The Monoamine Hypothesis of Depression Revisited: Could It Mechanistically Novel Antidepressant Strategies?

Chapter 7

The Monoamine Hypothesis of Depression Revisited: Could It Mechanistically Novel Antidepressant Strategies? Fiammetta Cosci* and Guy Chouinard† *Department of Health Sciences, University of Florence, Florence, Italy, † Clinical Pharmacology and Toxicology Program, McGill University and Mental Health Institute of Montreal Fernand Seguin Research Centre, Montreal, Canada

THE MONOAMINE HYPOTHESIS In the 1950s, the amine hypothesis of depression was proposed after it was observed that patients treated for hypertension with reserpine developed depression [1]. The functional deficiency of noradrenergic transmission in depression was, then, inferred from the effects of imipramine-like drugs and monoamine oxidase inhibitors on catecholamine metabolism, since both these types of drugs increase catecholamine at adrenergic receptor sites. A general hypothesis was put forward that depression was associated with a deficiency in the transmission within the monoamine systems, i.e., serotonin (5HT), noradrenaline, and dopamine [2–4].

Serotonin-Noradrenaline During these early years, evidence was accumulating on the important role of serotonin. 5HT is unlike the other biogenic amines, as the concentration of its precursor tryptophan in the brain can affect its rate of synthesis [5]. The brain tryptophan concentration is controlled in part by the free (i.e., non-albumin bound) serum tryptophan concentration [6,7]. Thus, as low brain 5HT was found to be implicated in the etiology of depression, tryptophan was tried as antidepressant. Although Coppen et al. [8] claimed that tryptophan, given alone, was as effective as electroconvulsive therapy in the treatment of depression, the results of clinical trials of tryptophan in depression were disappointing. Chouinard and collaborators suggested that the weak or uncertain action of tryptophan could be due to high rate of catabolism by tryptophan pyrrolase in the liver [9,10]. Since the breakdown of tryptophan in the liver can be reduced by nicotinamide, a tryptophannicotinamide combination was proposed as antidepressant treatment and showed to be superior to tryptophan alone [9]. The tryptophan-nicotinamide combination also showed to be as effective as imipramine in unipolar patients, providing the dose is kept within the therapeutic window [10]. In addition, tryptophan was found to enhance lithium carbonate antidepressant effects in bipolar patients who were resistant to lithium monotherapy [11]. Chouinard et al. conducted seven trials of the use of tryptophan in affective illness, first as an antidepressant [10,12,13], then as an antimanic [13,14] and, finally, as a mood stabilizer [14,15] when administered in combination with lithium. They completed a randomized crossover 1-year study in treatment-resistant patients (n ¼ 100) using the lithium-tryptophan combination [16], which led to the approval in Canada of a unique indication for tryptophan as an adjunctive medication to lithium. Unfortunately, the drug was withdrawn from the US market following reports of eosinophilia-myalgia syndrome [17], although no cases of eosinophilia-myalgia syndrome, or even significant increases in eosinophilia count, were found during all the trials with tryptophan conducted by Chouinard and coworkers (unpublished observations). Chouinard et al. [12] made tentative suggestions on the use of tryptophan as antidepressant. They proposed that the therapeutic daily dose should be higher for bipolar depressed patients than for unipolar depressed one; if tryptophan

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was given with nicotinamide or tricyclic antidepressants, the dose should be in the therapeutic window; and tryptophan should be given in divided doses to minimize fluctuations of its plasma concentration. The research on tryptophan was the first step of studying drugs that could have a more direct effect on brain serotonin through their effects on serotonin receptors, thus looking at an alternative pharmacological approach to giving a biogenic amine precursor such as tryptophan. One of these drugs was alprazolam, an atypical benzodiazepine [18], and another was clonazepam [19], an anticonvulsant with serotoninergic effects. Then, a third group of serotoninergic drugs, the selective serotonin reuptake inhibitors (SSRIs), which act differently from the precursor tryptophan and not through direct effect on the serotonin receptor as is the case of clonazepam, were developed. The first SSRI introduced was zimeldine. Kahn and collaborators conducted the first clinical trial in the treatment of obsessive-compulsive disorder (OCD) patients [20]. In 1985, Fontaine et al. [21] conducted a further investigation on the effects of zimeldine in OCD patients. The results showed a significant reduction of obsessive-compulsive symptoms. These results supported the use of a new class of serotoninergic antidepressants in the treatment of OCD. Zimeldine was removed from use as an antidepressant due to hypersensitivity reactions, which could be followed by Guillain-Barre syndrome [22]. In 1984, Chouinard and Jones [23] reported a case of a patient with depression who developed a hypersensitivity reaction to zimeldine with join pain, chills, and headache. One week after discontinuation of zimeldine, she was treated with fluoxetine and continued treatment for 4 months without any hypersensitivity reactions. This case report was important in the further development of SSRIs, because it showed that there was no crossover of the hypersensitivity reaction between fluoxetine and zimeldine [23]. On Feb. 11, 1981, Chouinard initiated the first proof-of-concept study of fluoxetine in the treatment of major depression [24]. They randomly assigned 51 patients to fluoxetine or amitriptyline for 5 weeks. After 1-week placebo washout period, the dose of fluoxetine was started at 20 mg/day and then increased to 40 mg and subsequently to 80 mg if well-tolerated. The results obtained with fluoxetine were comparable with those obtained with amitriptyline. Patients treated with fluoxetine also had lower side effects, in particular anticholinergic autonomic side effects. Later, several studies of the drug were carried out by Chouinard and colleagues and they initiated the final study that led to its approval as an antidepressant by the FDA in 1988 after ruling out its potential to cause phospholipidosis in humans [25]. Between 1988 and 1992, paroxetine, another SSRI, was shown to be efficacious in the treatment of major depression in randomized placebo-controlled multicenter trials [26–28]. The selectivity of both fluoxetine and paroxetine was attributed to their relatively low affinity for cholinergic, histaminergic, or catecholaminergic receptors [29]. Among SSRIs, paroxetine was, and is still, thought to be the most anticholinergic and with atropinic (e.g., dry mouth, sedation) side effects than other SSRIs. SSRIs showed also to produce transient excitatory side effects, which may be due to their interactions with other neurotransmitters, such as dopamine or norepinephrine [30]. SSRI interactions with dopamine neurotransmission have been reported mainly for fluoxetine [31,32]; fluoxetine may induce extrapyramidal symptoms such as akathisia [32] and dystonia [32] and may exacerbate parkinsonian symptoms in patients with Parkinson’s disease [32]. In addition, SSRIs were associated with excitatory side effects including anxiety, nervousness, and insomnia [24]. In this vein, Chouinard et al. [33] designed a comparative study between paroxetine and fluoxetine in patients with major depression to compare induction of nervousness and anxiety in the early stages of treatment. A total of 203 patients were randomized to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first 6 weeks; from week 7–12, dosing could be adjusted (the mean prescribed dose was 25.5 mg/day for paroxetine and 27.5 mg/day for fluoxetine). The two drugs showed comparable antidepressant and anxiolytic activity; the overall incidence of adverse effects was also comparable—although constipation, dyspepsia, tremor, sweating, and abnormal ejaculation were more common in paroxetine-treated subjects, nausea and nervousness were more frequent in fluoxetine-treated patients. Weight loss was more common under fluoxetine versus paroxetine. Chouinard and coworkers [34] also tested the efficacy of another SSRI, sertraline. They randomly assigned 448 patients to sertraline, amitriptyline, or placebo for 8 weeks. The mean final daily medication dose for the all-patients group was 145 mg and 104 mg for the sertraline- and amitriptyline-treatment groups, respectively. Both the sertraline- and amitriptyline-treatment groups showed a significantly greater improvement from baseline than the placebo group. The sertraline group had a higher proportion of gastrointestinal complaints and male sexual dysfunction than either the amitriptyline or the placebo group. The amitriptyline group showed a higher proportion of anticholinergic and sedative side effects and dizziness compared with patients who received either sertraline or placebo. Later, other SSRIs, such as fluvoxamine, citalopram and escitalopram, were studied and proposed to the market. After the second-generation antidepressants (i.e., SSRIs, bupropion), the selective serotonin-noradrenaline reuptake inhibitors (SNRIs) emerged as new class of effective antidepressants [35]. Tomoxetine is the most selective for noradrenaline among SNRIs. On Mar. 1, 1983, Chouinard et al. undertook the first proof-of concept study of tomoxetine in major depression, because it was a selective inhibitor of the uptake of noradrenaline with little affinity for adrenergic receptors

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[36]. This 12-week open-label study (n ¼ 10) included patients with recurrent major depression. After 1 week of placebo washout, the subjects were treated with tomoxetine for 12 weeks [37]. An initial dose of 40 mg/day was increased if necessary by 10-mg/day increments at a minimum interval of 3 days to a maximum of 70 mg/day. The results showed a significant improvement of depressive symptoms and global functioning. In addition, to the antidepressant effect of tomoxetine, they observed that all patients complained at one time of sleeping difficulty during treatment. Thus, a potentiating effect of tomoxetine on noradrenergic function was hypothesized. This was the first observation which, after further studies, allowed the FDA to approve tomoxetine as first nonstimulant treatment for attention-deficit hyperactivity disorder [38]. Running this study [37], Chouinard et al. also observed that patients who did not respond to tomoxetine had high drug blood concentrations, indicating an absence of metabolic pathway (personal communication). In addition, they treated the patients with 1/20 of the dose recommended and had a good response. This let them think about the need to verify patients’ drug response at low doses before administering higher ones, although these latter are recommended by the pharmaceutical producer (personal communication). Another interesting observation was that there was a patient, drug-resistant, who wanted to continue tomoxetine (this was possible only for a short time because of absence of enough toxicology from animals). The patient did not improve and was treated with electroconvulsive therapy, with no effects. Finally, he was treated with fluoxetine with great improvement (personal communication). Chouinard concluded that noradrenaline and serotonin were acting through the same mechanism, while bupropion and classical antipsychotics such as haloperidol (approved together with other classical antipsychotics in some European countries as antidepressant treatment if administered at low doses) are having an effect through dopamine. Nowadays, tomoxetine derivative, atomoxetine, is the drug of choice for attention-deficit hyperactivity in Canada and USA (the drug has been withdrawn from some European countries). The misfortune of tomoxetine was due to its complex metabolism in man, which leads to its withdrawal from clinical investigation following the initial trial of Chouinard [38]: some patients could not metabolize the drug, leading to toxic drug concentrations and lack of therapeutic effects. Reports later emerged of its beneficial action as an augmenting strategy in treatment-resistant patients [39], especially in case of a desipramine/nortriptyline augmentation, or if there was an earlier diagnosis of attention-deficit hyperactivity disorder [40], also under the light of negative impact on sexual function [41]. It is to be noted that both tomoxetine and atomoxetine showed to induce decreased appetite and weight loss [39,42]. Duloxetine is another SNRI which inhibits the reuptake of noradrenaline, serotonin, and dopamine, although it is a 3- to 4-fold more potent inhibitor of serotonin. Chouinard and coworkers initiated a proof-of-concept study using a multicenter double-blind placebo-controlled and active comparator-controlled trial (n ¼ 600) of duloxetine in outpatients with major depression [35]. They used a drug design with three phases: an acute therapy phase, an extension phase for responders, and a de-escalation phase for 2 weeks. After 1-week placebo washout period, patients were randomly assigned to placebo, clomipramine (the control drug), or 1 of 3 fixed doses of duloxetine (i.e., 5 mg, 10 mg, 20 mg) for 8 weeks. Duloxetine was shown to be efficacious in the treatment of depression [35]. Interestingly, later studies showed that duloxetine was efficacious for the treatment of neuropathic pain associated with diabetic peripheral neuropathy [43], and its use in neuropathic pain was approved by the FDA in 2005. Thereafter, the safety and efficacy of venlafaxine, if compared to trazodone or placebo, was studied in 225 patients with major depression for 6 weeks. After a single-blind placebo washout period, patients were randomly assigned to venlafaxine, trazodone, or placebo on a three-times-a-day flexible dosing schedule. The maximum daily dose was 200 mg of venlafaxine or 400 mg of trazodone. Venlafaxine produced more improvement in cognitive disturbance and retardation, while trazodone was more effective against sleep disturbance. Trazodone was significantly superior to placebo only at week 2, whereas venlafaxine was superior to placebo at weeks 4 and 6. Venlafaxine was most likely to cause nausea, whereas trazodone was associated with the most dizziness and somnolence [44]. From 1970s, drugs specifically acting on norepinephrine receptors were also developed, and the norepinephrine reuptake inhibitors (NRIs) emerged as an antidepressant class. The first double-blind controlled study testing the efficacy of viloxazine, if compared to imipramine, in 59 major depressive patients is dated 1974 [45]. The two drugs were administered at 300 mg/day and 150 mg/day, respectively, and showed comparable efficacy. However, later studies did not confirm a difference between viloxazine and placebo [46] and convulsive seizure while receiving viloxazine was reported [46]. In 1997–98, reboxetine, another NRI with no affinity for serotonin or dopamine uptake sites and little or no affinity for muscarinic, histaminergic, or adrenergic receptors [47], was studied. Reboxetine showed to be at least as effective as and better tolerated than desipramine and imipramine in the treatment of mixed populations of patients with mild to severe major depressive disorder [48,49]. Versiani et al. [50] compared the efficacy and tolerability of reboxetine with those of placebo over 6 weeks in the treatment of 56 hospitalized patients with severe major depressive disorder. After a 1-week placebo washout period, patients were randomly assigned to receive oral doses of placebo or reboxetine for up to 42 days. Reboxetine was administered according to a fixed-changing dose schedule starting with 6 mg (2 mg in the

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morning and 4 mg in the evening) on day 1, then increasing to 8 mg (4 mg twice daily) on day 2, and then to 10 mg (4 mg in the morning and 6 mg in the evening) from day 3 onward. Reboxetine was superior over placebo in terms of efficacy; the overall incidence of newly observed signs and symptoms was 86% in the reboxetine group and 46% in the placebo group. The most frequently reported adverse events in the reboxetine group were dry mouth and insomnia [50].

Dopamine Bupropion, a tert-butylamino derivative of meta-chloro-propiophenone, is a chemical derivative of diethylpropion, an amphetamine-like substance used as an anorectic. Bupropion was approved by the FDA in 1985 as a new antidepressant since it was unrelated to tricyclic or tetracyclic antidepressants and showed specific dopamine reuptake inhibiting properties [51]. In contrast to other antidepressants which inhibit the reuptake of both noradrenaline and serotonin, bupropion showed to have little effect on these two neurotransmitters and, unlike the tricyclics or tetracyclics, showed not to block muscarinic, histaminic, or alpha-adrenergic receptors. Proofs-of-concept studies of bupropion were carried out in two multicentric trials comparing bupropion and amitriptyline in depressed patients [52] and showed bupropion to be efficacious in the treatment of depression. These proof-of-concept studies remain of interest because the mechanism of action of bupropion as an antidepressant remains largely unknown and because it differs from standard antidepressants in that it has little effect on noradrenaline or serotonin reuptake and does not block muscarinic-histaminic or α-adrenergic receptors. However, it inhibits the neuronal reuptake of dopamine to some extent [52]. In the first multicenter study conducted by Chouinard [52], 124 depressed outpatients were randomly assigned to bupropion or amitriptyline for 13 weeks, preceded by a 1-week washout period and followed by a 1-week withdrawal period. Bupropion was given three times per day (the dose was equally divided), first at 300 mg/day, and then at 450 mg/day. In the second study [52], 92 depressed inpatients were included, and bupropion and amitriptyline were compared for a 6-week period. The dosage of bupropion was also increased from 300 mg/day to 450 mg/day and then further increased to a maximum of 750 mg/day. The results showed that bupropion was as effective as amitriptyline in the treatment of depression. Compared to amitriptyline, bupropion had greater dopaminergic side effects, as evidenced by insomnia, headache, decreased appetite, anorexia, nausea/vomiting, agitation/excitement, palpitations, and decreased libido. Bupropion-induced side effects were similar to those induced by dopamine agonists such as L-dopa or bromocriptine, although there was a lower incidence and severity, possibly because bupropion’s effects are limited to the inhibition of presynaptic dopamine reuptake. Of course, amitriptyline induced more weight gain and had more anticholinergic, antihistaminergic, and antiadrenergic side effects. Interestingly, bupropion did not induce orthostatic hypotension [53]. The results supported the use of bupropion as an antidepressant. It is worth noting that it was used in a similar drug design as in the Chouinard et al.’s proof-of-concept study of fluoxetine in depression. Later, bupropion was found to have another indication and was approved by the FDA in May 1997 for smoking cessation [54]. Bupropion was unique as a smoking cessation drug being the first drug which did not contain nicotine. In 1994, the CGP 25454A, a novel and selective presynaptic dopamine autoreceptor antagonist, was tested in animal models [55]. The molecule was a new benzamide derivative which showed in vitro to enhance the release of both dopamine and acetylcholine (it was 12.9 times more potent in increasing the release of dopamine than acetylcholine). CGP 25454A also produced a weak stimulation, suggested by a trend of increased spontaneous rearing and corroborated in animals by a significant potentiation of the elevated rearing induced by (+)-amphetamine. By contrast, at doses of 30–100 mg/kg, it exerted clear-cut sedative and neuroleptic-like properties [55]. In those years, clinical trials in patients with major depression were started but their results were not published, and the molecule was never marketed. Notwithstanding this, the study on CGP 25454A confirmed the role of dopamine in depression, confirmed the potential antidepressant activity of amphetamine, which was already proposed in 1940s and 1950s [56,57], and showed that drugs acting on the dopamine system might exert a different action depending on the dose. The fourth class of serotoninergic drugs that Chouinard and colleagues investigated were the antipsychotic drugs with antiserotonin properties [58,59]. In a multicenter, randomized, 2-year study comparing the risk of suicidal behavior in patients treated with clozapine vs olanzapine, Meltzer et al. [60] enrolled 980 patients with schizophrenia or schizoaffective disorder at high risk for suicide. The study showed that suicidal behavior was significantly less in patients treated with clozapine vs olanzapine: fewer clozapine-treated patients attempted suicide, required hospitalizations or rescue interventions to prevent suicide, or required concomitant treatment with antidepressants or anxiolytics or soporifics [60]. In those years (2002), FDA approved clozapine as a treatment against suicide in patients with schizophrenia. In 2003, Levy et al. [61] described the case of a schizophrenia patient without a history of obsessions or compulsions who developed risperidone-induced obsessive-compulsive symptoms that responded to fluoxetine. They suggested that the obsessive-compulsive symptoms resolved through two possible mechanisms of fluoxetine: first, increased serotonin through the reuptake and, second, inhibited the cytochrome P450 enzyme 2D6, thus increasing risperidone blood

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concentration. This last effect of fluoxetine confirms the inverse dosage-response relationship of atypical antipsychotics, such as risperidone, which may induce obsessive-compulsive symptoms at low dosages, owing to high 5-HT2-D2 antagonism, whereas they may improve obsessive-compulsive symptoms at high dosages, owing to high D2 antagonism [62]. There is now evidence supporting the efficacy of risperidone as adjunctive treatment for major depressive disorder, for the management of behavioral disturbances and psychosis in patients suffering from dementia [63] and as add on treatment of SSRI in OCD patients [63].

WITHDRAWAL FROM ANTIDEPRESSANTS The concept of drug-induced illness was first reported by Chouinard et al. [64,65] during antipsychotic withdrawal or switch, using the model of neuroleptic-induced tardive dyskinesia with the subtypes of withdrawal, overt, masked, and persistent [66]. The same concepts were applied to antidepressant withdrawal [67,68] and Fava et al. [69] were first to redefine the concept of behavioral toxicity of SSRIs by providing differentiation between adverse or emergent events that are limited to the period of psychotropic drug administration and effects that may persist long after SSRI discontinuation [69]. It is widely known that withdrawal symptoms may occur with all SSRIs and SNRIs [70] both in adults and in children [70–72], similarly to other psychotropic drugs, including benzodiazepines [73] and antipsychotics [66]. Unfortunately, withdrawal from SSRIs and other CNS drugs produces psychiatric symptoms that can be confounded with true relapse or recurrence of the original illness [70,73]. Different types of syndromes have been described and, in 2015, a comprehensive and new classification of SSRIs/ SNRIs withdrawal was proposed on the basis of the literature available and clinical observations and specific diagnostic criteria were formulated [68]. These diagnostic criteria identify three different syndromes: new withdrawal symptoms, rebound withdrawal, and persistent postwithdrawal disorders [68]. New withdrawal symptoms consist of symptoms which were not present before the beginning of the SSRI/SNRI treatment as well as before reduction or discontinuation of the drug. They are usually both unspecific and specific serotonin-related symptoms. Among the unspecific, nausea, headaches, tremor, sleep disturbances, decreased concentration, anxiety, irritability, agitation/aggression, and depression/dysphoria are mentioned. Among the specific serotonin-related symptoms, flu-like (e.g., flu), cardiovascular (e.g., tachycardia), gastrointestinal (e.g., diarrhea), neuromuscular (e.g., myoclonus), sensory (e.g., electric shock sensations), cognitive (e.g., confusion), and sexual symptoms (e.g., premature ejaculation) are mentioned. These symptoms are short-lasting and reversible [68]. Rebound symptoms consist of the return of symptoms which were present before the beginning of the SSRI/SNRI treatment, but were not present before reduction or discontinuation of the drug. They are more intense than before treatment, rapid, transient, reversible, may be associated to the psychological belief of the need of the drug, and typically improve rapidly after reintroduction of the drug [68]. Postwithdrawal disorders consist of the return of symptoms which were present before the beginning of the SSRI/SNRI treatment, but were not present before reduction or discontinuation of the drug or of the return of the original illness with additional symptoms (e.g., melancholic features for depression). They persist longer than 6 weeks after dose reduction or drug cessation, have greater intensity than before treatment, can be partially or totally reversible, and can respond partially or totally to reintroduction of discontinued [68]. When treatment with a CNS drug is discontinued, patients can experience classic new withdrawal symptoms, rebound and/or persistent postwithdrawal disorders, or relapse/recurrence of the original illness [66,74,75]. Thus, the three types of withdrawal syndromes mentioned above need to be differentiated from relapse and recurrence of the original illness. Relapse and recurrence are the gradual return of the original symptoms at the same intensity as before treatment, entailing a return of the same episode and a new episode of illness, respectively [66]. Initial withdrawal symptoms from CNS drugs have been reported to be more frequent and severe with high-potency drugs and drugs with a short elimination half-like [74,76]. CNS drugs with a shorter elimination half-life and rapid onset of action also carry a higher risk of dependence and high-dose use [74,76]. The priority is nowadays to properly diagnose persistent postwithdrawal disorders and find a way to treat and prevent them. This is because they are long-lasting, severe, and reduce the working, social, and family functioning of the patients. A proper diagnosis can be formulated following the Chouinard and Chouinard [68] diagnostic criteria and using the semistructured interview based on these criteria [76a]. Regarding the treatment and prevention of persistent postwithdrawal disorder, fluoxetine has been proposed to be used instead of SSRIs or SNRIs with a shorter elimination half-like since it is at lower risk to induce withdrawal [77,78]. In this vein, a switch from an SSRI/SNRI to fluoxetine has been proposed to manage withdrawal symptoms when they occur [68]. This strategy can be used instead of tapering the SSRI and seems to reduce the risk of withdrawal [68] (see Box 1).

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BOX 1 Management with Fluoxetine of a Case With Persistent Postwithdrawal Disorder X is a 52-year old woman who started paroxetine 20 mg/day at 30 years of age for a diagnosis of panic disorder. After 1 year of treatment with paroxetine, X was free from symptoms and started the tapering of the drug (15 mg instead of 20 mg/day). 48 h after the dose reduction, panic attacks returned at a greater severity than before treatment; thus, the patient increased paroxetine to 20 mg and in about 24 h the panic attacks disappeared. In the following 20 years the patients tried several times to taper paroxetine but every time she gave up due to the reappraisal of panic attacks. At the age of 52, X consulted a psychiatrist with the aim to taper and discontinue paroxetine. She started tapering paroxetine (a reduction of 2 mg was proposed) and once again she had the return of the original symptoms at a greater intensity than before treatment. Those symptoms were partially reversible and persisted for about 8 weeks after tapering. At the end of the 8 weeks, the patient was extremely distressed by the symptoms and asked to increase paroxetine. The psychiatrist introduced fluoxetine 10 mg and in about 5 days withdrawal symptoms faded away. Under fluoxetine, X was able to taper and discontinue paroxetine in about 8 weeks. Three weeks after discontinuing paroxetine, X tapered and discontinued fluoxetine without the occurrence of withdrawal symptoms.

Bupropion is also an interesting antidepressant treatment option having little effect on serotonin and not blocking muscarinic, histaminic, or alpha-adrenergic receptors, as tricyclic antidepressants do. Only one study found symptoms (i.e., acute dystonia) resulting from abrupt discontinuation of bupropion in two patients [79]. Unfortunately, no published clinical cases are currently available to support its use to treat persistent postwithdrawal disorder, although Clayton and colleagues [80] showed that it alleviates sexual dysfunction due to SSRI treatment. Interestingly, bupropion’s precursor diethylpropion has been poorly tested in major depression and there are no reports on its potential withdrawal effects. More investigations on bupropion and its precursors are warranted to verify whether they can be used as adjunctive medication to prevent withdrawal. Some clinical reports suggest managing persistent postwithdrawal disorder with clonazepam [68], which is an anticonvulsant with serotonergic effects without exerting a direct effect on the serotonin receptor (see Box 2). Another potential interesting option would be the anticonvulsant lamotrigine since it already showed to be effective in supersensitivity psychosis [75] and only one clinical case of lamotrigine withdrawal syndrome has been described in the literature [81]. Lamotrigine has been shown to be efficacious in preventing recurrences in depressive disorders [82]. Overall, anticonvulsants have shown to be efficacious in several withdrawal syndromes of various drugs [66]. Furthermore, considering the need in some cases not to neglect the active role of the patient in achieving recovery [83], a specific cognitive-behavioral therapy has been tested with positive results [84]. This specific psychotherapeutic protocol included the following ingredients: (a) explanatory therapy (i.e., accurate information on withdrawal, repeated reassurance and teaching the physiological principles underlying withdrawal phenomena); (b) monitoring of emergent symptoms in a diary according to the cognitive-behavioral model, followed by cognitive restructuring consisting of alternative interpretations of patient’s thought about his symptoms; (c) homework exposure for avoidance patterns; (d) lifestyle modifications; (e) techniques of decreasing abnormal reactivity to the social environment (i.e., learning ways to cope with stressful situations related to the level of arousal increased by drug withdrawal); (f ) teaching well-being therapy [84]. Although the priority is treating and preventing persistent postwithdrawal disorders, being long-lasting, severe, and disabling, it is also important to manage new withdrawal symptoms as well as rebound symptoms. Again, the first step is to formulate a correct diagnosis. Thus, the semistructured interview based on Chouinard and Chouinard [68] diagnostic criteria should be used [76a]. Thereafter, new withdrawal symptoms can be managed with clonazepam which is helpful to reduce unspecific symptoms like sleep disturbances, irritability, anxiety, agitation/aggression, and depression/dysphoria; it is also helpful to manage specific symptoms like the neuromuscular ones (e.g., myoclonus). Unspecific symptoms like nausea, headaches, tremor, and decreased concentration and specific serotonin-related symptoms like flu-like, cardiovascular, gastrointestinal, sensory, cognitive, and sexual symptoms can be managed using some ingredients of the specific

BOX 2 Management with Clonazepam of a Case With Persistent Postwithdrawal Disorder Y is a 35-year old woman who started sertraline 100 mg/day at the age of 31 years for a diagnosis of depression. After 4 years, Y started the tapering of the drug (75 mg instead of 100 mg/day) but 36 h after the dose reduction, panic attacks occurred, and the patient presented a reappraisal of depressive symptoms which were at a greater severity than before treatment. Both panic attacks and depressive symptoms were partially reversible and persisted for about 6 weeks after tapering. The patient was treated with clonazepam (1.5 mg/day) and withdrawal symptoms faded away in about 3 days. Thereafter, Y slowly tapered sertraline and discontinued it after 12 months.

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Verify if a diagnosis of withdrawal syndrome is satisfied according to Chouinard and Chouinard [68]

New withdrawal symptoms

Clonazepam

Ingredients of the specific cognitive behavioral therapy [81]

Rebound symptoms

Clonazepam

Ingredients of the specific cognitive behavioral therapy [81]

Persistent postwithdrawal disorder

Fluoxetine

Specific cognitive behavioral therapy [81]

Anticonvulsivants: lamotrigine

Clonazepam

Bupropion

FIG. 1 Steps of assessment and management of withdrawal syndromes.

cognitive-behavioral therapy proposed by Belaise et al. [84]. The ingredients might include: explanatory therapy, monitoring of emergent symptoms, lifestyle modifications, and techniques of decreasing abnormal reactivity to the social environment [84]. Patients with rebound symptoms can have benefits from the administration of clonazepam in case of return of anxious or depressive symptoms [85–87]. Once again, ingredients of the specific cognitive-behavioral therapy proposed by Belaise et al. [84], such as explanatory therapy, monitoring of emergent symptoms, lifestyle modifications, and techniques of decreasing abnormal reactivity to the social environment [84], can be of help. In addition, monitoring of the occurrence of the psychological belief of the need of the drug in a diary according to the cognitive-behavioral model, followed by cognitive restructuring consisting of alternative interpretations of patient thought about this symptom [84], seems extremely important to support the patient in avoiding going back to the SSRI/SNRI. In Fig. 1, we report the steps for assessing and managing patients with withdrawal syndromes.

CONCLUSIONS Antidepressant medications should be reconsidered under a new light on the basis of the literature. First, it is clear that they have a delayed and moderate efficacy, as suggested by the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study [88] and following research (e.g., [89,90]). It is also clear that their efficacy decreases in recurrent depression and in preventing relapse [88]. In addition, antidepressants, particularly SSRIs and SNRIs, often induce withdrawal symptoms at reduction or discontinuation [68]. Unfavorable long-term outcomes and paradoxical effects, such as depression inducing and symptomatic worsening, have been reported [91] and explained on the basis of the oppositional model of tolerance [92]. Finally, antidepressants may provoke disturbing [93,94] or persistent side effects (e.g., persistent

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sexual side effects) [95]. They may increase the risk of the occurrence of a medical disease (e.g., breast cancer, cardiovascular event) [94,96]; their long-term use may enhance the biochemical vulnerability to depression and worsen its long-term outcome and symptomatic expression [97], decreasing both its likelihood of subsequent response to pharmacological treatment and the duration of symptom-free periods [91]. In this framework, a rational use of antidepressants [98] is warmly encouraged keeping in mind the “primum non nocere” principle of Hippocrates’ oath. Indeed, the main concerns of SSRIs and SNRIs given as antidepressant, anti-panic, anti-obsessive compulsive, and anti-anxiety drugs are their long-term use, which was wrongly investigated by adopting the discontinuation concept approach to demonstrate their long-term efficacy. This design confounds therapeutic effects and withdrawal syndromes. Since these drugs may induce new illnesses, which include diseases for which they are approved to treat and efficacious, they should not be used long-term (i.e., more than 2 years) without the sequential integration of pharmacotherapy and psychotherapy [99]. This means that antidepressants might still be the first-line treatment of acute psychiatric disorders for which they showed to be superior to any other pharmacological or non-pharmacological interventions, while they should not be proposed as a long-term treatment (i.e., more than 2 years even at low doses). In case the patient needs a long-term intervention, pharmacological approaches (e.g., mood stabilizers, lamotrigine preferably and other anticonvulsivants, low-dose antipsychotics, or low-dose clonazepam) or nonpharmacological approaches (e.g., cognitive-behavioral therapy, well-being therapy [100]) or both which have demonstrated to be efficacious should be preferred.

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