The body treats drugs as foreign, or xenobiotic, substances, so it tends to metabolize them to facilitate elimination. Usually, the products of biotransformation are referred to as metabolites and tend to be more water soluble than the original molecule so the kidneys can more easily eliminate them (1, 2).

Usually, biotransformation produces chemically stable metabolites that are neither pharmacologically nor toxicologically active. In some cases, though, chemically reactive metabolites are generated and may be toxic. In addition, the reactions involved in biotransformation may produce chemically stable and pharmacologically active metabolites, termed “active metabolites” (3); those will be the primary focus of this article.

Active metabolites exhibit pharmacodynamic and pharmacokinetic properties that may be similar to or differ from the original compound. In either case, they alter its activities and play a role in its end result. In fact, the presence of active metabolites is akin to polytherapy (2–4). Many medications give way to active metabolites. They are only considered clinically relevant when this occurs in high enough quantities to have a pharmacological impact, are at least as active as the original compound, or exist in specific tissues, like the brain (1, 2).

An active metabolite can be entirely or only partially responsible for a drug’s therapeutic effect. Others may be pharmacologically active in a way not related to the original molecule’s main activity. Sometimes, a metabolite reverses or deactivates the original molecule’s pharmacological activity (3). It is widely believed that many psychoactive drugs’ effects are the result not only of the original molecule, but its active metabolites. Moreover, some drugs are inactive per se, and must be biotransformed in the body to become pharmacologically active; these have been called prodrugs.

At times, when an active metabolite improves the original compound’s pharmacodynamic, pharmacokinetic, or toxicological properties, it gets commercialized. Examples of this in psychopharmacology include desipramine (desmethyl imipramine), derivatives of the antidepressant imipramine, mesoridazine and paliperidone, derivatives of the antipsychotics thioridazine and risperidone, and oxazepam, diazepam’s metabolite (1, 3).

Antidepressants are a wide and varied group of drugs involving many active metabolites. Some such metabolites have even been commercialized as active agents in their own right. Table 1 presents the major known active metabolites and their corresponding antidepressants.

Nortriptyline is an active metabolite in amitriptyline and features distinctly potent inhibition of monoamine transporters, noradrenaline (NET), and serotonin (SERT) beyond that of its parent compound. Thus, while amitriptyline inhibits both transporters, its metabolite, nortriptyline, acts primarily as an inhibitor of NET reuptake (5). In turn, 10-OH-nortriptyline, considered an active metabolite of nortriptyline, is a stronger NET inhibitor and is less anticholinergic (6).

Desipramine is an active metabolite in imipramine, which inhibits reuptake of NET and SERT; the metabolite features almost selective NET inhibition. Desipramine and nortriptyline, in fact, are the strongest NET reuptake inhibitors of the tricyclic antidepressants commercially available (5). Desipramine, too, is converted into an active metabolite, desmethyl desipramine, which has more affinity for SERT than for NET. This metabolite reduces desipramine’s selectivity and adds to its overall antidepressant effect (7).

Trimipramine also involves several pharmacologically active metabolites. One is desmethyl trimipramine, which inhibits NET and SERT transporters as strongly as its parent compound. However, 2-OH-trimipramine is weaker and trimipramine-N-oxide preferentially inhibits SERT (8).

Other tricyclic antidepressants have active metabolites, but their differential profiles relative to their parent compounds have yet to be clearly elucidated. However, clomipramine is known to give way to desmethyl clomipramine, and doxepin to the metabolite desmethyl doxepin (2). Mianserin is demethylated to produce an active metabolite, N-desmethyl mianserin, whose longer half-life increases the effect of mianserin (9).

Mirtazapine undergoes extensive metabolism during its first pass through the liver, the major metabolic pathways in humans being N-demethylation, N-oxidation, and 8-hydroxylation, followed by conjugation. The demethylated metabolite, normirtazapine, remains pharmacologically active, but is three to four times less active than mirtazapine (4, 10).

Among selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, and sertraline are initially demethylated, generating desmethyl citalopram, norfluoxetine, and norsertraline, which also inhibit SERT (11). Norcitalopram’s steady state plasma concentration approaches nearly 40% of citalopram’s, and it actively inhibits SERT three to eight times less than citalopram (12, 13). What is more, norcitalopram is converted into desmethyl citalopram, which acts as a weak SERT reuptake inhibitor (4, 14). Fluvoxamine is metabolized into multiple metabolites and the carboxylic acid derived from it has been shown to inhibit SERT weakly compared to the parent compound (4, 15).

Fluoxetine is metabolized through N-demethylation into its major active metabolite, norfluoxetine, which is comparable to fluoxetine, from pharmacological perspective (5, 16). However, norfluoxetine easily permeates the blood-brain barrier, reaches higher plasma concentrations, and has a higher half-life than fluoxetine (17, 18). In patients suffering from depression, norfluoxetine reaches concentrations comparable or even higher than fluoxetine (19), so it likely contributes considerably to the drug’s major SERT inhibition, therapeutic effectiveness, and adverse effects (4).

Sertraline gives way to a demethylated metabolite called desmethyl sertraline, which is a weaker SERT reuptake inhibitor than sertraline in vivo. However, it may contribute to the prolonged SERT transporter inhibition achieved by administering sertraline; laboratory research has shown this to be more the case for mice than for rats. Nevertheless, it remains unclear how much norsertraline boosts the original compound’s therapeutic activity in humans (4, 11).

Venlafaxine is a dual uptake inhibitor of SERT and NET. In humans, most venlafaxine metabolism, almost 60%, takes place through O-demethylation. Other minor metabolic routes include N-demethylation, which produces N-desmethyl venlafaxine. O-desmethyl venlafaxine exhibits similar pharmacological activity to that of its parent compound, both in vitro and in vivo. The derivative N-desmethyl is also active, but has less capacity for SERT and NET reuptake inhibition than venlafaxine does (4, 5, 20).

Atomoxetine is a selective NET reuptake inhibitor employed in the treatment of attention deficit hyperactivity disorder (ADHD). It generates a series of oxidative metabolites. Of those, 4-hydroxy-atomoxetine stands out because it blocks NET with demonstrably similar ability to atomoxetine. Atomoxetine’s remaining oxidative metabolites, including N-desmethyl atomoxetine, all seem to be pharmacologically inactive (21).

Antipsychotics have a long history of effectiveness at treating depressive profiles. In 1954, Kielhoz suggested chlorpromazine was effective at treating depressive and manic episodes. Then Nahunek et al. (22) reported that the first atypical antipsychotic, clozapine, effectively treated endogenous depression. Today, atypical antipsychotics are recognized as effective at treating bipolar depression (23, 24), but in unipolar depression profiles, its efficacy has been mainly shown as a combined, or adjunctive, treatment in resistant profiles, an indication for which certain antipsychotics have received official approval (25, 26). The question this article aims to address is whether any of these antipsychotics’ active metabolites (see Tables 1 and 2) might participate in mechanisms of antidepressant activity.

Olanzapine, coupled with fluoxetine, was the first case of an atypical antipsychotic drug showing greater efficacy than each active principle separately (26, 27). Olanzapine produces various metabolites, of which conjugated 10-N-glucuronide has noteworthy applications in humans. Other minor metabolites include N-desmethyl olanzapine, 4-N-oxide-olanzapine, 2-hydroxymethyl olanzapine, and 4-N-glucuronide. It is noteworthy that both in vitro and in vivo, its primary metabolite, 10-N-glucuronide, is inactive. Of the three remaining, minor metabolites, N-desmethyl olanzapine and 2-hydroxymethylolanzapine display similar activity in vitro as their parent compound, while the rest are inactive or nearly so. These data indicate that all of olanzapine’s metabolites are less active than it, so their activity probably does not contribute to its pharmacological profile (28).

Of the available atypical antipsychotics, aripiprazole has proven effective as adjunctive treatment for major depression when it is resistant to treatment with antidepressants (29, 30). FDA has officially approved this indication. Aripiprazole’s antidepressant action may be due, first, to its role as a partial agonist of D₂, D₃, and 5-HT_1A receptors, and second, to its ability to block 5-HT₂ receptors (29). It is a piperazine derivative and may undergo an array of metabolic processes, depending on the species. Dehydro-aripiprazole is aripiprazole’s major metabolite in humans and exhibits a similar pattern of activity at the D₂ receptor (31). Dehydro-aripiprazole has a longer half-life than the original compound (32), suggesting it may contribute to its pharmacological efficacy. One of its metabolites, 2-3-dichlorophenylpiperazine, is an analog of m-Chlorophenylpiperazine (mCPP), an active metabolite of trazodone and nefazodone. This metabolite reaches a concentration in the brain 7% that of aripiprazole, so it could contribute only partially to that particular atypical antipsychotic’s antidepressant effect (33).

Risperidone has shown its effectiveness as adjunctive therapy, especially in conjunction with SSRIs, in patients with major depression (26). It is metabolized mainly by CYP450-2D6 (CYP2D6), generating 9-OH-risperidone, or paliperidone, through hydroxylation. When risperidone is administered, its pharmacological effects are due to the original molecule as well as its active metabolite. Considering that many patients who take risperidone orally exhibit plasma levels of 9-OH-risperidone 5–10 times higher than risperidone (34), we consider the metabolite to play an important role in the antipsychotic’s antidepressant effect (Table 2) (35). In fact, extended-release paliperidone, whether taken orally (36) or as an injection (37), has proven effective in treating schizoaffective disorder, a profile marked by a set of schizophrenia symptoms in addition to major depressive disorder. According to these clinical data, paliperidone seems to behave like a metabolite of risperidone and to have antidepressant activity. Nevertheless, to date, paliperidone has never been studied in the treatment of major depression, as monotherapy or adjunctive therapy. Yang and Liang (38) did, however, report one case where a patient with treatment-resistant depression was successfully treated with paliperidone as adjunctive therapy.

With regard to quetiapine, this particular atypical antipsychotic drug is extensively metabolized in the liver, where many of its metabolites are produced. Its most important metabolite is N-desalkyl quetiapine, also known as norquetiapine, which exhibits distinct pharmacological activity from quetiapine and plays a fundamental role in its antidepressant efficacy. This article will explore norquetiapine in depth in a special section below.

The efficacy of quetiapine in treating psychotic disorders, both schizophrenia and mania, as well as mood disorders and anxiety disorders, leads us to view it as a multifunctional psychoactive drug. Its broad spectrum of efficacy is likely due to its ability to modify systems of dopaminergic, noradrenergic, and serotonergic neurotransmission. Its effects appear to be mediated by the actions of both quetiapine and norquetiapine.

Quetiapine is a dibenzothiazepine derivative available in two different pharmaceutical forms: immediate-release (IR) and extended-release (XR) (39). Both forms are metabolized extensively by the liver into various metabolites, with only 1% eliminated unaltered, in this case in urine (40).

N-desalkyl quetiapine, also known as norquetiapine, is quetiapine’s key metabolite and is produced by the action of isoenzyme CYP3A4 in cytochrome P450. No genetic polymorphisms affect CYP3A4, so variations in quetiapine metabolism based on race or genetics are unlikely. However, there may be interaction at the level of this isoenzyme with some inductors (carbamazepine, phenytoin) that increase the proportion of norquetiapine, or with potent enzyme inhibitors (ketoconazole, itraconazole, erythromycin, and fluvoxamine) that slow its production (41, 42). On another note, there is more pharmacokinetic variability among older adults and patients with concomitant medications in the case of quetiapine than norquetiapine; norquetiapine levels are more stable (43). CYP2D6 also contributes to quetiapine metabolism, though to a lesser extent. This creates small quantities of 7-hydroxy quetiapine (44), whose activity has not yet been specifically determined. In addition, this isoenzyme metabolizes norquetiapine into 7-hydroxy-desalkyl-quetiapine, which is pharmacologically active (45).

According to Mauri et al. (46), quetiapine’s plasma concentrations do not seem sufficiently high to explain its action at receptors or its clinical effects, suggesting that active metabolites participate in its pharmacodynamics. However, the plasma concentrations of CNS drugs is a poor predictor of central activity because numerous other factors influence target engagement, including blood/brain barrier penetration, CNS accumulation, and receptor association/dissociation kinetics.

Norquetiapine and quetiapine interact with the dopaminergic, noradrenergic, and serotonergic systems, but differ qualitatively and quantitatively in their respective abilities to alter those systems’ functioning. As with other atypical antipsychotics, quetiapine can block 5-HT_2A receptors with greater affinity than D₂ receptors, which may explain its antipsychotic properties and lower propensity to cause extrapyramidal symptoms and hyperprolactinaemia (40). Furthermore, quetiapine shows affinity for different serotonergic and noradrenergic receptors, which may contribute to its antidepressant and anxiolytic effects (47). Also, its active metabolite, norquetiapine, is highly important in that in addition to inhibiting NET reuptake, it shows affinity for several SERT receptors (41, 42).

An overall picture of the receptor profiles of quetiapine and norquetiapine appears in the Figure 1.

Quetiapine is a multifunctional drug endowed with antidepressant properties through various mechanisms: noradrenergic, serotonergic, and dopaminergic. Quetiapine displays clinically significant efficacy in treating unipolar depression, both as a monotherapy (off-label use; only in Australia and Canada is this an officially approved indication) and as adjunctive therapy with antidepressants in patients who respond unsatisfactorily or not at all to antidepressants alone. Furthermore, quetiapine is the only drug demonstrated to be effective at treating unipolar and bipolar depression with no associated risk of veering into mania (68, 71).

The available data are sufficient to arrive at the conclusion that quetiapine’s antidepressant activity is mediated, at least in part, by the active metabolite norquetiapine, which selectively inhibits NET reuptake, is a partial 5-HT_1A receptor agonist, and acts as an antagonist at presynaptic α₂, 5-HT_2C, and 5-HT₇ receptors. Furthermore, its active metabolite contributes to quetiapine’s profile of undesirable effects because norquetiapine binds at H₁ histamine, α₁ adrenergic, and muscarine receptors. Norquetiapine’s activity profile is shared by no other known antipsychotic or antidepressant drug (49).

Norquetiapine clearly exemplifies the case of an active metabolite that, through metabolism, can make a drug originally introduced as an antipsychotic, in this case quetiapine, become a useful antidepressant agent.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.