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232 The APA Publishing Textbook of Mood Disorders, Second Edition
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TCAs and MAOIs seemed to increase synaptic concentrations of serotonin and catecholamines. Therefore, developing other drugs that worked in a similar fashion was
a goal in the 1960s and beyond. This led to the development of additional TCAs,
MAOIs, and tetracyclic antidepressants, and eventually to the development of selec
tive serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). In the 1970s, tetracyclic antidepressants were developed from TCAs.
Whereas TCAs were three-ringed compounds, tetracyclics were four-ringed com
pounds. When SSRIs and SNRIs were developed in the 1980s and 1990s, they represented a safer and better-tolerated alternative to TCAs, tetracyclics, and MAOIs.
The goal of this chapter is to review the classification, efficacy, safety, and tolerability of TCAs, tetracyclics, and MAOIs.
Classification, Safety, and Tolerability
Monoamine Oxidase Inhibitors
MAOIs have historically been classified based on their selectivity for specific isoforms
of monoamine oxidase (MAO). For example, MAOIs are classified by their selectivity
for the MAO-A versus the MAO-B receptor, with some MAOIs having activity at both
receptors. MAO-A receptors deaminate epinephrine, norepinephrine, and serotonin,
whereas MAO-B is involved in the catalyzation of benzylamine and β-phenylethyl-
amine. Dopamine and tyramine are catalyzed through both MAO-A and MAO-B.
In addition to classification based on activity at MAO-A or MAO-B receptors,
MAOIs are often subdivided into groups based on the reversibility or irreversibility of
their inhibitory effects at specific MAO receptors. MAOIs with selective MAO-A activity seem to have antidepressant properties similar to those of MAOIs that have activity
on both MAO-A and MAO-B receptors. Nonselective MAO-A/MAO-B inhibitors in
clude isocarboxazid and phenelzine. Selective MAO-A inhibitors include moclobemide (as well as other agents not commonly used in clinical practice). Selective MAOB inhibitors include selegiline and rasagiline, with the latter primarily used in Parkinson’s disease (Table 14–1).
Use of MAOIs requires patients to maintain a special diet in which they avoid
foods high in tyramine (e.g., certain cheeses, wine, beer, and cured meats) (Shulman
and Walker 1999). Consuming tyramine leads to elevated levels of norepinephrine
that cannot be effectively catalyzed because the MAOI blocks MAO, which breaks
down tyramine. This can lead to elevated blood pressure, hypertensive crisis, or other
serious side effects, including intracranial bleeding and death.
Individuals who are not taking MAOIs can tolerate high volumes of tyramine consumption, in the range of 40 mg or more per day. Individuals taking MAOIs, however,
may experience a hypertensive crisis at tyramine levels as low as 8 mg/day (Stahl and
Felker 2008). Therefore, patients who are prescribed MAOIs need to be educated on
consuming a low-tyramine diet (Sathyanarayana Rao and Yeragani 2009). Revised
dietary restrictions for patients taking MAOIs were published in 1999 because many
foods that were previously considered to contain high amounts of tyramine (e.g., certain recipes of pizza) are now considered safe (Shulman and Walker 1999). In addition,
use of the selegiline transdermal patch carries fewer dietary constraints in compari-
-
-
-
TABLE 14–1. Monoamine oxidase inhibitor (MAOI) classes, including
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FDA-approved dosage ranges
Nonselective MAO-A/MAO-B Selective MAO-A Selective MAO-B
inhibitors (irreversible) inhibitors inhibitors (irreversible)
233 Tricyclics, Tetracyclics, and Monoamine Oxidase Inhibitors
Phenelzine
(15–30 mg every 8 hours
to start; maintenance
15 mg/day)
Tr an yl c yp ro mi ne
(15 mg twice daily;
not to exceed 60 mg/day)
Clorgyline
(irreversible—
never marketed)
Moclobemide
(reversible—
300–600 mg/day
Selegiline
(6 mg/24 hours–
12 mg/24 hours
transdermal patch)
Pargyline
(discontinued)
son with oral MAOIs, with restrictions required for high, but not low, dosages of selegiline, as noted in the package insert (Merck 2006):
In its entirety, the data for [selegiline transdermal] 6 mg/24 hours support the recommendation that a modified diet is not required at this dose. Due to the more limited data
available for [selegiline transdermal] 9 mg/24 hours and 12 mg/24 hours, patients re
ceiving these doses should follow Dietary Modifications Required for Patients Taking
[selegiline transdermal] 9 mg/24 hours and 12 mg/24 hours.
-
In addition to dietary restrictions, individuals require a washout period of proserotonergic drugs before starting MAOIs. This washout period is based on the half-life
of the drug. Therefore, with the exception of fluoxetine, individuals switching from
SSRIs to MAOIs require a 2-week washout of the SSRI before starting an MAOI. Fluoxetine, because of its longer half-life, requires a washout of 5 weeks before starting
an MAOI. Patients taking MAOIs should avoid over-the-counter decongestants, cold
medications containing dextromethorphan, certain weight-loss medications, and
other drugs that have serotonergic effects or intensify the drug’s sympathomimetic
effects. A washout of other serotonergic drugs should be considered before starting
MAOIs and should be based on the half-life of the proserotonergic medication. Conway et al. (2015) argued that MAOIs can be initiated rapidly and without (or with
only minimal) washout under confinement or inpatient conditions.
Additional considerations for prescribers of MAOIs include the more common adverse effects of orthostatic hypotension, weight gain, sexual dysfunction, and insomnia, which are not unique to MAOIs and occur with other antidepressants that work
on biogenic amine neurotransmitters. Management of these more common adverse
effects associated with MAOIs can include lowering the dosage or discontinuing the
drug in cases where the effect is bothersome or more serious for the patient. Alternatively, watchful waiting may be an appropriate management strategy in certain situations in which the adverse effect is less bothersome or serious, because in some cases
the effects may resolve with time.
Tricyclic Antidepressants
TCAs historically were classified based on their chemical structure (i.e., primary vs.
secondary amine). However, in modern psychopharmacology, that historical classifi-
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cation has been replaced by classification based on the amount of action the TCA has
on serotonin versus norepinephrine reuptake inhibition. Secondary-amine TCAs (e.g.,
nortriptyline and desipramine) are selective inhibitors of norepinephrine, whereas the
tertiary-amine TCAs (e.g., imipramine and amitriptyline) block the reuptake of serotonin and norepinephrine (Table 14–2). However, TCAs have activity on more than
just serotonin and norepinephrine reuptake.
TCAs have antihistaminic, anticholinergic, and anti-α-adrenergic activity. This results in adverse effects, including weight gain, blurred vision, sexual dysfunction,
constipation, sedation, orthostatic hypotension, dizziness, and confusion (Table 14–
3). Doxepin is the most antihistaminic, and amitriptyline has the most anticholinergic
properties. Secondary-amine TCAs such as nortriptyline tend to have fewer sedative
effects and less orthostatic hypotension than tertiary-amine TCAs. Like managing
similar effects with MAOIs, management of these adverse effects associated with
TCAs can include lowering the dosage or discontinuing the drug in cases in which
the effect is bothersome or more serious for the patient. Alternatively, watchful wait
ing may be an appropriate management strategy in situations in which the adverse
effect is less bothersome or serious because, in some cases, the effect may resolve with
time. Serious effects of TCAs can include arrhythmias, cardiac toxicity (i.e., QRS widening; QTc prolongation), and dosage-dependent seizures (e.g., for clomipramine).
-
Tetracyclic Antidepressants
Tetracyclics are closely related to TCAs. Whereas TCAs contain three atomic rings,
tetracyclics contain four atomic rings. Mirtazapine is the tetracyclic antidepressant
that should be most familiar to readers (de Boer and Ruigt 1995). Mianserin was the
precursor for mirtazapine and also a tetracyclic drug. Setiptiline is also considered a
tetracyclic antidepressant, but it was only marketed in Japan. Some sources classify
maprotiline and amoxapine as tetracylics, but they are also sometimes grouped with
the secondary-amine TCAs. Molecularly, maprotiline has a central three-dimensional
ring structure with a side chain similar to that of a secondary-amine TCA, which is
the reason some authors classify it as a TCA. Amoxapine is structurally a metabolite
of loxapine and was first marketed in the early 1990s in the United States. In addition
to having antidepressant properties, amoxapine blocks dopamine type 2 (D
tors, similar to second-generation antipsychotics.
) recep-
2
Efficacy and Therapeutic Drug Monitoring
Monoamine Oxidase Inhibitors
Quitkin et al. (1979) published a review of MAOIs in the 1970s in which they described the use of MAOIs in “nonendogenous depression,” a term used at the time to
mean disabling depressive symptomatology or anxiety with mild neurotic symptoms
similar to anxious hysteria. In several studies, phenelzine at dosages greater than 30
mg/day demonstrated efficacy over placebo in treating nonendogenous depression.
In the 1990s, Thase et al. (1995) published results of a systematic review examining
the efficacy of MAOIs. They examined 55 randomized controlled trials (RCTs) of
MAOIs that had been published between 1959 and 1992. These trials included 36
235 Tricyclics, Tetracyclics, and Monoamine Oxidase Inhibitors
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TABLE 14–2. Secondary- and tertiary-amine tricyclic antidepressants (TCAs) with
FDA-approved dosage ranges
FDA-approved dosage range
Tertiary amines
Amitriptyline 25–300 mg/day
Imipramine 25–300 mg/day
Secondary amines
Amoxapine 25–400 mg/day
Clomipramine 25–250 mg/day
Desipramine 10–300 mg/day
Doxepin 25–300 mg/day
Nortriptyline 10–300 mg/day
Protriptyline 5–60 mg/day
Trimipramine 25–300 mg/day
TABLE 14–3. Potential adverse effects of tricyclic antidepressants
Anti-
Sedation
cholinergic
effects
Hypotension
Cardiac
effects
Seizures
Weight
gain
Amitriptyline
Desipramine
Nortriptyline + + + ++ + +
Note. Degree of severity: 0=very low; +=low; ++=moderate; +++=high.
+++
0/+
+++
+
+++
+
+++
++
++
+
++
+
RCTs of MAOIs versus placebo and 44 RCTs comparing MAOIs against TCAs or
other MAOIs. The systematic review noted the following conclusions:
1. Phenelzine demonstrated a small, statistically significant advantage over TCAs in
studies conducted in ambulatory populations of patients (not hospitalized).
2. When patients diagnosed with atypical depression were removed from the sample, MAOIs lost their slight advantage over TCAs.
3. Phenelzine had an effect size of 54.3%±9.6% when compared with placebo.
These data are consistent with the long-standing belief in the field, as reflected in
the third edition of the American Psychiatric Association (APA) Practice Guidelines for
the Treatment of Patients With Major Depressive Disorder (American Psychiatric Association 2010), that MAOIs are particularly useful in treating a subtype of major depressive disorder known as atypical depression, which is characterized by excessive sleep,
overeating and weight gain, fatigue, and mood reactivity to positive events. Despite
the inclusion of MAOIs in the APA practice guidelines, comparisons of MAOIs with
SSRIs did not always favor MAOIs as being superior for treating atypical depression.
A study by Pande et al. (1996) found fluoxetine and phenelzine to be equally effective
236 The APA Publishing Textbook of Mood Disorders, Second Edition
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in treating atypical depression. In addition, Søgaard et al. (1999) demonstrated sertraline to be more effective than moclobemide in treating atypical depression.
More recently, the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study compared tranylcypromine (up to 60 mg/day) with the combination of
mirtazapine (up to 45 mg/day) and venlafaxine (up to 300 mg/day) (Rush et al. 2006).
Participants in STAR*D who were assigned to tranylcypromine or to the mirtazapine/
venlafaxine combination had failed to respond to three sequential trials of antidepressants. Remission rates based on 17-item Hamilton Rating Scale for Depression (HAMD17) scores were modest for both groups: 7% for tranylcypromine versus 14% for the
venlafaxine/mirtazapine combination. The average responder to tranylcypromine
took approximately 8.6 weeks to develop a response, compared with 8.1 weeks for re
sponders to the combination treatment. Response and remission rates seemed limited
by adverse effects in both groups (Rush and Jain 2019).
Tricyclic Antidepressants
For TCAs, much has been written correlating drug level to therapeutic response,
safety, and tolerability (Burke and Preskorn 2004; Preskorn 1986; Preskorn et al. 1988,
1989). For example, with imipramine, clinical response is better when combined
plasma levels of imipramine and its metabolite desipramine exceed 150 ng/mL than
when combined levels are lower. However, combined levels of imipramine and desipramine in excess of 250 ng/mL are not associated with higher response rates but
instead result in more adverse effects. Nortriptyline, on the other hand, has a curvi
linear dose-response relationship in which optimal response occurs in the midrange
of blood levels (50–150 ng/mL) and not at the high or low range. With amitriptyline,
most patients demonstrate optimal response when combined serum levels of amitriptyline and its active metabolite nortriptyline are between 80 and 200 ng/mL; however, amitriptyline demonstrates significant cardiac toxicity when combined plasma
levels of amitriptyline and nortriptyline exceed 500 ng/mL.
Monitoring of plasma TCA levels is also important for preventing adverse effects.
For example, in comparison with patients who are cytochrome P450 (CYP) 2D6 exten
sive metabolizers, those who are CYP2D6 poor metabolizers may develop plasma
TCA levels fourfold higher or more (Macaluso and Preskorn 2011). Therefore, in in
dividuals with CYP2D6 poor metabolizer status, standard dosages of a TCA can lead
to toxic effects such as seizures or confusion.
Level 3 of STAR*D included the option to switch to nortriptyline, a TCA, or mirtazapine, a tetracyclic. Remission rates based on HAM-D17 data from STAR*D were
12% for the mirtazapine-treated group versus 20% for the nortriptyline-treated group
(Fava et al. 2006). Remission rates based on data from the 16-item Quick Inventory of
Depressive Symptomatology Self-Report were 8% for the mirtazapine group and 12%
for the nortriptyline group (Fava et al. 2006). However, none of these outcomes was
statistically significant. For patients who achieved remission, the mean time to remis
sion was 5.7 weeks for mirtazapine, compared with 6.3 weeks for nortriptyline.
-
-
-
-
-
Tetracyclic Antidepressants
Mirtazapine has a unique method of action. By blocking the presynaptic α2 heteroreceptors, it enhances serotonergic and noradrenergic neurotransmission (de Boer and
237 Tricyclics, Tetracyclics, and Monoamine Oxidase Inhibitors
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Ruigt 1995; Sitsen and Zivkov 1995). This boosts postsynaptic levels of serotonin in
addition to blocking postsynaptic serotonin (5-hydroxytryptamine [5-HT]) type 2A
(5-HT
Haddjeri et al. 1995). Mirtazapine’s 5-HT
ration with no sexual adverse effects (Preskorn 1999). Its 5-HT
contributes to the adverse effect of weight gain, whereas its 5-HT
), type 2C (5-HT2C), and type 3 (5-HT3) receptors (Anttila and Leinonen 2001;
2A
receptor blockade promotes sleep resto-
2A
receptor blockade
2C
receptor blockade
3
contributes to the lack of gastrointestinal adverse effects. In addition, mirtazapine
blocks histamine H
receptors, which contributes to its adverse effects of sedation and
1
weight gain. Mirtazapine is also associated with dizziness and transient elevations in
plasma lipids and liver function values.
Mirtazapine’s approved dosage range is 15–45 mg once daily; however, some studies have utilized higher dosages, in the range of 60 mg/day, although this use is offlabel (Merck 2012, 2017). Patients treated with mirtazapine for major depressive dis
order in acute clinical trials showed statistically significant symptomatic improvement compared with subjects given placebo within the first 1–2 weeks of treatment
(Alam et al. 2013; Lavergne et al. 2005). In addition, patients taking mirtazapine for
major depressive disorder showed continued improvements in response rates at 40
weeks in long-term clinical trials.
Conclusion
-
Prior to the development of drugs with novel mechanisms of action, modern antidepressants acting on biogenic amine neurotransmitters evolved from MAOIs and
TCAs, paving the way for newer and safer methods of treating depression. In modern
psychiatry, MAOIs and TCAs have niche uses in treating refractory illness or specific
subtypes of depression. Although the safety risks posed by these medications can be
serious and life threatening, many can be mitigated through careful patient selection,
appropriate clinical monitoring, and education of patients and families.
References
Alam A, Voronovich Z, Carley JA: A review of therapeutic uses of mirtazapine in psychiatric and
medical conditions. Prim Care Companion CNS Disord 15(5):PCC.13r01525, 2013 24511451
American Psychiatric Association: Practice Guideline for the Treatment of Patients With Major
Depressive Disorder, 3rd Edition. Washington, DC, American Psychiatric Association, 2010
Anttila SA, Leinonen EV: A review of the pharmacological and clinical profile of mirtazapine.
CNS Drug Rev 7(3):249–264, 2001 11607047
Burke MJ, Preskorn SH: Therapeutic drug monitoring of antidepressants, in Antidepressants:
Past Present and Future. Handbook of Experimental Pharmacology Vol. 157. Edited by
Preskorn SH, Stanga CY, Feighner JP, Ross R. Berlin, Springer-Verlag, 2004, pp 87–114
Conway CR, Gebara MA, Walker MC, et al: Clinical characteristics and management of treat-
ment-resistant depression. J Clin Psychiatry 76(11):1569–1570, 2015 26646033
de Boer T, Ruigt GSF: The selective alpha2-adrenoceptor antagonist mirtazapine (Org 3770) en-
hances noradrenergic and 5HT1A mediated serotonergic neurotransmission. CNS Drugs
4 (suppl 1):29–38, 1995
Fava M, Rush AJ, Wisniewski SR, et al: A comparison of mirtazapine and nortriptyline follow-
ing two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 163(7):1161–1172, 2006 16816220
238 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
Haddjeri N, Blier P, de Montigny C: Noradrenergic modulation of central serotonergic neuro-
transmission: acute and long-term actions of mirtazapine. Int Clin Psychopharmacol 10
(suppl 4):11–17, 1995 8930005
Hillhouse TM, Porter JH: A brief history of the development of antidepressant drugs: from
monoamines to glutamate. Exp Clin Psychopharmacol 23(1):1–21, 2015 25643025
Kuhn R: The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J
Psychiatry 115(5):459–464, 1958 13583250
Lavergne F, Berlin I, Gamma A, et al: Onset of improvement and response to mirtazapine in
depression: a multicenter naturalistic study of 4771 patients. Neuropsychiatr Dis Treat
1(1):59–68, 2005 18568129
Macaluso M, Preskorn SH: CYP 2D6 PM status and antidepressant response to nortriptyline
and venlafaxine: is it more than just drug metabolism? J Clin Psychopharmacol 31(2):143–
145, 2011 21346604
Merck: EMSAM (selegiline transdermal system). Whitehouse Station, NJ, Merck & Co, Febru-
ary 2006. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/
021708s000_021336s000lbl.pdf. Accessed November 12, 2020.
Merck: REMERON® (mirtazapine) tablets. Whitehouse Station, NJ, Merck & Co, 2012. Avail-
able at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/
020415s019,021208s010lbl.pdf. Accessed November 12, 2020.
Merck: Merck Medication Guide: Mirtazapine. Whitehouse Station, NJ, Merck & Co, 2017.
Available at: https://www.organon.com/product/usa/pi_circulars/r/remeron/remeron_tablets_pi.pdf. Accessed November 12, 2020.
Pande AC, Birkett M, Fechner-Bates S, et al: Fluoxetine versus phenelzine in atypical depres-
sion. Biol Psychiatry 40(10):1017–1020, 1996 8915561
Preskorn SH: Tricyclic antidepressant plasma level monitoring: an improvement over the dose-
response approach. J Clin Psychiatry 47 (1 suppl):24–30, 1986 2867088
Preskorn SH: Outpatient Management Of Depression: A Guide for the Primary Care Practi-
tioner, 2nd Edition. Caddo, OK, Professional Communications Inc, 1999
Preskorn SH, Dorey RC, Jerkovich GS: Therapeutic drug monitoring of tricyclic antidepres-
sants. Clin Chem 34(5):822–828, 1988 3131042
Preskorn SH, Jerkovich GS, Beber JH, et al: Therapeutic drug monitoring of tricyclic antidepres-
sants: a standard of care issue. Psychopharmacol Bull 25(2):281–284, 1989 2690169
Quitkin F, Rifkin A, Klein DF: Monoamine oxidase inhibitors: a review of antidepressant effec-
tiveness. Arch Gen Psychiatry 36(7):749–760, 1979 454092
Rush AJ, Jain SB: Clinical implications of the STAR*D trial. Handb Exp Pharmacol 250:51–99,
2019 30203327
Rush AJ, Trivedi MH, Wisniewski SR, et al: Acute and longer-term outcomes in depressed out-
patients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry
163(11):1905–1917, 2006 17074942
Sathyanarayana Rao TS, Yeragani VK: Hypertensive crisis and cheese. Indian J Psychiatry
51(1):65–66, 2009 19742203
Shulman KI, Walker SE: Refining the MAOI diet: tyramine content of pizzas and soy products.
J Clin Psychiatry 60(3):191–193, 1999 10192596
Sitsen JM, Zivkov M: Mirtazapine: clinical profile. CNS Drugs 4 (suppl 1):39–48, 1995
Søgaard J, Lane R, Latimer P, et al: A 12-week study comparing moclobemide and sertraline in
the treatment of outpatients with atypical depression. J Psychopharmacol 13(4):406–414,
1999 10667618
Stahl SM, Felker A: Monoamine oxidase inhibitors: a modern guide to an unrequited class of
antidepressants. CNS Spectr 13(10):855–870, 2008 18955941
Thase ME, Trivedi MH, Rush AJ: MAOIs in the contemporary treatment of depression. Neuro-
psychopharmacology 12(3):185–219, 1995 7612154
CHAPTER 15
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Selective Serotonin
Reuptake Inhibitors
and Related
Antidepressants
Richard C. Shelton, M.D.
The introduction of the selective serotonin reuptake inhibitors (SSRIs) had
an enormous impact on the practice of medicine in general and on the practice of psy
chiatry in particular. Prior to the introduction of fluoxetine in the U.S. market in late
1997, antidepressants were infrequently used in the primary care setting and, when
used, were frequently used at subtherapeutic dosages. Since then, antidepressants
have become among the most widely prescribed drugs worldwide, with a market representing billions of dollars per year. The SSRIs and later medications have changed
the face of the treatment of depression. This chapter reviews antidepressant medica
tions approved by the FDA since 1997.
-
-
Background and History
Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have a
high side-effect burden, cardiotoxicity, risk in overdose, and drug interactions that
limit their usefulness in practice. By the late 1960s, it was clear that newer treatments
with improved risk and tolerability profiles were needed. Because both the MAOIs
and TCAs appeared to work by enhancing monoaminergic synaptic transmission, in
cluding that of norepinephrine, serotonin, and, to a lesser degree, dopamine, investigators pursued the hypothesis that the therapeutic effects of these drugs resulted from
increased levels of these neurotransmitters, culminating in the monoamine hypothesis
-
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of depression (Schildkraut 1965). Initially, this largely focused on noradrenergic
mechanisms, but later work by investigators such as Arvid Carlsson, James Maas,
and others began to shift the focus toward serotonin as an important target of antide
pressant action (Nemeroff and Owens 2003). Pharmaceutical research in Europe and
the U.S. focused on developing drugs that block the serotonin reuptake site, referred
to as the serotonin transporter (SERT), without the concomitant receptor binding pro
file of the TCAs. This led to the synthesis of zimelidine, the first marketed SSRI, and
fluoxetine, the first SSRI marketed in the United States (Fuller et al. 1991; Huitfeldt
and Montgomery 1983; Montgomery et al. 1981a, 1981b)
Following the remarkable success of fluoxetine, various companies introduced
compounds that were relatively potent and selective antagonists of SERT. The “mod
ern” era of antidepressant treatment had begun in earnest. In parallel with this development, many companies continued to focus considerable efforts on the synthesis of
drugs that were similar to TCAs in action but were not serotonin selective. Much of
the development of antidepressants over the past 30 years or more has focused on the
goal of developing “cleaned-up” TCAs—drugs that inhibit the reuptake of norepinephrine, serotonin, or both but have low affinity for other receptors. The result was a
new generation of antidepressants, which includes the SSRIs, the selective norepi
nephrine reuptake inhibitors (NRIs), and the dual serotonin-norepinephrine reuptake
inhibitors (SNRIs).
-
-
-
-
Monoamine Transporters
Most antidepressant compounds, both old and newer, act by the blocking the transporter proteins for serotonin, norepinephrine, or both. SERT and the norepinephrine
transporter (NET) are chemically related structures with distinct genetic loci. They are
part of a larger family of transporters powered by Na+/K+ ATPases. The function of
a transporter is to remove the neurotransmitter from the synapse, thus terminating
stimulation of the postsynaptic neuron. In addition, the transporter serves as a recy
cling agent, allowing the presynaptic cell to reuse the serotonin that it collects (Blakely
et al. 1994; Qian et al. 1995).
Like other members of the transporter family, SERT is a glycoprotein complex embedded in a plasma membrane by 12 transmembrane domains. Its glycosylation plays
an important role in protein folding and protecting against degradation (Blakely et al.
1994). These transporters are located on the axon terminals and cell bodies of serotonergic neurons. Each transporter contains binding sites for serotonin, sodium, chlorine, potassium, and pharmacological agents (e.g., SSRIs, cocaine, and amphetamines).
To initiate serotonin reuptake, SERT binds extracellular serotonin, sodium, and chlo
rine. This induces a conformational change in SERT that moves these ions and serotonin into the cell, where they are released. Intracellular potassium then binds to the
complex, another conformational change ensues, and the complex returns to its initial
configuration. SSRIs inhibit SERT by binding to a site on the SERT protein at a location
other than the active uptake site for serotonin (allosteric inhibition). Thus, SSRIs do not
completely prevent the SERT from functioning because they do not prevent the binding of serotonin. However, therapeutic dosages of SSRIs decrease SERT functioning by
60%–80%.
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NET is structurally and functionally very similar to SERT, and many antidepressants inhibit both of these transporters. In addition, NET has a moderate affinity for
dopamine, and therefore antidepressants that act on NET enhance transmission of
both norepinephrine and dopamine (Pacholczyk et al. 1991). Some brain regions, par
ticularly the frontal cortex, have low levels of dopamine transporters, and NET is the
principal mechanism for reuptake of dopamine in these areas (Morón et al. 2002).
Thus, even highly selective NET inhibitors, such as atomoxetine (a medication used
for ADHD), can enhance both norepinephrine and dopamine transmission. Finally, at
least one antidepressant, sertraline, has a modest effect on the transporter for dopamine directly, although the clinical implications of this are unknown (Owens et al.
1997). Binding affinities for the NET and SERT (expressed as the inhibition constant
[Ki]) are listed in Table 15–1.
Desensitization of specific serotonin and norepinephrine receptors, which occurs
after reuptake blockade, has been postulated to be the principal mechanism of action
of antidepressants (Sulser et al. 1978). Hyman and Nestler (1996) have suggested that
this desensitization serves as a marker of adaptation rather than the mechanism
through which therapeutic actions are mediated. Enhanced transsynaptic signaling
by norepinephrine and serotonin leads to downstream effects of gene expression that
may, ultimately, result in therapeutic effects. Thus, rather than being directly associ
ated with the antidepressant effects, receptor desensitization could primarily be related to the amelioration of side effects.
-
-
Therapeutic Implications of Serotonin
and Norepinephrine Reuptake Blockade
Antidepressants, including the SSRIs, SNRIs, and NRIs, are indicated for not only the
treatment of depression but also various other psychiatric conditions, particularly
anxiety disorders. Table 15–2 lists the antidepressants available in the United States,
their trade names and dosage ranges, and their FDA-approved indications.
Over the past 30 years, data have emerged to suggest that mood is not a simple
“good” versus “bad” or “high” versus “low” construct. Rather, several component
features have emerged. For example, L.A. Clark and Watson (1991) conceptualized
the mood-anxiety spectrum as composed of three dominant bimodal factors. These
emerged from factor analytic studies of mood descriptors in large healthy control and
symptomatic populations, and comprise “somatic anxiety,” “positive affect,” and
“general distress” (also termed “negative affect”) (L.A. Clark and Watson 1991; R.A.
Clark et al. 1994; Watson et al. 1995a, 1995b). Somatic anxiety involves physiological
arousal, with features such as tachycardia, tachypnea, tremor, diaphoresis, and other
evidence of acute fear, and is found in panic attacks. Positive affect suggests a bimodal
dimension with a positive emotional state involving enthusiasm, motivation, and optimism at one end and anhedonia, which is fairly specific to depression, at the other
end. General distress refers to a range of negative emotions (e.g., sadness, anxiety,
worry, rumination, tension) and general dissatisfaction and is common to both anxiety and mood disorders (Brown et al. 1998). Focusing on these components may contribute to misdiagnosis or multiple diagnostic assignments (i.e., “comorbidity”).
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