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'''Second-generation [[antidepressant]]s''' are used to treat [[depression]] and are a "structurally and mechanistically diverse group of drugs that are not [[tricyclic antidepressant|tricyclics]] or [[monoamine oxidase inhibitor]]s. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake."<ref>{{MeSH|Second-generation antidepressants}}</ref>
'''Second-generation [[antidepressant]]s''' are the most recently developed class of drugs used to treat depression. They are characterized by dissimilarity to [[tricyclic antidepressant]]s and [[monoamine oxidase inhibitor]]s, and heterogeneity of chemical form and pharmacological action. Most second-generation antidepressants commonly used in the practice of psychiatry inhibit the reuptake of monoamine neurotransmitters, most commonly [[serotonin]], less frequently [[norepinephrine]], and occasionally [[dopamine]].<ref>{{MeSH|Second-generation antidepressants}}</ref>


==Classification==
==Classification==
Second-generation antidepressants are classified by the [[biogenic amine receptor]] that they affect.
Second-generation antidepressants are classified by the [[biogenic amine receptor]] that they affect.
===Selective serotonin reuptake inhibitors(SSRI)===
===Selective serotonin reuptake inhibitors(SSRI)===
* [[Citalopram]] (generic)
{{main|Selective serotonin uptake inhibitor}}
* [[Citalopram]] (generic). The [[United States of America]] [[Food and Drug Administration]] has issued a warning to not use higher doses because of use of the [[cytochrome P-450]] system and also arrhythmias.<ref>{{cite web |url= http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm297624.htm |title=Safety Alerts for Human Medical Products &#62; Celexa (citalopram hydrobromide) - Drug Safety Communication: Revised Recommendations, Potential Risk of Abnormal Heart Rhythms |author=anonymous |work=fda.gov |year=2012 [last update] |accessdate=March 29, 2012}}</ref>
* [[Escitalopram]]
* [[Fluoxetine]] (generic)
* [[Fluoxetine]] (generic)
* [[Sertraline]]
* [[Paroxetine]] (generic). May cause more sexual dysfunction.<ref name="pmid22147715">{{cite journal| author=Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M et al.| title=Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. | journal=Ann Intern Med | year= 2011 | volume= 155 | issue= 11 | pages= 772-85 | pmid=22147715 | doi=10.1059/0003-4819-155-11-201112060-00009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22147715  }} </ref>
* [[Sertraline]] (generic). May cause more diarrhea.<ref name="pmid22147715">{{cite journal| author=Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M et al.| title=Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. | journal=Ann Intern Med | year= 2011 | volume= 155 | issue= 11 | pages= 772-85 | pmid=22147715 | doi=10.1059/0003-4819-155-11-201112060-00009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22147715  }} </ref>


===Serotonin 5-HT2–receptor agonist===
===Serotonin 5-HT<sub>2A</sub>–receptor antagonist===
* [[Nefazodone]]
* [[Nefazodone]]


===Serotonin norepinephrine reuptake inhibitors (SNRI)===
===Serotonin norepinephrine reuptake inhibitors (SNRI)===
* [[Duloxetine]]
* [[Duloxetine]]
* [[Venlafaxine]] (generic)
* [[Milnacipran]]
* [[Venlafaxine]] (generic) May cause more nausea and vomiting.<ref name="pmid22147715">{{cite journal| author=Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M et al.| title=Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. | journal=Ann Intern Med | year= 2011 | volume= 155 | issue= 11 | pages= 772-85 | pmid=22147715 | doi=10.1059/0003-4819-155-11-201112060-00009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22147715  }} </ref>
 
===Noradrenergic and specific serotonergic antidepressant (NaSSA)===
[[Mirtazapine]] is a noradrenergic and specific serotonergic antidepressant (NaSSA). Mirtazapine is a tetracyclic compound, is also classified as a [[tricyclic antidepressant]] by the [[National Library of Medicine]] in the [[United States of America]].<ref>{{MeSH|Mirtazapine }}</ref>


===Norepinephrine uptake inhibitor===
===Norepinephrine uptake inhibitor===
* [[Maprotiline]]
* [[Maprotiline]] is a tetracyclic compound.


===Dopamine reuptake inhibitor===
===Dopamine reuptake inhibitor===
Line 24: Line 31:
==Mechanism of action==
==Mechanism of action==
[[Depression]] may be due to the monoamine-deficiency hypothesis, which is a "deficiency in [[serotonin]] or [[norepinephrine]] neurotransmission in the brain."<ref name="pmid18172175">{{cite journal |author=Belmaker RH, Agam G |title=Major depressive disorder |journal=N. Engl. J. Med. |volume=358 |issue=1 |pages=55–68 |year=2008 |pmid=18172175 |doi=10.1056/NEJMra073096|url=http://content.nejm.org/cgi/content/full/358/1/55}}</ref>
[[Depression]] may be due to the monoamine-deficiency hypothesis, which is a "deficiency in [[serotonin]] or [[norepinephrine]] neurotransmission in the brain."<ref name="pmid18172175">{{cite journal |author=Belmaker RH, Agam G |title=Major depressive disorder |journal=N. Engl. J. Med. |volume=358 |issue=1 |pages=55–68 |year=2008 |pmid=18172175 |doi=10.1056/NEJMra073096|url=http://content.nejm.org/cgi/content/full/358/1/55}}</ref>
By blocking the ''reuptake'' by the ''releasing'' neuron of [[norepinephrine]], [[serotonin]] or both, second-generation antidepressants may overcome the mono-amine deficiency.<ref name="isbn0-07-145153-6">{{cite book |author=Katzung, Bertram G. |authorlink= |editor= |others= |title=Basic and Clinical Pharmacology |edition=10th |chapter=Antidepressant Agents |chapterurl= |language= |publisher=McGraw-Hill Medical Publishing Division |location=New York |year=2006 |origyear= |pages= |quote= |isbn=0-07-145153-6 |oclc= |doi= |url=http://www.accessmedicine.com/resourceTOC.aspx?resourceID=16 |accessdate=}}</ref> Some members of this class, perhaps in a dose-dependent manner, also block [[dopamine]] release.
In contrast, some first-generation antidepressants act through an alternate mechanism. [[Monoamine oxidase inhibitor]]s raise levels of dopamine, norepinephrine and serotonin, in the synaptic gap between the releasing and receiving neurons, by blocking one of two subtypes of the enzyme in the receiving cell which metabolizes the three bioamines. These medications are named for the enzyme they suppress, [[monoamine oxidase]]. [[Tricyclic antidepressant]]s suppress catechol-O-methyl transferase, and inhibit the reuptake of serotonin and norepinephrine, but also produce significant side effects, most prominently [[anticholinergic]] in nature.


==Effectiveness==
==Effectiveness==
Line 34: Line 45:
* "when treating symptom clusters in patients with accompanying depression, second-generation antidepressants did not differ in efficacy in treating accompanying [[anxiety]], [[pain]], and [[Somatoform disorder|somatization]]. Limited evidence suggests that some agents may be more effective in treating [[insomnia]]"
* "when treating symptom clusters in patients with accompanying depression, second-generation antidepressants did not differ in efficacy in treating accompanying [[anxiety]], [[pain]], and [[Somatoform disorder|somatization]]. Limited evidence suggests that some agents may be more effective in treating [[insomnia]]"
* "most of the second-generation antidepressants had similar adverse effects...paroxetine was associated with an increased risk for sexual dysfunction."
* "most of the second-generation antidepressants had similar adverse effects...paroxetine was associated with an increased risk for sexual dysfunction."
The effectiveness is antidepressants depends on the severity of a patient's depression. This relationship may be due to thedeclining effect of placebo among more severely depressed patients.<ref name="pmid20042812">{{cite journal| author=Lo B| title=Commentary: Conflict of interest policies: an opportunity for the medical profession to take the lead. | journal=Acad Med | year= 2010 | volume= 85 | issue= 1 | pages= 9-11 | pmid=20042812
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=20042812 | doi=10.1097/ACM.0b013e3181c46e96 }} </ref>
Second-generation antidepressants are not clearly safer than [[tricyclic antidepressant]]s.<ref name="pmid21810375">{{cite journal| author=Coupland CA, Dhiman P, Barton G, Morriss R, Arthur A, Sach T et al.| title=A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database. | journal=Health Technol Assess | year= 2011 | volume= 15 | issue= 28 | pages= 1-202, iii-iv | pmid=21810375 | doi=10.3310/hta15280 | pmc= | url= }} </ref>
{| class="wikitable" align="right"
|+ The effectiveness of antidepressants depending on severity of depression<ref name="pmid20042812">{{cite journal| author=Lo B| title=Commentary: Conflict of interest policies: an opportunity for the medical profession to take the lead. | journal=Acad Med | year= 2010 | volume= 85 | issue= 1 | pages= 9-11 | pmid=20042812
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=20042812 | doi=10.1097/ACM.0b013e3181c46e96 }} </ref>
!American Psychiatric Association classification of severity<ref name="isbn1-58562-218-4">{{cite book |author=First, Michael B. |title=Handbook of Psychiatric Measures, Second Edition |publisher=American Psychiatric Publishing, Inc |location= |year=2007 |pages= |isbn=1-58562-218-4 |oclc= |doi= |accessdate=}}</ref>!! [http://healthnet.umassmed.edu/mhealth/HAMD.pdf Hamilton Depression Rating Scale] (HDRS)!![[Number needed to treat]]!!Clinical significance (NICE)<ref>National Institute for Clinical Excellence. [http://guidance.nice.org.uk/CG90 Depression: Management of Depression in Primary and Secondary Care]. London, England: National Institute for Clinical Excellence; 2004.</ref>
|-
| Mild to moderate|| < 19|| 16|| No
|-
| Severe|| 19 - 22|| 11|| No
|-
| Very severe|| > 22|| 4|| Yes
|}
[[Meta-analysis|Meta-analyses]] conflict about the relative effectiveness of the second-generation antidepressants with no difference reported<ref>{{Cite journal | volume = 149 | issue = 10 | pages = 734-750 | last = Gartlehner | first = Gerald | coauthors = Bradley N. Gaynes, Richard A. Hansen, Patricia Thieda, Angela DeVeaugh-Geiss, Erin E. Krebs, Charity G. Moore, Laura Morgan, Kathleen N. Lohr | title = Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians | journal = Ann Intern Med | accessdate = 2008-11-18 | date = 2008-11-18 | url = http://www.annals.org/cgi/content/abstract/149/10/734 }}</ref> and superiority of [[sertraline]] and [[escitalopram]] reported. <ref>Cipriani A. et al (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. The Lancet {{doi|10.1016/s0140-6736(09)60046-5}}</ref>


==References==
==References==
<references/>
<references/>

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Second-generation antidepressants are the most recently developed class of drugs used to treat depression. They are characterized by dissimilarity to tricyclic antidepressants and monoamine oxidase inhibitors, and heterogeneity of chemical form and pharmacological action. Most second-generation antidepressants commonly used in the practice of psychiatry inhibit the reuptake of monoamine neurotransmitters, most commonly serotonin, less frequently norepinephrine, and occasionally dopamine.[1]

Classification

Second-generation antidepressants are classified by the biogenic amine receptor that they affect.

Selective serotonin reuptake inhibitors(SSRI)

For more information, see: Selective serotonin uptake inhibitor.

Serotonin 5-HT2A–receptor antagonist

Serotonin norepinephrine reuptake inhibitors (SNRI)

Noradrenergic and specific serotonergic antidepressant (NaSSA)

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). Mirtazapine is a tetracyclic compound, is also classified as a tricyclic antidepressant by the National Library of Medicine in the United States of America.[4]

Norepinephrine uptake inhibitor

Dopamine reuptake inhibitor

Mechanism of action

Depression may be due to the monoamine-deficiency hypothesis, which is a "deficiency in serotonin or norepinephrine neurotransmission in the brain."[5]

By blocking the reuptake by the releasing neuron of norepinephrine, serotonin or both, second-generation antidepressants may overcome the mono-amine deficiency.[6] Some members of this class, perhaps in a dose-dependent manner, also block dopamine release.

In contrast, some first-generation antidepressants act through an alternate mechanism. Monoamine oxidase inhibitors raise levels of dopamine, norepinephrine and serotonin, in the synaptic gap between the releasing and receiving neurons, by blocking one of two subtypes of the enzyme in the receiving cell which metabolizes the three bioamines. These medications are named for the enzyme they suppress, monoamine oxidase. Tricyclic antidepressants suppress catechol-O-methyl transferase, and inhibit the reuptake of serotonin and norepinephrine, but also produce significant side effects, most prominently anticholinergic in nature.

Effectiveness

Regarding the use of second-generation antidepressants, clinical practice guidelines by the American College of Physicians recommend:[7] [8]

  • "when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences"
  • "second-generation antidepressants did not significantly differ in efficacy, effectiveness, or quality of life. Mirtazapine had a significantly faster onset of action"
  • "when treating symptom clusters in patients with accompanying depression, second-generation antidepressants did not differ in efficacy in treating accompanying anxiety, pain, and somatization. Limited evidence suggests that some agents may be more effective in treating insomnia"
  • "most of the second-generation antidepressants had similar adverse effects...paroxetine was associated with an increased risk for sexual dysfunction."

The effectiveness is antidepressants depends on the severity of a patient's depression. This relationship may be due to thedeclining effect of placebo among more severely depressed patients.[9]

Second-generation antidepressants are not clearly safer than tricyclic antidepressants.[10]

The effectiveness of antidepressants depending on severity of depression[9]
American Psychiatric Association classification of severity[11] Hamilton Depression Rating Scale (HDRS) Number needed to treat Clinical significance (NICE)[12]
Mild to moderate < 19 16 No
Severe 19 - 22 11 No
Very severe > 22 4 Yes

Meta-analyses conflict about the relative effectiveness of the second-generation antidepressants with no difference reported[13] and superiority of sertraline and escitalopram reported. [14]

References

  1. ↑ Anonymous (2024), Second-generation antidepressants (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. ↑ anonymous (2012 [last update]). Safety Alerts for Human Medical Products > Celexa (citalopram hydrobromide) - Drug Safety Communication: Revised Recommendations, Potential Risk of Abnormal Heart Rhythms. fda.gov. Retrieved on March 29, 2012.
  3. ↑ 3.0 3.1 3.2 Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M et al. (2011). "Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis.". Ann Intern Med 155 (11): 772-85. DOI:10.1059/0003-4819-155-11-201112060-00009. PMID 22147715. Research Blogging.
  4. ↑ Anonymous (2024), Mirtazapine (English). Medical Subject Headings. U.S. National Library of Medicine.
  5. ↑ Belmaker RH, Agam G (2008). "Major depressive disorder". N. Engl. J. Med. 358 (1): 55–68. DOI:10.1056/NEJMra073096. PMID 18172175. Research Blogging.
  6. ↑ Katzung, Bertram G. (2006). “Antidepressant Agents”, Basic and Clinical Pharmacology, 10th. New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. 
  7. ↑ Gartlehner, Gerald; Bradley N. Gaynes, Richard A. Hansen, Patricia Thieda, Angela DeVeaugh-Geiss, Erin E. Krebs, Charity G. Moore, Laura Morgan, Kathleen N. Lohr (2008-11-18). "Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians". Ann Intern Med 149 (10): 734-750. Retrieved on 2008-11-18.
  8. ↑ Qaseem, Amir; Vincenza Snow, Thomas D. Denberg, Mary Ann Forciea, Douglas K. Owens, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (2008-11-18). "Using Second-Generation Antidepressants to Treat Depressive Disorders: A Clinical Practice Guideline from the American College of Physicians". Ann Intern Med 149 (10): 725-733. Retrieved on 2008-11-18.
  9. ↑ 9.0 9.1 Lo B (2010). "Commentary: Conflict of interest policies: an opportunity for the medical profession to take the lead.". Acad Med 85 (1): 9-11. DOI:10.1097/ACM.0b013e3181c46e96. PMID 20042812. Research Blogging.
  10. ↑ Coupland CA, Dhiman P, Barton G, Morriss R, Arthur A, Sach T et al. (2011). "A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database.". Health Technol Assess 15 (28): 1-202, iii-iv. DOI:10.3310/hta15280. PMID 21810375. Research Blogging.
  11. ↑ First, Michael B. (2007). Handbook of Psychiatric Measures, Second Edition. American Psychiatric Publishing, Inc. ISBN 1-58562-218-4. 
  12. ↑ National Institute for Clinical Excellence. Depression: Management of Depression in Primary and Secondary Care. London, England: National Institute for Clinical Excellence; 2004.
  13. ↑ Gartlehner, Gerald; Bradley N. Gaynes, Richard A. Hansen, Patricia Thieda, Angela DeVeaugh-Geiss, Erin E. Krebs, Charity G. Moore, Laura Morgan, Kathleen N. Lohr (2008-11-18). "Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians". Ann Intern Med 149 (10): 734-750. Retrieved on 2008-11-18.
  14. ↑ Cipriani A. et al (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. The Lancet DOI:10.1016/s0140-6736(09)60046-5
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