Continuing Education Activity

While antidepressants may be the drug of choice for depression, they also have FDA approval as treatments for other medical disorders. For example, antidepressants are useful in the treatment of obsessive-compulsive disorder, social phobia, panic disorder, generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Antidepressants also have non-FDA approved, off-label indications. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of antidepressant therapy in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients receiving antidepressant medications for conditions that respond to this medication class.


  • Identify the approved and off-label indications for antidepressant medications.
  • Summarize the mechanism of action of the various class members in the antidepressant drug class.
  • Outline the adverse events, contraindications, and potential toxicities of various antidepressant medications.
  • Explain the importance of antidepressant therapy and how it affects therapeutic strategy as it pertains to improving care coordination and communication among the interprofessional team when using these agents to achieve therapeutic outcomes.


While antidepressants may be the drug of choice for depression, they also have FDA approval as treatments for other medical disorders. For example, antidepressants are useful in the treatment of obsessive-compulsive disorder, social phobia, panic disorder, generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD).[1] Antidepressants also have non-FDA approved, off-label indications. For example, tricyclic antidepressants are prescribed for pain, insomnia, and migraine. Trazodone, a serotonin modulator, is used off-label for insomnia.[2]

Mechanism of Action

The different classes of antidepressants all work in slightly different ways and target certain neurotransmitters to modulate mood and behavior. All currently licensed antidepressants are believed to work by increasing the neurotransmitters serotonin or norepinephrine, or both, in the synapse. The mechanisms to increase these neurotransmitters vary, though antidepressant drugs target reuptake by the nerve terminals.[3] For example, selective serotonin reuptake inhibitors (SSRIs) work by inhibiting 5-HT reuptake by the presynaptic cleft in a synapse, thus increasing available serotonin levels.[4] Serotonin and norepinephrine reuptake inhibitors (SNRIs) block serotonin reuptake, like SSRIs, however, they also block norepinephrine reuptake in the synapse.[5]

Atypical antidepressants have different mechanisms of action. Bupropion, for example, works by inhibiting the reuptake of dopamine and norepinephrine at the presynaptic cleft.[6] Another atypical antidepressant, agomelatine, works by agonizing melatonin receptors MT1 and MT2 while antagonizing serotonergic 5-HT2C receptors, promoting dopamine and norepinephrine release.[7] Serotonin modulators, like nefazodone, may work by down-regulating postsynaptic serotonin 5-HT2A receptors.[6]

Tricyclic antidepressants, like amitriptyline, are thought to work by inhibiting the reuptake of serotonin and norepinephrine.[8]

Lastly, monoamine oxidase inhibitors (MAOIs), work by inhibiting the monoamine oxidase enzyme, which catabolizes serotonin, norepinephrine, and dopamine.[9] Another antidepressant drug that does not work by blocking reuptake is mirtazapine. Mirtazapine works by blocking alpha-2 adrenergic receptors on the cell bodies and nerve terminals, promoting the release of norepinephrine into the synapse. Furthermore, mirtazapine antagonizes 5-HT and 5-HT receptors, which has been shown to increase norepinephrine and dopamine in the cortical regions of the brain.[3]


Currently, commercially available antidepressants are available to be administered in the form of oral tablets, oral extended-release tablets, oral suspensions, topical creams, and transdermal patches. Studies are examining alternative administration routes, via inhalation, intranasal, sublingual, and rectal forms. These alternative routes are not yet commercially available for antidepressant therapy.[10]

Adverse Effects

Among the most prevalent side effects of antidepressants include sexual dysfunction, drowsiness, weight gain, insomnia, anxiety, dizziness, headache, dry mouth, blurred vision, nausea, rash, and tremor. Patients may also describe asthenia and malaise while on antidepressant therapy. Clinicians may note symptoms of hyperprolactinemia, syndrome of inappropriate antidiuretic hormone (SIADH), and hyponatremia in patients taking antidepressants.[11]


There are several scenarios where antidepressant use may be contraindicated. These scenarios vary between and within classes. Antidepressants should be used with caution in patients with known hypersensitivities or who are taking other psychotropic medications. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), for example, should not be taken with other SSRIs, monoamine oxidase inhibitors, tricyclic antidepressants, and other psychotropics; this is due to the risk of serotonin syndrome, which can lead to severe neuromuscular and autonomic symptoms.[12]

Tricyclic antidepressants can provide another good example of relative contraindications in antidepressant therapy. Clinicians should be mindful when prescribing tricyclic antidepressants to individuals with cardiovascular disease. Tricyclic antidepressants have been shown to cause orthostatic hypotension. Additionally, in patients with preexisting bundle-branch disease, tricyclic antidepressants may lead to heart block.[13] Buproprion, an atypical antidepressant, has seizure disorder listed as a major contraindication. This contraindication applies to patients with an active seizure diagnosis or with a history of prior seizure activity. Like other antidepressants, bupropion should not be used in patients taking monoamine oxidase inhibitors, or drugs that can lower the seizure threshold.[14]


Clinicians may find utility in monitoring antidepressant levels in their patients. This strategy, termed therapeutic drug monitoring, is based on serum or plasma concentrations of antidepressants, which researchers believe is a more reliable index than dosage. Therapeutic drug monitoring of antidepressants is particularly useful with agents that have a reliable therapeutic range established. Nonetheless, it may also be helpful in patients who are refractory to treatment, are having adverse effects, or have a history of noncompliance. Therapeutic drug monitoring is expensive, so clinicians must weigh the benefits to the cost of the study.[14]


The toxicity of antidepressants varies greatly not only between classes but within them as well. Antidepressants are frequently used to self-poison in an attempt to commit suicide, particularly in women. In general, the older tricyclic antidepressants (TCAs) are more toxic than newer antidepressant classes. Such as selective serotonin reuptake inhibitors (SSRIs). Researchers can track drug toxicity using the fatal toxicity index, a ratio of self-poisoning mortality rates to prescription rates. Researchers may also employ the use of a case fatality index, which compares fatal versus non-fatal self-poisoning attempts. With that said, clinicians may wish to alter treatment strategies depending on a patient’s suicide risk.[15]

Enhancing Healthcare Team Outcomes

While antidepressants are beneficial on their own in the treatment of depression and their other indications, many patients fail to receive adequate treatment. To effectively manage depression, a clinician must employ an interprofessional team-centered approach to effectively detect and diagnose the depression, provide patient education, use evidence-based pharmacotherapy, provide close-follow up for compliance, identify side effects, and determine treatment effectiveness.[16] Studies show multiple factors contribute to patient compliance with antidepressant medications. Generally, concerns about drug side effects were predictive of adherence.[17] Patient comorbidities can also contribute to compliance with antidepressant medications. Particularly, conditions that impact one’s cognitive status can lead to noncompliance.[18] Alcohol or substance abuse, cardiovascular disease, metabolic conditions, low age, low-income residents, and old generation antidepressant medication usage were all predictive of lower adherence, particularly in the acute phase.[19]

Identifying and addressing these concerns is pivotal in the management of depression and the prescription of antidepressant medications. Several randomized controlled trials support the collaborative care approach in treating depression. Suggestions are that the program includes a depression care manager, psychiatric consultant, prescribing physician, and the patient. The depression care manager will manage the antidepressants, provide education, and coordinate referrals if necessary. The psychiatric consultant will be responsible for improving treatment strategies in patients who are not meeting expectations.[20]

Other members of the healthcare team who must contribute to antidepressant care include the pharmacist and the nursing staff. Psychiatric specialty nurses are best equipped to recognize treatment failure, counsel patients on the medication, monitor adverse events, and assess compliance. Pharmacists can verify agent selection, dosing, and perform medication reconciliation for drug interactions. Both pharmacists and nurses need open access to the prescriber if they find any areas of concern - in this way, all members of the interprofessional team function as one unit, driving positive patient outcomes. [Level V]

Article Details

Article Author

Zachary Sheffler

Article Editor:

Sara Abdijadid


2/7/2021 4:31:26 PM

PubMed Link:




Schatzberg AF, New indications for antidepressants. The Journal of clinical psychiatry. 2000;     [PubMed PMID: 10926050]


Wong J,Motulsky A,Abrahamowicz M,Eguale T,Buckeridge DL,Tamblyn R, Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ (Clinical research ed.). 2017 Feb 21;     [PubMed PMID: 28228380]


Harmer CJ,Duman RS,Cowen PJ, How do antidepressants work? New perspectives for refining future treatment approaches. The lancet. Psychiatry. 2017 May;     [PubMed PMID: 28153641]


Sangkuhl K,Klein TE,Altman RB, Selective serotonin reuptake inhibitors pathway. Pharmacogenetics and genomics. 2009 Nov;     [PubMed PMID: 19741567]


Lambert O,Bourin M, SNRIs: mechanism of action and clinical features. Expert review of neurotherapeutics. 2002 Nov;     [PubMed PMID: 19810918]


Horst WD,Preskorn SH, Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. Journal of affective disorders. 1998 Dec;     [PubMed PMID: 10333980]


Hickie IB,Rogers NL, Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet (London, England). 2011 Aug 13;     [PubMed PMID: 21596429]


Gillman PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British journal of pharmacology. 2007 Jul;     [PubMed PMID: 17471183]


Fiedorowicz JG,Swartz KL, The role of monoamine oxidase inhibitors in current psychiatric practice. Journal of psychiatric practice. 2004 Jul;     [PubMed PMID: 15552546]


Kaminsky BM,Bostwick JR,Guthrie SK, Alternate Routes of Administration of Antidepressant and Antipsychotic Medications. The Annals of pharmacotherapy. 2015 Jul;     [PubMed PMID: 25907529]


Nierenberg AA,Ostacher MJ,Huffman JC,Ametrano RM,Fava M,Perlis RH, A brief review of antidepressant efficacy, effectiveness, indications, and usage for major depressive disorder. Journal of occupational and environmental medicine. 2008 Apr;     [PubMed PMID: 18404015]


Drug interactions with selective serotonin reuptake inhibitors, especially with other psychotropics. Prescrire international. 2001 Feb;     [PubMed PMID: 11503857]


Glassman AH,Bigger JT Jr, Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review. Archives of general psychiatry. 1981 Jul;     [PubMed PMID: 7247643]


Zwar N,Richmond R, Bupropion sustained release. A therapeutic review of Zyban. Australian family physician. 2002 May;     [PubMed PMID: 12043548]


Hawton K,Bergen H,Simkin S,Cooper J,Waters K,Gunnell D,Kapur N, Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. The British journal of psychiatry : the journal of mental science. 2010 May;     [PubMed PMID: 20435959]


Dwight-Johnson M,Unutzer J,Sherbourne C,Tang L,Wells KB, Can quality improvement programs for depression in primary care address patient preferences for treatment? Medical care. 2001 Sep;     [PubMed PMID: 11502951]


Aikens JE,Kroenke K,Swindle RW,Eckert GJ, Nine-month predictors and outcomes of SSRI antidepressant continuation in primary care. General hospital psychiatry. 2005 Jul-Aug;     [PubMed PMID: 15993253]


Brown C,Battista DR,Bruehlman R,Sereika SS,Thase ME,Dunbar-Jacob J, Beliefs about antidepressant medications in primary care patients: relationship to self-reported adherence. Medical care. 2005 Dec;     [PubMed PMID: 16299431]


Akincigil A,Bowblis JR,Levin C,Walkup JT,Jan S,Crystal S, Adherence to antidepressant treatment among privately insured patients diagnosed with depression. Medical care. 2007 Apr;     [PubMed PMID: 17496721]


Gilbody S,Bower P,Fletcher J,Richards D,Sutton AJ, Collaborative care for depression: a cumulative meta-analysis and review of longer-term outcomes. Archives of internal medicine. 2006 Nov 27;     [PubMed PMID: 17130383]