline re-uptake inhibitors (NARIs) are thought to restore the levels of noradrenaline in the synaptic cleft by binding at the noradrenaline re-uptake transporter preventing the re-uptake and subsequent degradation of noradrenaline. This re-uptake blockade leads to the accumulation of noradrenaline in the synaptic cleft and the concentration of noradrenaline returns to within the normal range. This action of NARIs is though to contribute to the alleviation of the symptoms of depression. In the presence of the NARI, small amounts of noradrenaline continue to be degraded in the synaptic cleft.

Benzodiazepines Used As Anxiolytics

Diazepam, Triazolam, Alprazolam, Clonazepam, Prazepam Others

MAOI Properties

Drugs of the monoamine oxidase inhibitor (MAOI) type were among the first to be introduced clinically as antidepressants. They are now largely superseded by other types of antidepressants with improved efficacies and fewer side effects. Important examples are phenelzine and tranylcypromine. These bind covalently to the monoamine oxidase enzyme, resulting in non-competitive, irreversible inhibition; however, they do not distinguish between the two isozymes (MAO-A, MAO-B). Studies have demonstrated that the therapeutic effect of MAOIs is associated with MAO-A inhibition. This led to the development of moclobemide, which functions as a reversible, competitive inhibitor of MAO-A (RIMA). Clorgyline, although MAO-A-selective, is an irreversible inhibitor of the enzyme. The unwanted side effects of MAOIs include hypotension; atropine-like side effects (sympathomimetic effect); weight gain; and excessive CNS stimulation. The side effects associated with moclobemide are much milder than those reported with other MAOIs; they are also transient and disappear when treatment stops.

SSRI Properties

Drugs of the selective serotonin re-uptake inhibitor (SSRI) type include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. These are currently the most commonly prescribed antidepressants. In addition to showing selectivity with respect to 5-HT over noradrenaline uptake inhibition, they are as efficacious as tricyclic antidepressants but without the anticholinergic side-effects. The unwanted effects of SSRIs include nausea, anorexia, insomnia and sexual dysfunction; caused by stimulation of different subtypes of 5-HT receptor.

Biotransformation of Benzodiazepines Chlordiazepoxide, Diazepam, Prazepam, and Clorazepte all get converted to desmethyldiazepam, which is an active metabolite, as is N- desmethyldiazepam, aka oxazepam Alprazolam and triazolam are converted to alpha-hydroxy metabolites that are about half as potent as the original drugs Flurazepam is converted to two active metabolites, hydroxyethyl flurazepam an desalkyl flurazapem

Estazolam, oxazepam, and lorazepam, which are quickly metabolized, have the least residual (drowsiness) effects

The GABA-A Receptor Areas of the brain GABAa receptors are found include: Each protein subunit is actually a string of amino acids which passes in and out of the cell membrane four times GABA requires both alpha and beta components in order to bind. GABAa receptors are typically made up of two alpha and two beta subunits among the five subunits, though the particular subunit composition often varies widely among brain regions and species. In fact, among GABAa receptors, 17 different combinations of subunits have been identified This allows for a great deal of functional diversity

Found in a variety of areas of the brain -Ionotropic receptor Made up of five protein subunits that create a channel that remains closed until the receptor is activated -Activation of the GABA-A receptor opens the channel and results in an influx of Cl- ions -The influx of Cl- ions causes hyperpolarization of the postsynaptic neuron, and decreases the occurrence of action potentials

Benzodiazpeine Mechanism of Action Bzds are believed to bind between the interface subunits of the GABA-A receptor Thought to compete with GABA modulin for a binding site on the receptor Enhance GABAergic transmission Increase frequency of Cl- channel opening

GABA is an inhibitory transmitter GABA modulin is an endogenous protein; when it binds to the GABA receptor, it inhibits the binding of GABA to the receptor Benzo binding allows GABA to bind and activate the receptor more easily. The exact makeup of subunits of various GABAa receptors is thought to influence how effective benzos activate each receptor Bzds increase frequency of channel openings

GAD Obsessive- complsive Panic & phobia patients behavior

GAD - people have general symptoms of autonomic hyperactivity, motor tension, etc, for at least a month Obsessive-compulsive - patients show repetitive ideas (obsessive) or behaviors (compulsive) Panic disorders - acute attacks of fear/panic as compared to chronic anxiety as seen in GAD Phobias - include claustrophobia, agoraphobia, social phobias

Types of Pathological Anxiety

Generalized anxiety disorder (GAD), Obsessive-compulsive disorders,Panic disorders & Phobias

Noradrenaline Pathways in Depression:

In depression the transmission of noradrenaline is reduced from both of the principal noradrenergic centres - the locus coeruleus and the caudal raphe nuclei. An increase in noradrenaline in the frontal/prefrontal cortex modulates the action of selective noradrenaline reuptake inhibition and improves mood. Increasing noradrenaline transmission to other areas of the frontal cortex modulates attention.

Mechanism of HPA Axis in Depression

In depression, the hypothalamic-pituitary-adrenal (HPA) axis is upregulated with a down-regulation of its negative feedback controls. Corticotropin-releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocorticotropin hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands; adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

SNRI "Side Effects"

Increased BP, Increased agitation, anxiety, Nausea, Similar to SSRIs

MOA

Increased HR and FOC is predominantly an effect of epinephrine acting through beta receptors. Norepinephrine, in particular, causes widespread vasoconstriction, resulting in increased resistance and hence arterial blood pressure. Dilation of bronchioles assists in pulmonary ventilation. Stimulation of lipolysis in fat cells provides fatty acids for energy production in many tissues and aids in conservation of dwindling reserves of blood glucose. Increased metabolic rate: oxygen consumption and heat production increase throughout the body in response to epinephrine. Medullary hormones also promote breakdown of glycogen in skeletal muscle to provide glucose for energy production. Dilation of the pupils particularly important in situations where you are under conditions of low ambient light. Inhibition of certain "non-essential" processes: an example is inhibition of gastrointestinal secretion and motor activity.

SSRI "Side Effects"

Increased anxiety, Insomnia and Sexual dysfunction -SSRIs have effects on all kinds of neural systems

Bupropion

Inhibits both DA and NE reuptake. Thought to indirectly downregulate/desensitize b-adrenergic receptors. a-adrenergic receptors also desensitize One main effect appears to be to cause an increase in DA in the nucleus accumbens N.B: The nucleus accumbens is a key structure in the brain's reward pathways Also increases firing rates in the locus coreuleus

For typical antidepressants

It takes a 3-4 period before a measurable therapeutic response depending on patients

Noradrenaline Pathways in the "Normal" Brain

Many regions of the brain are supplied by the noradrenergic systems. The principal centres for noradrenergic neurones are the locus coeruleus and the caudal raphe nuclei. The ascending nerves of the locus coeruleus project to the frontal cortex, thalamus, hypothalamus and limbic system. Noradrenaline is also transmitted from the locus coeruleus to the cerebellum. Nerves projecting from the caudal raphe nuclei ascend to the amygdala and descend to the midbrain.

NaSSa and NRIA Properties

Mirtazapine is a new antidepressant that enhances both noradrenergic and serotonergic activity and is currently the only member of the noradrenergic and specific serotonergic antidepressant (NaSSA) class. It exerts its effects by blocking α2 auto- and hetero-receptors, which results in enhanced release of noradrenaline from noradrenergic terminals and increased 5-HT release from serotonergic terminals. The increase in 5-HT transmission is specifically mediated via 5-HT1 receptors, as mirtazapine selectively antagonises 5-HT2 and 5-HT3 receptors. The most common side effects are sedation (H1 histamine receptor block) and increased appetite with weight gain. Dry mouth is also common, but other anticholinergic features such as blurred vision and urinary retention are not, suggesting a symapthomimetic effect. Reboxetine exhibits specificity for inhibiting the noradrenaline re-uptake transporter and is known as a noradrenaline re-uptake inhibitor (NARI). Common side effects seen with reboxetine are atropine-like side effects (sympathomimetic effect) and allergic rashes.

MAO-A Inhibitors MOA

Monoamine oxidase A (MAOA) is an enzyme involved in the metabolism of the monoamines, eg 5-HT and noradrenaline. It converts the monoamines into their corresponding carboxylic acid via an aldehyde intermediate. MAOA regulates both the free intraneuronal concentration and the releasable stores of 5-HT and noradrenaline. MAOA inhibitors, such as phenelzine, bind to and inhibit MAOA, preventing monoamine degradation. This results in greater stores of monoamines available for release. MAOA inhibitors are used in the treatment of depression. People with depression have lower than normal levels of the monoamines and MAOA inhibitors restore the levels to within the normal range.

MAO-B Inhibitor (Selegeline) MOA

Monoamine oxidase B (MAOB) is an enzyme involved in the metabolism of dopamine. It converts dopamine to its corresponding carboxylic acid via an aldehyde intermediate. MAOB regulates both the free intraneuronal concentration of dopamine and the releasable stores. MAOB inhibitors, such as selegiline, bind to and inhibit MAOB, preventing dopamine degradation. This results in greater stores of dopamine available for release. MAOB inhibitors are used in the treatment of depression. People with depression have lower than normal levels of dopamine and MAOB inhibitors restore the levels to within the normal range.

NE is involved in:

Mood regulation, Higher cognitive function, Reticular activating system regulation & Limbic system function

what are major functions disrupted in depression?

Mood, Feeding , Circadian rhythms, Activity levels (RAS function), HPA axis function & Many others

Benzodiazepines

Most frequently used GABAergic agents Prevent anxiety but (generally) cause little sedation

Role of Norepinephrine in Anxiety -Norepinephrine originates from brainstem nuclei - mainly the locus coeruleus Half of all the neurons in the brain which use noradrenaline (norepinephrine) as the neurotransmitter are in the locus ceruleus.

NE is considered an excitatory neurotransmitter Cell bodies originate in the locus coeruleus, A1/A5 adrenergic areas of the brainstem Plays a major role in the reticular activating system, which is involved in arousal

NaSSA Overall MOA

NaSSA Block a2 autoreceptors, a2 receptors on on 5HT neurons, Increased release of NE, 5-HT, Decreased NE, 5-HT Receptor #/sensitivity, NE and 5-HT production, receptor #/sensitivity reach a new homeostatic point, Overall increase in synaptic NE/5-HT

Barbiturates: older drug Key thing to know is that they aren't a good choice for use as anxiolytics Addictive - tolerance and dependence develops easily

Not a good choice for use as anxiolytics General CNS depressants Low margin of safety Highly addictive

Barbiturates

Not really used much More addictive and less safe than benzodiazepines

The GABA-A Receptor

Oligomeric glycoprotein. Major player in Inhibitory Synapses. Contains a chloride (Cl-) Channel. Binding of GABA causes the channel to open and Cl- to flow into the cell with the resultant membrane hyperpolarization. Barbiturates increase the duration of GABA-gated channel openings

The Monoamine Theory of Depression

Reserpine causes long-term depletion of monoamines from synaptic vesicles so patients recieving reserpine showed significantly depressed moods. -Agents that increase synaptic monoamine levels (MAO inhibitors) are effective for treating depression

Medical causes of anxiety:

Respiratory (asthma), Endocrine (hyper cort, acth); Cardiovascular; Metabolic (thyroid); Neurologic (chronic pain)

SSRI Overall MOA

SSRI blocked reuptake of 5-HT, Increased synaptic 5-HT, decreased 5-HT receptor#/sensitivity, 5-HT production receptor #/sensitivity reach a new homeostatic setpoint...Over all increase in synaptic 5-HT

5-HT Pathways in the Brain

Serotonin transmission from both the caudal raphe nuclei and rostal raphe nuclei is reduced in patients with depression compared with non-depressed controls. Increasing the levels of serotonin in these pathways, by reducing serotonin reuptake and hence increasing serotonin function, is one of the therapeutic approaches to treating depression.

Tricyclic Antidepressants Overall MOA

TCA blocked reuptake of NE,5-HT, Increased synaptic NE, 5-HT, Decreased NE, 5-HT receptor#/sensitivity, NE and 5-HT production, receptor #/sensitivity reach a homeostatic setpoint...Overall increase in synaptic NE/5-HT

Nefazodone MOA

The antidepressant nefazodone is thought to alleviate some of the symptoms of depression by enhancing 5-HT neurotransmission. Ii inhibits the re-uptake of 5-HT and acts as an antagonist at 5-HT2 receptors. These two mechanisms may enhance 5-HT1A mediated neurotransmission. Nefazodone also weakly inhibits the re-uptake of noradrenaline. Two of the three metabolites of nefazodone (hydroxynefazodone and m-chlorophenylpiperazine) have similar affinities to the parent compound.

Nefazodone: Adverse Effects

The antidepressant nefazodone is thought to alleviate some of the symptoms of depression by inhibiting the re-uptake of 5-HT and acting as an antagonist at 5-HT2 receptors. Antagonism of noradrenaline α1 receptors leads to some of the adverse effects associated with nefazodone treatment, such as postural hypotension.

NaSSa MOA

The mechanism of action of noradrenergic and specific serotonergic antidepressants (NaSSAs) Depression is associated with reduced levels of monoamines in the brain. Noradrenergic and specific serotonergic antidepressants (NaSSAs), such as mirtazapine, have a dual mechanism of action that increases the concentration of 5-HT and noradrenaline in the synaptic cleft to within the normal range. NaSSAs bind to and inhibit both noradrenaline a2-autoreceptors and noradrenaline a2-heteroeceptors. This action prevents the negative feedback effect of synaptic noradrenaline on 5-HT and noradrenaline neurotransmission, and neurotransmission sustained. NaSSAs also block 5-HT2 and 5-HT3 receptors on the post-synaptic membrane, which causes enhanced 5-HT1 mediated neurotransmission

5-HT Pathways in the Brain

The principal centres for serotonergic neurones are the rostral and caudal raphe nuclei. From the rostral raphe nuclei axons ascend to the cerebral cortex, limbic regions and specifically to the basal ganglia. Serotonergic nuclei in the brain stem give rise to descending axons, some of which terminate in the medulla, while others descend the spinal cord.

The goal of Anxiolytics is

To reduce anxiety without causing sedation

Tricyclics: Adverse Effects

Tricyclic antidepressants (TCAs) are a group of drugs used to treat affective, or 'mood', disorders. Despite being an important group of antidepressant drugs they are not ideal, due to a number of unwanted side effects. Side effects of the TCAs include sedation, caused by histamine H1 receptor blockade; postural hypotension, due to α adrenoreceptor blockade; and blurred vision, dry mouth and constipation, due to muscarinic acetylcholine receptor blockade.

Tricyclic Antidepressant MOA

Tricyclic antidepressants (TCAs) are a group of drugs used to treat affective, or 'mood', disorders. Mood disorders are associated with reduced levels of monoamines in the brain. TCAs binding to 5-HT and noradrenaline re-uptake transporters prevents the re-uptake of these monoamines from the synaptic cleft and their subsequent degradation. This re-uptake blockade leads to the accumulation of 5-HT and noradrenaline in the synaptic cleft and the concentration returns to within the normal range.

TCA Properties:

Tricyclic antidepressants (TCAs) are an important group of antidepressants in clinical use; they include imipramine, clomipramine, amitriptyline and desipramine. The main effect of TCAs is to block the uptake of monoamines by nerve terminals, by competing for the binding site of the carrier protein. Most TCAs are non-selective and inhibit noradrenaline and 5-HT uptake to a similar degree, but have much less effect on dopamine uptake. TCAs produce a number of side effects, mainly due to interference with autonomic control, including atropine-like effects (muscarinic cholinergic receptor block), postural hypotension (α1-adrenergic receptor block) and sedation (H1 histamine receptor block). Poor dental health, due to effects of TCAs on salivary secretion, is a common problem among middle-aged and elderly patients.

N.B;Benzodiazepines Compete with GABA Modulin to Facilitate GABA Receptor Binding

True

GABA-ergic Anxiolytics

Two main classes are benzos and barbs Barbs are older drugs - more addictive

Monoamine Oxidase Inhibitors

Work by inhibiting the action of the "A" isoform of MAO in the presynaptic neuron: Monoamines need to be transported back into the presynaptic neuron for MAOIs to have an effect

Agents that selectively increase NE neural transmission:

are often effective in treating depression

NE generally

has excitatory actions

Buspar

is a 5-HT1a partial agonist Which means it __________ cAMP second messenger signaling It is also a mixed agonist/antagonist on DA and GABA receptors Its overall effects are thought to include increasing 5-HT secretion throughout the brain

Bipolar depression is characterized by

periods of depression or mania

Specific NE Uptake Inhibitors (NARIs)

work by specifically blocking noradrenergic reuptake. these are -Reboxetine (Edronax) -Atomoxetine (Strattera)