Tips and pearls

The SNRI class of antidepressants is approved for the treatment of MDD and also a myriad of anxiety disorders

Each SNRI (except for levomilnacipran) appears to be more serotonergic at low doses, and more noradrenergic at higher doses, allowing the clinician to tailor treatment based upon how much of each neurotransmitter is desired

It may be possible to create SNRI-like mechanisms of action or facilitate both neurotransmitters through rational polypharmacy approaches when one starts with an SSRI monotherapy

Classically, a clinician may add a predominant NRI TCA such as desipramine (Norpramin) or the NDRI bupropion-XL (Wellbutrin-XL) to an SSRI

• – A more novel approach would be to augment with certain atypical antipsychotics that have NRI potential (quetiapine [Seroquel]), ziprasidone (Geodon), stimulants, or the ADHD medication atomoxetine in order to convert an SSRI into an SNRI-similar mechanism of action. Mirtazapine (Remeron) does not have an NRI component but can facilitate NET through alpha-2a receptor antagonism

Two-minute tutorial

Is quetiapine (Seroquel) an antipsychotic, anti-manic, antidepressant, anxiolytic, or a hypnotic?

Quetiapine (Seroquel) and its slow-release preparation quetiapine-XR (Seroquel-XR) are multifactorial drugs. The parent drug and its metabolite, norquetiapine, both have complicated, multimodal pharmacodynamic profiles, which lend themselves to treating a myriad of psychiatric symptoms

These two products carry approvals for the treatment of schizophrenia, manic or mixed states associated with bipolar disorder, as monotherapy or as adjunctive treatment to lithium or divalproex, bipolar depression, maintenance treatment in bipolar disorder in conjunction with those patients already taking lithium or divalproex, as adjunctive therapy in patients with MDD who have failed to respond to initial antidepressant therapy, and have published data currently suggesting its use for GAD. Clinically, quetiapine (Seroquel) and quetiapine-XR (Seroquel-XR) are often used in an off-label manner to treat the symptom of insomnia

These drugs may exhibit different pharmacological properties at different dosing levels. For example, these two agents appear to be better at treating MDD at lower doses, mania at moderate doses, and psychosis at high doses. In the literature, dosing strategies range from 50 mg/d to 1500 mg/d

Although many of the atypical antipsychotics appear to be effective in treating affective disorder symptoms, the risks and benefits must be weighed by both the clinician and the patient equally, given the ability of atypical antipsychotics to cause metabolic and movement disorders

Pharmacodynamics of quetiapine and norquetiapine

Higher doses (400–800 mg/d) are required to control the symptoms associated with mania or psychosis, as its D2 receptor antagonism is quite weak due to low affinity compared to all other atypical antipsychotics. Doses greater than 800 mg/d and up to 2400 mg/d have been noted in anecdotal reports

This does not suggest it has low effectiveness, but rather requires more dosing milligrams to maintain at least 60% D2 receptor occupancy to stop psychosis or mania. This low affinity may allow for quetiapine to maintain a lower EPS side-effect profile as a benefit

Quetiapine is approved as a monotherapy for bipolar depression, and also as an augmentation strategy when added to SSRI or SNRI antidepressants in unipolar MDD. D2 antagonism cannot explain its antidepressant effectiveness

Multiple, confirmative, regulatory studies have consistently shown that lower doses of quetiapine are effective in treating depressive states (150–600 mg/d). Quetiapine also has some limited data in the treatment of GAD at doses starting at 50 mg/d

Treating depression or anxiety at these lower doses likely does not inhibit DA transmission compared to higher doses used in mania or schizophrenia

Its antidepressant effects may come from several different mechanisms of action

• – This drug has marked H1 receptor antagonism (antihistamine properties), which promotes sedation and weight gain. H1 receptor antagonism is also the theoretical mechanism of anxiolysis utilized by the approved anxiolytic agent, hydroxyzine (Vistaril/Atarax), and a mechanism for hypnosis utilized by over the counter diphenhydramine (Benadryl) products and the prescription sleep-inducing agent doxepin (Silenor). Therefore, H1 receptor blockade in certain patients causes sedation and somnolence as adverse effects, but in others may be regarded as providing the positive clinical effects of anxiolysis and hypnosis, which are beneficial in those with MDD or GAD

• – Quetiapine also has 5-HT2A and 2C receptor antagonism. The former lowers EPS risk and also allows more cortical noradrenergic transmission to occur. The 5-HT2C blockade hypothetically allows for loss of interneuronal GABA inhibition in the brainstem, with resultant increases in cortical DA transmission from the VTA and NE from the LC. Facilitation of these two monoamines may improve mood, drive, motivation, concentration, and vigilance

• – Finally, 5-HT2C antagonism may allow for improved sleep architecture, sleep efficiency, and greater slow wave sleep capacity. The antihistamine and promonoamine properties are suggestive of an antidepressant profile

• – Specifically, the active norquetiapine metabolite has two interesting features

  • It allows for 5-HT1A receptor partial agonism similar to the approved anxiolytic buspirone (BuSpar) and the recently approved novel antidepressant vilazodone (Viibryd)

  • It has NRI properties similar to properties possessed by approved unipolar antidepressants such as venlafaxine-XR (Effexor-XR), duloxetine (Cymbalta), bupropion-XL (Wellbutrin-XL), and nortriptyline (Pamelor)

In summary, the quetiapine products possess several defined anxiolytic and antidepressant pharmacodynamic properties:

• – 5-HT2A and 2C receptor antagonism (similar to nefazodone [Serzone], mirtazapine [Remeron], and trazodone [Desyrel])

• – 5-HT1A partial receptor antagonism (similar to buspirone [BuSpar], vilazodone [Viibryd], and vortioxetine [Brintellix])

• – NRI properties (similar to bupropion-XL [Wellbutrin-XL], and atomoxetine [Strattera])

• – H1 receptor antagonism (similar to hydroxyzine [Vistaril], and doxepin [Silenor])

These five distinct properties may lend to the ability of this drug to treat depression and/or anxiety as a monotherapy or augmentation strategy

Posttest self-assessment question and answer

What pharmacologic properties of quetiapine (Seroquel) lend themselves to providing clinical antidepressant and anxiolytic properties?

A. 5-HT1A partial receptor agonism (similar to buspirone [BuSpar], vilazodone [Viibryd])

B. NRI properties (similar to bupropion-XL [Wellbutrin-XL])

C. H1 receptor antagonism (similar to hydroxyzine [Vistaril], doxepin [Silenor])

D. SSRI properties similar to fluoxetine (Prozac)

E. GABA-A receptor modulating properties similar to diazepam (Valium)

F. A, B, and C

G. All of the above

Answer: F

Quetiapine possesses 5-HT1A receptor partial agonism and NRI properties, both via its active metabolite norquetiapine. It also has antihistaminergic properties allowing for sedation, anxiolysis, and hypnosis. It does not possess SSRI or BZ-like qualities.

References

1.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Revised, 5th edn. Washington, DC: American Psychiatric Association Press, 2013.

2.Stahl SM. Stahl’s Essential Psychopharmacology, 4th edn. New York, NY: Cambridge University Press, 2013.

3.Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide, 5th edn. New York, NY: Cambridge University Press, 2014.

4.Malcovati L, Della Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol 2005; 23:7594–603.

5.Rickels K, Pollack MH, Sheehan DV, Haskins JT. Efficacy of venlafaxine extended-release (XR) capsules in non-depressed outpatients with generalized anxiety disorder. Am J Psychiatry 2000; 57:968–74.

6.Schwartz TL, Stahl SM. Treatment strategies for dosing the second generation antipsychotics. CNS Neurosci Ther 2011; 17:110–17.

7.Kroeze WK, Roth BL. The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis. Biol Psychiatry 1988; 44:1128–42.

8.Stahl SM. Enhancing outcomes from major depression: using antidepressant combination therapies with multifunctional pharmacologic mechanisms from the initiation of treatment. CNS Spectr 2010; 15:79–94.

9.Stahl SM. Essential Psychopharmacology: The Prescriber’s Guide, 4th edn. New York, NY: Cambridge University Press, 2011.

10.Schwartz TL, Stahl SM. Optimizing antidepressant management of depression: current status and future perspectives. In: Cryan JF, Leonard BE, eds. Depression: From Psychopathology to Pharmacotherapy. Basel: Karger, 2010; pp. 254–67.

11.Sorbera LA, Rabasseda X., Silvestre J, Castaner J. Vilazodone hydrochloride–antidepressant–5-HT1A partial agonist–5-HT reuptake inhibitor. Drugs Future 2001; 26:247–52.

12.Katzman MA, Vermani M, Jacobs L, et al. Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial. J Anxiety Disord 2008; 8:1480–6.

13.Wang Z, Kemp DE, Chan PK, et al. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. Intern J Neuropsychopharmacol 2011; 14:131–42.

14.Katzman MA, Brawman-Mintzer O, Reyes EB, et al. Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial. Intern Clin Psychopharmacol 2011; 26:11–24.

Patient file

The Case:

Interruptions, ammonia, and dyskinesias, oh my!

The Question:

Can stimulants complicate bipolar presentations?

The Psychopharmacological dilemma:

Finding an effective treatment for mania and mixed features without exacerbating symptoms and side effects