DPN

For patients who have a major depressive episode, unipolar, bipolar, or mixed, and who receive treatment and improve to the level 50% reduction of symptoms or more, this outcome is called a response. Was previous goal. Now goal is complete remission w/o relapse

Act early and aggressively to prevent disease progression. 

Selective Serotonin reuptake Inhibitors (SSrIs)

Although the action of SSRIs at the presynaptic axon terminal has classically been emphasized, it now appears that events occurring at the somatodendritic end of the serotonin neuron (near the cell body) may be more important in explaining the therapeutic actions of the SSRIs

Therapeutic action may be d/t initial desensi and downreg of receptors and now SE can no longer turn itself off from receptor feedbeck bc theyre desensitized. Therefore SE is now free flowing and not regulated. 

Fluoxetine: An SSRI with 5HT2C Antagonist Properties -  patients, even from the first dose, detect an energizing and fatigue-reducing effect of fluoxetine, with improvement in concentration and attention as well. approved for bulimia tx. long half life 2-3 days

Sertraline: An SSRI with Dopamine Transporter (DAT) Inhibition and σ1 Binding - sometimes added to bupropion, both with weak DAT inhib, leading to enhanced activation. can be issue in pt w/ panic disorder req slower titration/dose

Paroxetine: An SSRI with Muscarinic Anticholinergic and Norepinephrine Transporter (NET) Inhibitory Actions - more calming, even sedating, early in treatment compared to the more activating actions of both fluoxetine and sertraline. inhib nitric oxide synthase can mean SEXUAL DYSFUNCTION in MEN. WITHDRAWAL sx with SUDDEN discontinuation. 

Fluvoxamine: An SSRI with σ1 Receptor Binding Properties - considered more of an agent for the treatment of OCD in the US.  has shown therapeutic activity in both psychotic and delusional depression. low half life, sometimes 2x a day dosing. anxiolytic actions

Citalopram: An SSRI with a “Good” and a “Bad” Enantiomer - has favorable findings in the treatment of depression in the elderly, but has a somewhat inconsistent therapeutic action at the lowest dose, often requiring dose increase to optimize treatment. higher doses increases risk of QT PROLONGATION. mild antihistamine properties

Escitalopram: The Quintessential SSRI - removeS the unwanted R enantiomer (like in cita). NO antihistamine properties. NO high dose restrictions to avoid QT PROLONGATION. Can be potent at lower doses.  considered perhaps the best-tolerated SSRI, with the fewest cytochrome P450 (CYP450)-mediated drug interactions. 

Serotonin Partial Agonist reuptake Inhibitors (SPArIs)

Vilazodone - combines SERT inhibition with 5HT1A partial agonism.  combination of serotonin reuptake inhibition with 5HT1A partial agonism has long been known by clinicians to enhance the unipolar antidepressant properties and tolerability of SSRIs/SNRIs. causes more immediate and robust elevations of brain 5HT levels than SSRIs do alone. Immediate fake SE in the form of agonism more immediate effects. downstream actions of 5HT1A receptors that lead to enhanced dopamine release may be hypothetically responsible for enhanced antidepressant and precognitive effects. reduced sexual dysfunction and the relative lack of weight gain.  

Serotonin–Norepinephrine reuptake Inhibitors (SNrIs) (SERT and some NET inhib)

NET Inhibition Increases Dopamine in the Prefrontal Cortex. NET inhibition increases both NE and DA in the prefrontal cortex. Thus, SNRIs have two-and-a-half mechanisms: boosting serotonin throughout the brain, boosting NE throughout the brain, and boosting DA in the prefrontal cortex

NET inhib - NET more affinity for DA. no DAT in the PFC and NET inhib. 

Venlafaxine - approved and widely used for several anxiety disorders as well. sweating and elevated blood pressure SIDE EFFECTS likely d/t NET INHIB. unk if better in unipolar dpn. Controlled release for 1/day dosing, favorable bc immediate release causes SE OF NAUSEA. sudden dc causes WITHDRAWAL SX.

Desvenlafaxine - Venlafaxine is a substrate for CYP450 2D6, which converts it to an active metabolite desvenlafaxine. Greater NET inhib. plasma levels of V about half that of D after admin. this is favorable is taking a drug that is a CYP450 2D6 INHIB which puts V back in the lead. The more V is favored by this process the less NET inhib. the development of desvenlafaxine as a SEPARATE drug may solve this problem

Duloxetine -  slightly more potent SERT than NET inhibition. All sorts of pain are improved by this SNRI, from diabetic peripheral neuropathic pain, to fibromyalgia, to chronic musculoskeletal pain such as that associated with osteoarthritis and low back problems. validated that painful physical (somatic) symptoms are a legitimate set of symptoms that accompany depression and are not just a form of emotional pain

Twice daily then 1x/day after tolerant

may have a lower incidence of hypertension and milder withdrawal reactions than venlafaxine

-  THIS IS WHERE I WAS SUPPOSED TO STOP LOL BUT GO OFF I GUESS - 

Milnacipran - relatively more potent NET than SERT inhibitor. may be particularly useful in chronic pain related conditions, not just fibromyalgia where it is approved, but possibly as well for the painful physical symptoms associated with unipolar depression and chronic neuropathic pain.  favorable pharmacological profile for the treatment of cognitive symptoms, including cognitive symptoms of unipolar depression and fibromyalgia (fibro-fog). Short half life 2x/day. SE urinary hesitancy (add a1 antag) and sweating

Levomilnacipran  - independently developed for unipolar major depressive disorder in the US. may target fatigue and lack of energy as potential clinical advantages. controlled release so ONCE a day compared to non-levo version.

Norepinephrine–Dopamine reuptake Inhibitors (NDrIs): Bupropion

only has weak reuptake blocking properties for dopamine (DAT inhibition), and for norepinephrine (NET inhibition). 

-SSRIs must be dosed to occupy a substantial fraction of SERTs, perhaps up to 80% or 90%-

the SLOW dat occupancy allows for effect w/o ADDICTION bc of HIGH. often used post SSRI/SNRI when patient have inc negative sx or red positive affect. 

Agomelatine -  approved to treat unipolar depression in many countries outside of the US. agonist actions at melatonin 1 (MT1) and melatonin 2 (MT2) receptors and antagonist actions at 5HT2C receptors. Melatonin actions in SCN can resync CIRCADIAN RHYTHMS and reverse phase delay of dpn

-5HT2C receptors are located in the midbrain raphe and prefrontal cortex where they regulate the release of dopamine and norepinephrine, an action thought to improve depressive symptoms-

Mirtazapine - no monoamine action. multifunctional drug with five principal mechanisms of action: 5HT2A, 5HT2C, 5HT3, α2-adrenergic, and H1 histamine antagonism. the α2 antagonist mirtazapine is often combined with SNRIs for treatment of cases that do not respond to an SNRI alone (double/synergistic effect)

- α2 antagonism causes dual 5HT–NE action bc heterorecptors (a2) that when antag disinhibs NE AND 5HT-

-Blocking these 5HT3 receptors can therefore protect against chemotherapy-induced nausea and vomiting as well as against serotonin-induced gastrointestinal side effects that can accompany agents that increase serotonin-

-5HT3 antagonism is a powerful disinhibitor of glutamate release (Figure 7-42) and of acetylcholine and norepinephrine, actions that theoretically release neurotransmitters downstream to have antidepressant action-

Serotonin Antagonist/reuptake Inhibitors (SArIs) 

Trazadone prototype. Nefazadone. act predominantly via its highest-affinity receptor interactions at low doses, and will recruit its lower-affinity receptor actions at higher doses. low doses as HYPNOTIC (5HT2A (slow wave sleep), α1 subtypes, and H1. 

trazodone blocks the actions of serotonin at 5HT2A and 5HT2C receptors, accounting for its profile of LACK OF sexual dysfunction and reduction of anxiety and insomnia

Vortioxetine - drug approved for treating unipolar depression and which causes SERT inhibition as well as having antagonist actions at 5HT3 and 5HT7 receptors, with agonist actions at 5HT1A receptors. 

Vortioxetine improves cognition better than other antidepressants in unipolar major depression, as demonstrated by superior performance on the DSST measuring processing speed

Neuroactive Steroids - brexanolone - Administered by a 60-hour intravenous infusion for postpartum depression. pregnant women have high circulating and presumably brain levels of naturally occurring allopregnanolone, this restores and gives time for them to regen. vuln women are susceptible to dpn in this period.

bind to GABAA receptors at a specific allosteric site called the neuroactive steroid site, which enhances the inhibitory action of GABA at GABAA receptors, at the benzo insensitive tonic site. GABA is reduced in post mortem dpn patients

SAGE-217 - is a synthetic orally active allopregnanolone analogue in clinical testing as a rapid-onset antidepressant for major depressive disorder

TREATMENT RESISTANT DPN

Serotonin/Dopamine Antagonists/Partial Agonists as Augmenting Agents for Treatment-Resistant Unipolar Depression

Olanzapine–Fluoxetine Combination - Both olanzapine and fluoxetine are 5HT2C antagonists, and, in combination, the net 5HT2C antagonism is greater than with either drug alone.  often associated with unacceptable weight gain and METABOLIC disturbances

Quetiapine -  approved for schizophrenia, acute bipolar mania, and bipolar maintenance. can cause a great deal of sedation and moderate weight gain and metabolic disturbance due to its other receptor actions

-GENERAL MEME- antag action at various 5HT receptors cause unwanted side fx.

Aripiprazole - D2/5HT1A partial agonist is approved for schizophrenia, acute bipolar mania, and bipolar maintenance and is one of the most extensively prescribed augmenting agents to SSRIs/ SNRIs in unipolar major depression. generally well tolerated with little weight gain but some patients experience akathisia. NOT APPROVED for bipolar dpn

Brexpiprazole - D2/5HT1A partial agonist is approved for schizophrenia and also for adjunctive treatment in unipolar depression. NOT APPROVED for bipolar dpn. some indication of reduced akathisia with brexpiprazole compared to aripiprazole. Alpha-1 antagonist actions of brexpiprazole could also potentially contribute to its evidence of efficacy for agitation in Alzheimer disease and in PTSD (as augmentation of sertraline)

-When this glutamatergic neuron is inhibited by an α1 antagonist, its innervation of the substantia nigra reduces GABA tone there, allowing disinhibition of dopamine release into the motor striatum and reduction of drug-induced parkinsonism- 

-the lowest frequency and severity of drug-induced parkinsonism induced by dopamine blockers is for those that also have robust α1 and 5HT2A antagonist actions, namely, brexpiprazole, quetiapine, clozapine, and iloperidone-

The enhancement of dopamine release in the prefrontal cortex by simultaneous α1 and 5HT2A blockade may theoretically contribute as well to improving “top-down” control of agitation in Alzheimer disease and PTSD symptoms, which are seen in ongoing studies of brexpiprazole

Carpirazine is a D3/D2/5HT1A partial agonist as well as a 5HT2A/α1/α2 antagonist. approved for the treatment of acute bipolar mania and bipolar depression; it also has evidence of efficacy as an adjunct to SSRI/SNRIs in unipolar depression

Ketamine - off-label for treatment-resistant depression.  given to patients with multiple failures on various drugs for depression. has  binding properties at the NMDA subtype of glutamate receptor, its putative mechanism of antidepressant action, and at the σ1 receptor. causes an immediate burst of downstream glutamate release after blocking NMDA receptors. AMPA receptor activation might have neuro regen properties

BDNF and VEGF, ketamine inc both these growth factors

Esketamine - The S enantiomer of ketamine. active as an acute rapid-onset antidepressant, and it is administered intranasally and rapidly, so that longer intravenous infusions are not necessary. After twice-weekly initiation, esketamine can be given intranasally in weekly or biweekly dosing as an augmenting agent to standard drugs for depression.

Other Drug Combinations for Treatment-Resistant Depression

Lithium - As augmentation for treatment-resistant unipolar depression, lithium is administered in doses lower than those used for mania, but it has fallen out of favor in recent years

Buspirone is a 5HT1A partial agonist, so putting it together with an SSRI/SNRI is very much similar to the use of vilazodone or vortioxetine

5HT1A property other examples - quetiapine, aripiprazole, brexpiprazole, and cariprazine

Thyroid Hormones - act by binding to nuclear ligand receptors to form a nuclear ligand-activated transcription factor. abn thyroid labs have hx of dpn overlap. out of favor lately

Triple-Action Combo: SSRI/SNRI + NDRI some of the most popular combinations of two drugs for depression utilized in the US. covers all 3

Arousal Combos - complaints of residual fatigue; loss of energy, motivation, and sex drive; and problems concentrating/problems with alertness may be approached by combining either a stimulant (dopamine transport inhibitor or DAT inhibitor) with an SNRI, or modafinil (another DAT inhibitor) with an SNRI. triple monoamine axn

Second-Line Monotherapies Used for Treatment-resistant Depression

Tricyclic Antidepressants - discovered to block the reuptake pumps for norepinephrine (i.e., NET), or for both norepinephrine and serotonin (i.e., SERT)

Tricyclic antidepressants are not merely drugs for depression since one of them (clomipramine) has anti-obsessive–compulsive disorder; many of them have anti-panic effects at antidepressant doses and efficacy for neuropathic and low back pain at low doses

PROBLEM - all of them share at least four other unwanted pharmacological actions, namely, blockade of muscarinic cholinergic receptors, H1 histamine receptors, α1-adrenergic receptors, and voltage-sensitive sodium channels. weakly block voltage-sensitive sodium channels in the heart and brain at therapeutic doses. in OD can lead to coma/arrhythmia/arrest/sz/CNSstuff/death

Monoamine Oxidase Inhibitors (MAOIs) - Although best known as powerful drugs to treat depression, the monoamine oxidase inhibitors (MAOIs) are also highly effective therapeutic agents for certain anxiety disorders such as panic disorder and social anxiety disorder. SSRIs replaced them 

The MAOIs phenelzine, tranylcypromine, isocarboxazid, and selegiline are all irreversible enzyme inhibs. MAO-A must be substantially inhibited for antidepressant efficacy to occur. MAO-B inhib can boost the action of concomitantly administered levodopa in Parkinson’s disease and reduce on/off motor fluctuations

MAO-A plus MAO-B inhibition is one of the few therapeutic strategies available to increase dopamine in depression, and therefore to treat refractory symptoms of diminished positive affect

The Dietary Tyramine Interaction with MAOIs - may develop a hypertensive crisis after ingesting tyramine in the diet, classically from cheese

TWO drug-drug INTERACTIONS to AVOID - those that can raise blood pressure by sympathomimetic actions and those that can cause a potentially fatal serotonin syndrome by serotonin reuptake inhibition