Pharmacological management of depression

Pharmacological management of depression

1. Pharmacological Management of Depression By : Dr. Priyash Jain JR-2

2. Content General Considerations An overview of Antidepressants Drug Treatment of Depression Refractory Depression Antidepressants in special population Symptom based approach to depression Antidepressant combinations Newer antidepressants

3. General Considerations

4. General Considerations Antidepressants are not recommended as a first‐line treatment in recent‐onset, mild depression – active monitoring, individual guided self‐help, cognitive behavioural therapy (CBT) or exercise are preferred. Antidepressants are recommended for the treatment of moderate to severe depression and for dysthymia.

5. General Considerations Discuss with the patient choice of drug and utility/availability of other, non‐pharmacological treatments. Discuss with the patient likely outcomes, such as gradual relief from depressive symptoms over several weeks. Prescribe a dose of antidepressant (after titration, if necessary) that is likely to be effective. For a single episode, continue treatment for at least 6–9 months after resolution of symptoms (multiple episodes may require longer). Withdraw antidepressants gradually ; always inform patients of the risk and nature of discontinuation symptoms.

6. General Considerations It is widely held that antidepressants do not exert their effects for 2–4 weeks. This is a myth. All antidepressants show a pattern of response in which the rate of improvement is highest during weeks 1–2 . Selective serotonin reuptake inhibitors (SSRIs) are well tolerated compared with the older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), and are generally recommended as first‐line pharmacological treatment for depression.

7. An overview of Antidepressants

8. An overview of Antidepressants SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) Citalopram, Escitalopram Fluoxetine, Fluvoxamine Paroxetine, Sertraline SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs ) Desvenlafaxine, Venlafaxine Duloxetine, * Levomilnacipran * ansofaxine , *nefopam * - Newer drugs

9. An overview of Antidepressants TRICYCLIC ANTIDEPRESSANTS (TCAs) Amitriptyline, Nortriptyline, Protriptyline Amoxapine, Doxepin Clomipramine, Desipramine, Imipramine, Trimipramine MONOAMINE OXIDASE INHIBITORS (MAOIs) Isocarboxazid , Phenelzine, Selegiline, Tranylcypromine

10. An overview of Antidepressants Norepinephrine-dopamine reuptake inhibitor ( NDRI ) such as bupropion. Serotonin receptors antagonist with serotonin reuptake inhibition ( SARI ) such as trazodone, nefazodone, and *vortioxetine. Serotonin 5-HT1A autoreceptor partial agonist with serotonin reuptake inhibition ( SPARI ) such as *vilazodone Noradrenergic α2 - receptor antagonist with specific serotonergic receptors-2 and -3 antagonism ( NASSA ) such as mirtazapine and * mianserin . Norepinephrine reuptake inhibitor with serotonin receptors antagonism ( NRISA ) such as *maprotiline. Melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2B and 5-HT2C receptors antagonism ( MASSA ) – Agomelatine, Ramelteon, Tasimalteon * - Newer drugs

11. Minimum Effective Doses

12. Drug Treatment of Depression

13. Drug Treatment of Depression

14. Drug Treatment of Depression Switching between drug classes in cases of poor tolerability is not clearly supported by published studies but has a strong theoretical basis. Having said that, in practice, many patients who cannot tolerate one SSRI will readily tolerate another. Switch treatments early (e.g. after a week or two) if adverse effects are intolerable or if no improvement at all is seen by 3–4 weeks. Opinions on when to switch vary somewhat but it is clear that antidepressants have a fairly prompt onset of action and that non‐response at 2–6 weeks is a good predictor of overall non‐response.

15. Refractory Depression

16. Refractory Depression

17. First choice Agent Disadvantages Lithium Sometimes poorly tolerated at higher plasma levels Potentially toxic Usually needs specialist referral Plasma level monitoring is essential (and TFTs, e‐GFR) May not be effective in patients refractory to multiple treatments Combine olanzapine and fluoxetine Risk of weight gain Most data relate to bipolar depression Add quetiapine Dry mouth, sedation, constipation can be problematic Weight gain risk in the longer Term

18. First choice Agent Disadvantages Add aripiprazole Akathisia and restlessness common at standard doses (≥10 mg/day) Insomnia may be problematic SSRI + bupropion Not licensed SSRI or venlafaxine + mianserin (30 mg/day) or mirtazapine Theoretical risk of serotonin syndrome (inform patient) Risk of blood dyscrasia with Mianserin

19. Second Choice Agent Disadvantages Add ketamine (0.5 mg/ kg IV over 40 minutes) IV needs to be administered in hospital Cognitive effects (confusion, dissociation, etc.) do occasionally occur Associated with transient increase in BP, tachycardia and arrhythmias. Pre‐ treatment ECG required with IV form Adverse effects may have been underestimated Repeated treatment necessary to maintain effect Not widely available

20. Second Choice Agent Disadvantages Add lamotrigine Slow titration Risk of rash Appropriate dosing unclear Two failed RCTs SSRI + buspirone Up to 60 mg/day Higher doses required Poorly tolerated (dizziness common) Not widely used Add risperidone Hypotension Hyperprolactinaemia Generally less robust RCT support than for other SGAs

21. Second Choice Agent Disadvantages Add tri‐iodothyronine (20–50 μg /day) Higher doses have been safely used Clinical and biochemical TFT monitoring required Usually needs specialist referral Some negative studies No advantage over antidepressant alone in non‐refractory illness High‐dose venlafaxine (>200 mg/day) Limited support in literature Nausea and vomiting more common Discontinuation reactions common Can increase BP. Blood pressure monitoring essential

22. Other reported treatments Amantadine Buprenorphine Cabergoline D‐ cycloserine Stimulants: amfetamine ; methylphenidate Oestrogens Pindolol Tryptophan Zinc

23. Psychotic Depression TCAs are probably drugs of first choice in psychotic depression. SSRIs/SNRIs are a second‐line alternative when TCAs are poorly tolerated. Augmentation of an antidepressant with olanzapine or quetiapine is recommended . ECT should always be considered where a rapid response is required or where other treatments have failed.

24. Role of Folic Acid Folate deficiency can contribute to depressed mood and folate supplementation is beneficial in patients, and a plausible mechanism implicates serotonin. In many studies, folate deficiency was associated with low levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). In one study, supplementation with folate restored CSF 5-HIAA levels to normal. There is also a decrease in serotonin synthesis in patients with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency , a disorder of folate metabolism.

25. Role of Folic Acid While the mechanism relating folate deficiency to low serotonin is not known, it may involve S-adenosylmethionine (SAMe). SAMe is a major methyl donor formed from methionine. Folate is involved in a cycle that regenerates methionine from homocysteine after SAMe is demethylated to S-adenosylhomocysteine, with subsequent conversion to homocysteine. Thus, there is some consistency in what is known about the interrelations of folate, SAMe and depression. Ability of folate to potentiate the action of standard antidepressant therapies.

26. Role of Folic Acid

27. Antidepressants in special population

28. Childhood and Adolescent depression Psychological intervention be considered as first‐line treatment for depression in children and adolescents and specifically so in cases of mild to moderate depression. SSRI + CBT (But controversial evidence available) Fluoxetine is the recommended first‐line pharmacological treatment and is superior to placebo in children and adolescents Fluoxetine and escitalopram are the only antidepressants approved by the US Food and Drug Administration (FDA) for adolescents and fluoxetine is the only FDA‐approved medication for pre‐pubertal children (from age 8 years).

29. Childhood and Adolescent depression If there is no response to fluoxetine and pharmacotherapy is still considered to be the most favourable option, an alternative SSRI such as sertraline or escitalopram should be considered.

30. Childhood and Adolescent depression Sertraline, citalopram and escitalopram are quickly metabolised by children and twice daily dosing should be considered. When prescribing SSRIs it is important that the dose is increased slowly to minimise the risk of treatment‐emergent agitation and that patients are monitored closely for the development of treatment‐emergent suicidal thoughts and acts. antidepressants increase the risk of suicidal behavior and aggression . The TADS study: the combined treatment of fluoxetine and CBT reduced the risk of suicidal events to the greatest extent

31. Depression during pregnancy and post partum Patients who are already receiving antidepressants and are at high risk of relapse are best maintained on the same antidepressant during and after pregnancy. Those who develop a moderate‐severe or severe depressive illness during pregnancy should be treated with antidepressant drugs. If initiating an antidepressant during pregnancy or for a woman considering pregnancy, previous response to treatment must be taken into account. The antidepressant that has previously proved to be effective should be considered. For previously untreated patients, sertraline may be considered .

32. Depression during pregnancy and post partum When taken in late pregnancy, SSRIs may increase the risk of persistent pulmonary hypertension of the newborn. The absolute risk is very low. The neonate may experience discontinuation symptoms, which are usually mild, such as agitation and irritability, or rarely respiratory distress and convulsions (with SSRIs). The risk is assumed to be particularly high with short half‐life drugs such as paroxetine and venlafaxine. Continuing to breastfeed and then ‘weaning’ by switching to mixed (breast/bottle) feeding may help reduce the severity of reactions.

33. Depression during pregnancy and post partum Paroxetine has been specifically associated with cardiac malformations, particularly after high dose (>25 mg/day) first‐trimester A higher risk of some cardiac birth defects has been reported to be associated with paroxetine and fluoxetine compared with other SSRI (controversial evidence)

34. Antidepressants in Hepatic failure and Renal failure SSRIs - All are hepatically metabolised and accumulate on chronic dosing. Dosage reduction (including reduction of maximum dose by 50% and/or reduced dosing frequency) may be required. Citalopram, escitalopram and paroxetine have minimal effects on hepatic enzymes and may be the SSRIs of choice although occasional hepatotoxicity has been reported. All are hepatically metabolised , highly protein bound and will accumulate. They vary in their propensity to cause sedation and constipation. All are associated with raised LFTs and rare cases of hepatitis. Sedative TCAs such as trimipramine, imipramine, dosulepin (dothiepin) and amitriptyline are best avoided.

35. Antidepressants in Hepatic failure and Renal failure No agent clearly preferred to another, however: citalopram (care: QTc‐prolonging effects) and sertraline are suggested as reasonable choices

36. Symptom- Based approach to treating depression

37. Symptom-based antidepressant selections First, symptoms are constructed into a diagnosis and then deconstructed into a list of specific symptoms that the individual patient is experiencing Next, these symptoms are matched with the brain circuits that hypothetically mediate them Finally, available treatment options that target these neuropharmacological mechanisms are chosen to eliminate symptoms one by one

38. Symptom-based antidepressant selections Example 1 in a patient with the symptoms of “problems concentrating” and “decreased interest” as well as “fatigue,” this approach suggests targeting both NE and DA with first-line antidepressants plus augmenting agents that act on these neurotransmitters Example 2 on the other hand, for “insomnia,” this symptom is hypothetically associated with an entirely different malfunctioning circuit regulated by different neurotransmitters

39. Symptom-based antidepressant selections therefore, the treatment for this symptom calls for a different approach, namely the use of hypnotics that act on the GABA system or sedating antidepressants that work to block rather than boost the serotonin or histamine system possibly faster way of reducing specific symptoms with more tolerable treatment selections for that patient than a purely random approach

40. Antidepressant Combinations

41. Antidepressant Combinations Given the disappointing number of patients who attain remission from a major depressive episode even after four consecutive treatments and who can maintain that remission over the long run the paradigm of prescribing a sequence of monotherapies each with a single mechanism of therapeutic action for major depression is rapidly changing to one of administering multiple simultaneous pharmacologic mechanisms , often with two or more therapeutic agents.

42. Antidepressant Combinations Triple-action combo: SSRI/SNRI ± NDRI

43. Antidepressant Combinations California rocket fuel : SNRI plus mirtazapine This potentially powerful combination utilizes the pharmacologic synergy obtained by adding the enhanced serotonin and norepinephrine release from inhibition of both dual serotonin and norepinephrine reuptake by an SNRI to the disinhibition of both serotonin and norepinephrine release by the α2 antagonist actions of mirtazapine This combination can provide very powerful antidepressant action for some patients with unipolar major depressive episodes.

44. Antidepressant Combinations California rocket fuel: SNRI plus mirtazapine

45. Antidepressant Combinations Arousal combos The frequent complaints of residual fatigue, loss of energy, motivation, sex drive, and problems concentrating/problems with alertness may be approached by combining either a stimulant or modafinil with an SNRI to recruit triple monoamine action and especially enhancement of dopamine. lisdexamfetamine , which links the amino acid lysine to the stimulant d-amphetamine, and which slows the delivery and potentially reduces the abuse liability of d-amphetamine after oral administration, is in late-stage clinical testing as an augmenting agent to SSRIs/SNRIs in treatment-resistant depression.

46. Newer antidepressants

47. Newer Antidepressants Triple reuptake inhibitors (TRIs) or serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs) are in clinical testing to confirm that if one mechanism is good (i.e., SSRI) and two mechanisms are better (i.e., SNRI), then maybe targeting all three mechanisms of the trimonoamine neurotransmitter system would be the best in terms of efficacy. amitifidine , GSK-372475, BMS-820836, tasofensine , PRC200-SS, SEP-225289

48. Newer Antidepressants Multimodal agents - it appears that combining multiple modes of monoaminergic action may enhance efficacy for some patients with depression reuptake blockade (at SERT, DAT, NET) with actions at G-protein receptors (e.g., 5HT1A,5HT2C,5HT7, α2 receptors) with actions at ion-channel receptors (5HT3 receptors and possibly NMDA receptors). vilazodone (combination of SERT plus 5HT1A partial agonist actions) Vilazodone has been speculated to have three potential benefits including faster onset of action, greater efficacy, and better tolerability owing to its SPARI properties

49. Newer Antidepressants Vortioxetine acts via all three modes with a combination of five pharmacologic actions: reuptake blocking mode (SERT), Gprotein receptor mode (5HT1A and 5HT1B/D partial agonist, 5HT7 antagonist), and ion-channel mode (5HT3 antagonist). The clinical properties of vortioxetine suggest antidepressant efficacy without sexual dysfunction, and the pharmacologic properties suggest the potential for either pro-cognitive effects, or enhanced antidepressant efficacy compared to agents with fewer modes of action and effects on fewer neurotransmitters.

50. Newer Antidepressants NMDA Blockade One of the most interesting developments in recent years has been the observation that infusions of subanesthetic doses of ketamine can exert an immediate antidepressant effect in patients with treatment resistant unipolar or bipolar depression, and can immediately reduce suicidal thoughts. Unfortunately, the effects are not sustained for more than a few days, but this has led investigators to search for an oral ketamine-like agent that could have rapid onset and sustained efficacy in treatment-resistant patients.

51. Newer Antidepressants Ketamine acts as an open channel inhibitor at NMDA glutamate receptors and causes downstream release of glutamate One candidate for an “oral ketamine” that acts on NMDA receptors is the cough medicine dextromethorphan. Both ketamine and dextromethorphan share actions not only at NMDA receptors, but also at σ receptors, µ-opioid receptors, SERT, and NET, but with different affinities Esketamine , the S-enantiomer of racemic ketamine, which has a higher affinity for the NMDA receptor than the R-enantiomer, has recently been approved

52. Newer Antidepressants Glutamate activity heavily modulates synaptic potentiation; this is specifically modulated through NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors. Ketamine is an NMDA receptor antagonist; however, its rapid antidepressant effects may also be related to indirect effects on AMPA receptor signaling and the mammalian target of rapamycin (mTOR) pathway. it may be that blockade of the NMDA receptor leads to rapid activation of AMPA and mTOR signaling pathways. this in turn would lead to rapid AMPA-mediated synaptic potentiation.

53. Newer Antidepressants

54. Newer Antidepressants

55. Newer Antidepressants Rapastinel (former developmental code names GLYX-13, BV-102) is a novel antidepressant. acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex. In addition to rapastinel , another novel congener compound NRX-1074 ( Apimostinel ) has been developed. Apimostinel is an orally bioavailable compound and is more potent than rapastinel .

56. Newer Antidepressants Agomelatine belongs to the melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2B and 5-HT2C receptors antagonism (MASSA) class . Resynchronization of biological rhythms may be a therapeutically relevant property for an antidepressant agent as depression involves a disruption of normal circadian rhythm.

57. Newer Antidepressants Estrogen based treatment options for perimenopausal women many different kinases that are controlled by estrogens regulate neurotransmitter transporters. E2 can rapidly alter several signaling pathways to cause efflux of dopamine via the DAT; PKC and MEK (the enzyme upstream of the MAPK-ERKs) are activated by E2. Multiple estrogens induce activation of MAPKs which in turn affect DAT.

58. Newer Antidepressants Estradiol replacement therapy (ERT) has demonstrated efficacy in treating perimenopause-related depression. Unfortunately, there are long-term risks associated with ERT. Selective estrogen receptor modulators (SERMS), such as raloxifene, and phytoestrogens, such as rimostil , have estrogen-like properties and may offer a safer alternative to ERT.

59. Newer Antidepressants Brexanolone Brexanolone (BRX) is a solution of allopregnanolone that modulates the GABA-A receptor BRX might be an ideal treatment in women with access to hospitals and who have a history of severe PPD with a prolonged recovery time or limited response to psychotherapy or serotonin reuptake inhibitors. The findings of efficacy studies are limited because they did not report outcomes for study subjects beyond 30 days; therefore, further trials are needed to assess BRX’s long-term efficacy and safety and its place in treatment algorithms.

60. Newer Antidepressants Drugs acting on HPA axis pexacerfont, a CRF1 antagonist Antalarmin , a novel CRH receptor type 1 antagonist Glucocorticoid receptor antagonists like metyrapone, ketoconazole, and aminoglutethimide. Vasopressin 1B receptor antagonists - TS-121, ABT‐436.

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62. References Raloxifene and Rimostil for Perimenopause-Related Depression - Full Text View - ClinicalTrials.gov. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT00030147. Published 2021. Accessed March 23, 2021. Walf , A. A., & Frye, C. A. (2010). Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior , whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats. Behavioural pharmacology, 21(3), 231–240. https://doi.org/10.1097/fbp.0b013e32833a5cb0

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