Definition and clinical presentation

’Apathy syndrome’ is defined as the syndrome whose main clinical characteristic is a primary loss of motivation which is not due to any intellectual impairment, emotional distress, or decreased consciousness (Marin et al., Reference Marin, Biedrzycki and Firinciogullari1991).

In patients with depressive, anxiety, or other psychiatric disorders, pharmacotherapy with antidepressants (principally with SSRIs, but sometimes with antidepressants from other classes) may induce an array of clinically significant manifestations, collectively termed ‘apathy syndrome’ or ‘emotional blunting’ (or the more narrow term ‘inability to cry’) (e.g. Hoehn-Saric et al., Reference Hoehn-Saric, Lipsey and McLeod1990; Hoehn-Saric et al., Reference Hoehn-Saric, Harris, Pearlson, Cox, Machlin and Camargo1991; George & Trimble, Reference George and Trimble1992; Garland & Baerg, Reference Garland and Baerg2001; Barnhart et al., Reference Barnhart, Makela and Latocha2004; Padala et al., Reference Padala, Padala, Majagi, Garner, Dennis and Sullivan2020). These manifestations often have an insidious onset and include lack of motivation or dullness and, more generally, a decrease in emotional responsiveness to circumstances which would have triggered intense mood reactions before antidepressant treatment had started. Antidepressants not only alleviate depressive symptoms but may also ‘attenuate’ or ’set aside everyday concerns’ (Kelly et al., Reference Kelly, Posternak and Alpert2008; Sansone & Sansone, Reference Sansone and Sansone2010; Szmulewicz et al., Reference Szmulewicz, Samane, Caravotta, Martino, Igoa, Hidalgo-Mazzei, Colom and Strejilevich2016).

This decreased responsiveness involves many aspects of emotions, including crying, irritation, sadness, and creativity (Scoppetta et al., Reference Scoppetta, di Gennaro and Scoppetta2005). It has been suggested that the well-known effect of SSRI on sexual desire and interest may be a concomitant and potential marker of the apathy syndrome induced by these medications (Sansone & Sansone, Reference Sansone and Sansone2010; Szmulewicz et al., Reference Szmulewicz, Samane, Caravotta, Martino, Igoa, Hidalgo-Mazzei, Colom and Strejilevich2016; Opbroek et al., Reference Opbroek, Delgado, Laukes, McGahuey, Katsanis, Moreno and Manber2002).

Antidepressant-induced apathy appears both dose-dependent and reversible (Padala et al., Reference Padala, Padala, Majagi, Garner, Dennis and Sullivan2020). Patients can often differentiate between loss of interest as a symptom of depression from the apathy associated with SSRI treatment (Hoehn-Saric et al., Reference Hoehn-Saric, Lipsey and McLeod1990; Barnhart et al., Reference Barnhart, Makela and Latocha2004). However, apathy symptoms are frequently not reported and often remain untreated, with subsequent clinical, social, and professional consequences. A proportion of patients may consider antidepressant-induced apathy to be beneficial, but probably most consider them to be the cause of difficulties such as financial and working problems (Price et al., Reference Price, Cole and Goodwin2009).

Apathy manifestations often emerge soon after an antidepressant is started and are most frequently reversible after drug discontinuation, and their emergence does not appear associated with patients’ age or diagnosis (Padala et al., Reference Padala, Padala, Majagi, Garner, Dennis and Sullivan2020). In particular, the onset of apathy with SSRIs use may be very quick. Thus, in a functional magnetic resonance imaging study in a sample of healthy volunteers, 1 week of citalopram administration was associated with reduction in activity in the reward networks of ventral striatum and ventral medial/orbitofrontal cortex (McCabe et al., Reference McCabe, Mishor, Cowen and Harmer2010). Some data suggest that apathy emergence is an effect specific to SSRIs administration, as apathy manifestations during treatment with SSRIs can remit after switching to an antidepressant from another class (Hoehn-Saric et al., Reference Hoehn-Saric, Lipsey and McLeod1990; Hoehn-Saric et al., Reference Hoehn-Saric, Harris, Pearlson, Cox, Machlin and Camargo1991; Padala et al., Reference Padala, Padala, Monga, Ramirez and Sullivan2012). However, an internet-based survey in patients with major depressive disorder (MDD) found no difference regarding the prevalence of emotional blunting with differing antidepressant medicines (including SSRIs, SNRIs, mirtazapine, bupropion, and amitriptyline), though it appeared less evident with bupropion (Goodwin et al., Reference Goodwin, Price, De Bodinat and Laredo2017). More recently, Sato et al (Reference Sato, Sodeyama, Matsuzaki and Shiratori2020) reported two cases of venlafaxine-induced apathy but attributed it to the serotoninergic component of the drug. More details regarding the above-mentioned studies are included in sub-section ‘Clinical trials, case reports, and internet/telephone surveys’.

Antidepressant-induced apathy appears independent of the psychiatric disorder for which medication is prescribed and has been found in all age groups of patients with depressive or anxiety disorders (see for a review: Szmulewicz et al., Reference Szmulewicz, Samane, Caravotta, Martino, Igoa, Hidalgo-Mazzei, Colom and Strejilevich2016). Antidepressant-induced apathy also seems to be independent of treatment outcome and may be clinically present even after depressive and anxiety symptoms have remitted (Fava et al., Reference Fava, Graves, Benazzi, Scalia, Josifescu, Alpert and Papakostas2006; Popovic et al., Reference Popovic, Vieta, Fornaro and Perugi2015). Importantly, some clinicians consider violent behaviour in SSRI-treated adolescents to be related, at least in part, to the experience of medication-induced apathy (Lee & Keltner, Reference Lee and Keltner2005).

Differential diagnosis and clinical measures of apathy

Clinicians must take into account that apathy manifestations are included in the clinical presentation of other medical conditions, such as (apathetic) hyperthyroidism, dementia, frontal lobe lesions, and cannabis use (Barnhart et al., Reference Barnhart, Makela and Latocha2004). Additionally, apathy symptoms may be an adverse effect of medication, a residual symptom, or an early manifestation of relapse (Kelly et al., Reference Kelly, Posternak and Alpert2008). It has been suggested that the presence of apathy without concurrent fatigue is more indicative that it is antidepressant-induced (Barnhart et al., Reference Barnhart, Makela and Latocha2004). Although the symptoms of apathy and depression overlap, they are considered distinct clinical entities (Levy et al., Reference Levy, Cummings, Fairbanks, Masterman, Miller, Craig, Paulsen and Litvan1998; Monga & Padala, Reference Monga and Padala2015). Patients with apathy can demonstrate a lack of concern, while depressed patients show pathological self-criticism and a negative outlook – two symptoms which are usually absent in apathy (Landes et al., Reference Landes, Sperry, Strauss and Geldmacher2001). Furthermore, at a nosological level, it is considered important to define the exact relationship between apathy and anhedonia – the latter defined as the (complete) inability to experience pleasure, as manifested in facial expression, speech, behaviour, lifestyle, and the individual’s account of personal experience. Thus, Starkstein and Leentjens (Reference Starkstein and Leentjens2008) emphasise that this relationship depends on how apathy is conceptualised. If apathy is considered a state of absence of feeling and emotional sensitivity, anhedonia should be considered a mandatory symptom of apathy. If, on the other hand, apathy is considered a state of diminished motivation, anhedonia may not be a necessary diagnostic criterion.

As it is often difficult to trace apathy manifestations and differentiate them from depressive symptoms, a number of clinical measures have been developed for this purpose, including the Apathy Evaluation Scale (Marin et al., Reference Marin, Biedrzycki and Firinciogullari1991), the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) (Rothschild et al., Reference Rothschild, Raskin, Wang, Marangell and Fava2014; Rothschild, Reference Rothschild2008), the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) (Rothschild et al., Reference Rothschild, Raskin, Wang, Marangell and Fava2014; Fava et al., Reference Fava, Iosifescu, Pedrelli and Baer2009), and the Oxford Questionnaire on the Emotional Side effects of Antidepressants (OQESA) (Price et al., Reference Price, Cole, Doll and Goodwin2012). Most recently, novel clinical evaluation methods combining text, audio, and video features were used for the early detection and differential diagnosis of apathy and depression in patients with mild cognitive impairment (Zhou et al., Reference Zhou, Yao, Han, Wang, Li and Li2022). Of note, clinical measures must be part of a broader, comprehensive neuropsychiatric evaluation, including the assessment of patient’s social and physical context, her/his education, social class, interests and goals, and cultural parameters (Marin & Wilkosz, Reference Marin and Wilkosz2005).

Prevalence

The prevalence of antidepressant-induced apathy may be high. An early study found that up to 80% of 15 patients with SSRI-induced sexual dysfunction also reported clinically significant emotional blunting (Opbroek et al., Reference Opbroek, Delgado, Laukes, McGahuey, Katsanis, Moreno and Manber2002). Goodwin et al (Reference Goodwin, Price, De Bodinat and Laredo2017) reported that among 669 MDD patients undergoing monotherapy with either an SSRI (citalopram, escitalopram, fluoxetine, paroxetine, or sertraline) or a non-SSRI-antidepressant (amitriptyline, bupropion, desvenlafaxine, duloxetine, mirtazapine, or venlafaxine), the overall prevalence of emotional blunting was 46%. A retrospective chart review of 125 outpatients receiving only SSRIs found that up to 92% demonstrated clinically significant apathy (Padala et al., Reference Padala, Padala, Majagi, Garner, Dennis and Sullivan2020). Regarding paediatric populations, 5% of 45 patients with anxiety disorders receiving the SSRI fluvoxamine demonstrated apathy symptomatology, without concomitant depression (Reinblatt & Riddle, Reference Reinblatt and Riddle2006). More data about the prevalence of antidepressant-induced apathy are mentioned in sub-section ‘Clinical trials, case reports, and internet/telephone surveys’.

Aetiology

The mechanisms underlying the syndrome are not clarified fully. Due to the effect of SSRIs on pathological emotional lability, a serotoninergic hypothesis has been proposed: SSRIs may exert their therapeutic effect by elevating the ‘threshold’ for feeling intense emotions and subsequently by reducing emotional ‘responsiveness’ (Scoppetta et al., Reference Scoppetta, di Gennaro and Scoppetta2005). As clinically similar emotional blunting can be observed after damage to the anterior cingulate cortex, which receives extensive dopaminergic input from the ventral tegmental area, abnormal dopaminergic activity is also conjectured to be a cause of apathy (Padala et al., Reference Padala, Padala, Majagi, Garner, Dennis and Sullivan2020). Furthermore, in healthy subjects, an inverse association was found between ‘crying proneness’ (as reflected in the ‘crying easily’-item of the Symptom Checklist-90 measure) and cerebrospinal fluid levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), suggesting that central noradrenergic mechanisms may contribute to crying behaviour (Markianos et al., Reference Markianos, Evangelopoulos, Koutsis and Sfagos2001).

Hoehn-Saric et al (Reference Hoehn-Saric, Lipsey and McLeod1990, Reference Hoehn-Saric, Harris, Pearlson, Cox, Machlin and Camargo1991) proposed two alternative mechanisms. The first is that SSRIs directly modulate frontal lobe activity through changes in serotoninergic systems. Alternatively, SSRI administration may alter serotoninergic systems and subsequently modulate midbrain dopaminergic systems which project to the prefrontal cortex: that is, SSRIs indirectly modulate frontal lobe activity by inhibiting the release of dopamine. In this respect, agonism of 5HT_-2C receptors may play a particular role (Gobert et al., Reference Gobert, Rivet, Lejeune, Newman-Tancredi, Adhumeau-Auclair, Nicolas, Cistarelli, Melon and Millan2002; Arnone et al., Reference Arnone, Horder, Cowen and Harmer2009). More precisely, SSRI-induced chronic increases of serotonin levels in the nucleus accumbens leads – due to 5HT_-2C agonism – may lead to a down-regulation of dopamine turn-over in neurobiological structures closely associated with apathy. The subsequent SSRI-induced ‘frontal hypo-dopaminergic’ state may manifest as apathy (Hoehn-Saric et al., Reference Hoehn-Saric, Lipsey and McLeod1990; Hoehn-Saric et al., Reference Hoehn-Saric, Harris, Pearlson, Cox, Machlin and Camargo1991; Lee & Keltner, Reference Lee and Keltner2005; Szmulewicz et al., Reference Szmulewicz, Samane, Caravotta, Martino, Igoa, Hidalgo-Mazzei, Colom and Strejilevich2016; Levy & Dubois, Reference Levy and Dubois2006).

Emotional blunting may reduce a focus on depressed feelings or negative experiences (Harmer et al., Reference Harmer, Sheley, Cowen and Goodwin2004). Moncrieff and Cohen (Reference Moncrieff and Cohen2005, Reference Moncrieff and Cohen2006) have proposed that antidepressants work through a ‘drug-centred’ mechanism, altering a patient’s mental state which subsequently impacts MDD psychopathology, rather than through a ‘disease-centred’ way, that is, by reversing specific biological mechanisms underlying disease.

SSRIs may alter neurocognitive processes underlying recognition of an array of emotions, including happiness, sadness, fear, disgust, and surprise, both in MDD patients and in healthy controls (Harmer et al., Reference Harmer, Sheley, Cowen and Goodwin2004; Harmer et al., Reference Harmer, de Bodinat, Dawson, Dourish, Waldenmaier, Adams, Cowen and Goodwin2011). Some researchers suggest antidepressants with a different mechanism of action – such as reboxetine (Harmer et al., Reference Harmer, Sheley, Cowen and Goodwin2004), mirtazapine (Arnone et al., Reference Arnone, Horder, Cowen and Harmer2009), or agomelatine (Harmer et al., Reference Harmer, de Bodinat, Dawson, Dourish, Waldenmaier, Adams, Cowen and Goodwin2011) – may modify biological factors underlying the processing of happiness and sadness, but not of other emotions. However, further evidence is needed concerning this hypothesis.

Treatment options

Clinical trials

An open-label study explored the effectiveness of olanzapine for treatment of prominent apathy in the absence of depression in 21 patients with non-psychotic MDD in full remission, all receiving long-term pharmacotherapy with an SSRI (Marangell et al., Reference Marangell, Johnson, Kertz, Zboyan and Martinez2002). The rationale for adding olanzapine to SSRI treatment was that it can enhance dopamine availability in the frontal cortex by blocking serotonin-induced inhibition of dopamine release. Following initial response, olanzapine was administered for 8 weeks at a stable dose (5.4 ± 2.8 mg/day). Clinically significant improvements were seen in all measures of apathy.

In a clinical trial, up to 80% of 15 patients with SSRI (fluoxetine, paroxetine, or sertraline)-induced sexual dysfunction also reported clinically significant apathy, including reductions regarding ability to cry, irritation, care about others’ feelings, sadness, erotic dreaming, creativity, surprise, anger, expression of their feelings, worry over things or situations, sexual pleasure, and interest in sex (Opbroek et al., Reference Opbroek, Delgado, Laukes, McGahuey, Katsanis, Moreno and Manber2002). However, Balon (Reference Balon2002) criticised this study for using a clinical measure of apathy without validity, and for not specifying which aspects of the broad term ’sexual functioning’ were impaired in patients. Moreover, he stressed that some ‘emotional blunting’ manifestations could be personality traits or residual MDD symptoms. The issue of whether apathy symptoms are medication-induced or residual symptoms of MDD is a frequent puzzle (e.g. Fava et al., Reference Fava, Graves, Benazzi, Scalia, Josifescu, Alpert and Papakostas2006; 31, 42).

A cross-sectional study explored side effects of long-term pharmacotherapy with antidepressants in 117 MDD patients who had initially responded to a 3-month acute treatment (Fava et al., Reference Fava, Graves, Benazzi, Scalia, Josifescu, Alpert and Papakostas2006): a study-specific questionnaire was used to inquire for apathy, among other side effects. Up to 30–40% of the patients reported apathy and loss of motivation. The authors concluded that apathy is frequent in long-term pharmacotherapy of MDD and may be due both to medication and residual psychopathology.

A retrospective case–control study – using a 20-year database – investigated the specificity of SSRIs to cause emotional blunting in antidepressant-treated elderly inpatients (N = 384) with MDD and/or dysthymia (Wongpakaran et al., Reference Wongpakaran, van Reekum, Wongpakaran and Clarke2007). A study-specific clinical measure of apathy – combining items from established depression rating scales – was used. At discharge, depressive symptomatology was significantly reduced, irrespective of the type of antidepressant prescribed. However, SSRI-treated patients demonstrated significantly greater apathy. Both the age range 70–75 years and the length of hospital stay predicted post-treatment apathy.

A qualitative study explored the phenomenology of SSRI-induced apathy in 38 SSRI-treated depressed or anxious patients, through interviews and inquiry of relevant posts in patient-oriented websites (Price et al., Reference Price, Cole and Goodwin2009). Findings suggested that SSRI administration is associated with ‘emotional detachment’ ranging from ‘just not caring’ for stimuli eliciting anxiety prior to treatment to generalised emotional numbing. More precisely, eight key framework ‘themes’ were identified, including ‘general effects on all emotions’, ‘reduction of positive or negative emotions’, ‘emotional detachment’, ‘just-not-caring’ manifestations, fears of ‘changed personality’, ‘effects on everyday life (helpful and unhelpful)’ and ‘it’s because of my pills!’ statements, in which patients attributed their apathy symptoms to SSRI treatment. Notably, apathy manifestations were considered as beneficial by an unspecified proportion of patients, but others considered them as the cause of their financial and working problems.

A multicentre, double-blind, randomised study found that in 423 SSRI-treated patients with MDD in remission, but with clinically significant apathy, switching to the SNRI duloxetine was similarly effective to switching to another SSRI (escitalopram) regarding the reduction in apathy (Raskin et al., Reference Raskin, George, Granger, Hussain, Weizhing and Marangell2012). The authors suggest that the serotoninergic component of duloxetine may reduce its efficacy to alleviate apathy symptomatology and that a ‘pure’ noradrenergic drug might prove more effective. Of note, another 60 patients who had been receiving escitalopram already at baseline, and continued this medication for a further 8 weeks, also demonstrated an improvement in apathy. Data from this study were additionally used to assess the underlying structure of the RSAT and the Massachusetts General Hospital CPFQ for measuring apathy (Rothschild, Reference Rothschild2008; Fava et al., Reference Fava, Iosifescu, Pedrelli and Baer2009).

The clinical efficacy, safety, and tolerability of agomelatine have been confirmed (Pompili et al., Reference Pompili, Serafini, Innamorati, Venturini, Fusar-Poli, Sher, Amore and Girardi2013). A randomised, controlled, double-blind 24-week trial suggests that ‘emotional blunting’” is less frequent with agomelatine (25–50 mg/day) than with escitalopram (10–20 mg/day), although the drugs had similar efficacy in treating MDD (Corruble et al., Reference Corruble, de Bodinat, Belaïdi and Goodwin2013). Apathy manifestations included lack of emotions’ intensity (agomelatine = 28% vs. escitalopram = 60%) and lack of care for issues previously considered as important (agomelatine 16% vs. escitalopram 53%). The authors suggest that emotional blunting may not be a side effect of antidepressants, but a symptom of MDD that conventional clinical measures fail to trace and where agomelatine is superior to escitalopram. They also propose that the OQESA – used to evaluate apathy in the study – should be considered a clinical measure of MDD.

In another study, up to 22.6% of MDD patients and 18.2% of patients with an anxiety disorder demonstrated apathy manifestations after at least 6 months of successful SSRI monotherapy (Popovic et al., Reference Popovic, Vieta, Fornaro and Perugi2015). The overall incidence of apathy in the sample (N = 67) was 20.4%. The authors attribute the higher incidence of SSRI-induced apathy to the ‘real-world setting’, in contrast to the more rarefied environment of clinical trials, and hypothesised that partial responders, receiving combined pharmacotherapy, will have a higher incidence of apathy.

In another study, 57 depressed patients treated with serotoninergic antidepressants reported significantly greater subjective difficulty in identifying feelings, when compared to 441 controls (Kajanoja et al., Reference Kajanoja, Scheinin, Karukivi, Karlsson and Karlsson2018). A 16-week prospective study investigated various adverse effects of antidepressants in 98 MDD patients and found that as depressive symptoms (rated by the Montgomery-Asberg Depression Rating Scale, MADRS) gradually improved, apathy symptoms (OQESA) decreased (Ascibasi et al., Reference Ascibasi, Cokmus, Dikici, Ozkan, Alci, Altunsoy, Kuru, Yuzeren and Aydemir2020): furthermore, at Week 8 and Week 16, patients in remission demonstrated significantly lower apathy manifestations compared to non-remitted patients. The OQESA and the MADRS scores were significantly correlated in all assessments, suggesting that severity of apathy may be related to both the medication and the intensity of depressive symptoms.

A retrospective chart review of 119 outpatients with MDD or other diagnoses found that clinically important apathy emerged significantly more often and was more severe in SSRI-treated patients when compared to those treated with a non-SSRI antidepressant (92% vs. 61%) (Padala et al., Reference Padala, Padala, Majagi, Garner, Dennis and Sullivan2020). Antidepressant-induced apathy was observed in all psychiatric disorders, especially in patients with dementia, and with all the SSRIs administered (citalopram, escitalopram, paroxetine, fluoxetine, sertraline).

Case reports

Hoehn-Saric et al (Reference Hoehn-Saric, Lipsey and McLeod1990) were the first to report the presence of apathy, indifference, loss of initiative, or disinhibition (without concurrent sedation or hypomania) in three MDD patients receiving 20 mg/day fluoxetine and two patients with panic disorder receiving fluvoxamine 300 mg/day and 400 mg/day, respectively. Clinical manifestations were dose-related and completely resolved (N = 4) or improved after dose reduction (n = 1), or after switching to another class of antidepressants. Remission of apathy took longer to achieve in fluoxetine-treated patients, possibly due to its longer half-life when compared to that of fluvoxamine.

A 23-year-old patient treated with high doses of fluoxetine (100 mg/day) for obsessive-compulsive disorder (OCD) demonstrated apathy, indifference, inattention, and perseveration and found to be associated with a decrease in cerebral blood flow in the frontal lobes and changes in neuropsychological measures suggesting frontal lobe impairment (Hoehn-Saric et al., Reference Hoehn-Saric, Harris, Pearlson, Cox, Machlin and Camargo1991). Apathy completely resolved 4 weeks after discontinuing fluoxetine, concurrently with normalisation of cerebral blood flow and neuropsychological measurements. Likewise, an OCD patient with comorbid Tourette syndrome demonstrated a clinically significant ‘frontal lobe syndrome’ characterised mainly by apathy and indifference after a 4-week fluvoxamine (150 mg/day) treatment (George & Trimble, Reference George and Trimble1992), this syndrome resolving after dose reduction.

A 17-year-old female with MDD experienced fluoxetine (30 mg/day)-induced apathy which improved after dose reduction (to 20 mg/day) and augmentation with bupropion (150 mg/day) (Garland & Baerg, Reference Garland and Baerg2001). Sertraline-induced apathy was described in a 48-year-old male with MDD and ‘personality change due to medical condition’, which resolved after dosage reduction (Kodela & Venkata, Reference Kodela and Venkata2010). Likewise, the panic symptoms of a 39-year-old female improved with sertraline (50 mg/day), but she also demonstrated flattening of emotions and a ‘like-nothing-matters’ feeling: these apathy manifestations abated after dosage reduction to 25 mg/day (Sato & Asada, Reference Sato and Asada2011).

In another report, among six patients demonstrating SSRI-induced loss of motivation, four improved only by discontinuing medication, and two resolved after switching to a dopaminergic agent (bupropion) (Padala et al., Reference Padala, Padala, Monga, Ramirez and Sullivan2012). In another report, a 70-year-old male MDD patient improved moderately after 6 months of escitalopram treatment (10 mg/day), but later demonstrated apathy manifestations, including loss of drive and motivation, without however worsening of depression (De Berardis et al., Reference De Berardis, Valchera, Fornaro, Serroni, Marini, Moschetta, Martinotti and Di Giannantonio2013): co-administration of agomelatine (25 mg/day) for 9 weeks both reversed the escitalopram-induced apathy and preserved the therapeutic gains of the latter, which subsequently was discontinued.

In another report, a 42-year-old male patient with depression and epilepsy received a carbamazepine–topiramate–sertraline combination, which reduced depression and terminated seizures: however, he demonstrated apathy which did not remit after carbamazepine cessation, but only after administration of amisulpride (15 mg/day) (Monga & Padala, Reference Monga and Padala2015). The case of a 67-year-old female MDD patient was reported, who while receiving combined fluoxetine–venlafaxine–mirtazapine–aripiprazole pharmacotherapy experienced severe symptoms of apathy which abated after discontinuation of all antidepressants and co-administration of methylphenidate (25 mg/day)-modafinil (200 mg/day)-olanzapine (10 mg/day) (Kim et al., Reference Kim, Koo, Lee and Cheon2019).

Additionally, two male MDD patients receiving venlafaxine (75 and 37.5 mg/day, respectively) experienced mild apathy symptoms which abated after increasing the dosage to 150 mg/day (Sato et al., Reference Sato, Sodeyama, Matsuzaki and Shiratori2020). The authors consider the serotoninergic mechanisms that prevail with low doses of venlafaxine to cause apathy, which subsequently abates with dosage increases which result in a better serotonin/norepinephrine balance.

Internet/telephone surveys and investigation of patient-oriented websites

In a telephone survey (semi-structured interview) of 161 MDD patients who had completed SSRI therapy, up to 20% reported ‘apathy’, while 16.1% suffered from loss of ambition (Bolling & Kohlenberg, Reference Bolling and Kohlenberg2004). Another study explored reviews in three popular health Internet-websites concerning the antidepressants escitalopram, duloxetine, vilazodone, and vortioxetine (Hughes et al., Reference Hughes, Lacasse, Fuller and Spaulding-Givens2017): participants (N = 3243) reported suffering from anxiety, depressive, or bipolar disorders. Patients receiving vilazodone or vortioxetine more often reported ‘emotional instability’. ‘Emotional numbing’ was more often reported by patients on escitalopram (10.7%) or duloxetine (8.2%), compared to those on vortioxetine (5.9%) or vilazodone (4.1%): overall, 9.4% of subjects reported ‘emotional blunting’.

The adverse effects reported by 258 patients receiving antidepressants (SSRIs, TCAs, ‘other’) were compared to those reported by clinicians, through an internet-based medicine reporting system (van Geffen et al., Reference van Geffen, van der Wal, van Hulten, de Groot, Egberts and Heerdink2007). Up to 10.8% of patients reported ‘apathy’, while none of the clinicians reported apathy in their antidepressant-treated patients. Up to 46% of the patients who reported apathy perceived it as ‘very negative’, and up to 54% discontinued pharmacotherapy.

In a patient-oriented website, the views of 468 subjects receiving venlafaxine or fluoxetine were explored (Goldsmith & Moncrieff, Reference Goldsmith and Moncrieff2011). Apathy manifestations (‘flat mood’, ‘unable to cry very often’, ‘numb’, ‘blank’, ‘no motivation’, ‘lack of interest’, ‘distanced from life’, ‘loss of humour’, ‘less creative’, ‘less motivated’, ‘it seems less me’, etc.) were reported by 17% and 19% of responders to venlafaxine and fluoxetine, respectively. Apathy was associated with cognitive impairment, reduced libido, and sedation. The authors suggested that antidepressant-induced reduced libido is not an isolated effect but related to emotional blunting caused by these medications. Moreover, feelings of emotional blunting or indifference coexisted with activation/arousal effects and emotional instability and – most importantly – with suicidal thoughts. The researchers suggest that emotional blunting reduces normal inhibitions, which in turn results in the emergence of suicidal ideation (Goldsmith & Moncrieff, Reference Goldsmith and Moncrieff2011).

An internet-based survey investigated the rate of antidepressant-induced emotional blunting in 669 currently depressed patients under monotherapy with either an SSRI (citalopram, escitalopram, fluoxetine, paroxetine, or sertraline) or a non-SSRI-antidepressant (amitriptyline, bupropion, desvenlafaxine, duloxetine, mirtazapine, or venlafaxine) and 150 drug-free, previously depressed controls (Goodwin et al., Reference Goodwin, Price, De Bodinat and Laredo2017). Overall, the rate of emotional blunting in currently depressed patients was 46% (men vs. women = 52% vs. 44%). Contrary to the notion that apathy is seen only in SSRI-treated patients, the authors found no major differences between agents in apathy emergence, although it appeared less evident with bupropion. Currently, depressed patients had significantly higher emotional blunting scores on the OQESA compared to controls, while total blunting score was correlated with depression severity. Of those reporting emotional blunting, 37% had a negative perception of the condition, but up to 38% had a positive perception. In summary, this study suggests that almost half of MDD patients receiving antidepressants demonstrate emotional blunting. Moreover, it suggests that emotional blunting is not merely a side effect of antidepressants but also a symptom of depression and associated with a poorer outcome.

An internet-based survey designed to elicit experiences with antidepressants (SSRIs, TCAs, and venlafaxine), of 1829 adults who had started pharmacotherapy in the preceding 5 years (52% were treated for >3 years) (Read et al., Reference Read, Cartwright and Gibson2014; Cartwright et al., Reference Cartwright, Gibson, Read, Cowan and Dehar2016), found a high prevalence of apathy symptoms, including ‘feeling emotionally numb’ (60%), ‘reduction in positive feelings’ (42%), and ‘caring less about others’ (39%): all apathy manifestations were reported as being associated with ’suicidality’.

Another online survey, in 38 countries, asked 1431 users of antidepressants for the presence and severity of symptoms ‘as a result of taking the antidepressant’ (Read & Williams, Reference Read and Williams2018). Apathy manifestations included ‘feeling emotionally numb’ (71%; the most frequently reported adverse effect), ‘reduction in positive feelings’ (60%), and ‘caring less about others’ (54.5%). Less than 5% of patients reported being informed prior to pharmacotherapy about the potential emergence of medication-induced apathy. The authors conclude that asking people directly reveals far higher rates of medication-induced manifestations than clinicians consider, including apathy. In another online survey, 342 users of antidepressants were asked open questions concerning their pharmacotherapy (e.g. ‘Is there anything else you would like to tell us about your experience of taking medication?’): up to 5.8% reported that their feelings were blunted by the antidepressant, using terms like ‘flattened’ or ‘numbed’ (Read et al., Reference Read, Grigoriu, Gee, Diggle and Butler2020).

Camino et al (Reference Camino, Strejilevich, Godoy, Smith and Szmulewicz2022) recently analysed 450 posts from a patient-oriented website – 50 on each of the most prescribed antidepressants, including bupropion, citalopram, duloxetine, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, and venlafaxine. Sertraline, paroxetine, and fluoxetine were associated with frequent reports of emotional blunting, but bupropion with very few. The presence of emotional blunting was among the side effects (the other being suicidality, irritability, cognitive disturbances, and withdrawal symptoms) that were inversely associated with satisfaction with antidepressant treatment. After adjusting for confounders, only emotional blunting was more frequently reported by users of serotoninergic agents, as compared to non-serotoninergic agents. The authors concluded that patients/users may prefer receiving a non-serotonergic agent over a serotonergic one, due to the lower propensity of the former to induce emotional blunting.

Recently, Christensen et al (Reference Christensen, Ren and Fagiolini2022) reported data from an internet-based survey of 752 MDD patients (female = 62%) in acute (N = 300) or remission phase, currently receiving a prescribed antidepressant, who reported emotional blunting during the last 6 weeks. Emotional blunting was assessed using the Oxford Depression Questionnaire. Antidepressant agents taken by patients included agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine, and vortioxetine. Up to 44% of patients rated their emotional blunting as ‘extremely severe’. Up to 45% of study patients believed that antidepressant medication was the cause of their emotional blunting: as a result, one-third of patients were either considering stopping or had stopped the medication.

Studies in children and adolescents

Previous data have also suggested the presence of SSRI-induced apathy in paediatric populations (Garland & Baerg, Reference Garland and Baerg2001; Reinblatt & Riddle, Reference Reinblatt and Riddle2006). Its prevalence in children treated for anxiety disorders was reported to be 5% (Reinblatt & Riddle, Reference Reinblatt and Riddle2006). Garland and Baerg (Reference Garland and Baerg2001) were the first to report five ‘typical cases’ (2 OCD, 2 depressed and one anxious) of SSRI (fluoxetine, paroxetine)-induced apathy and lack of motivation – one accompanied by disinhibition – in a 10-year-old child and in four adolescents (14–17 years old). Symptoms were dose-related and reversible after dosage reduction without (N = 4) or with bupropion (150 mg/day) co-administration. The authors stress that the delayed onset, subtlety of symptoms, lack of subjective awareness, and the resulting disability indicate a need for clinicians to inform families for the possible emergence of apathy when children/adolescents are prescribed SSRIs. Another study reported that among 45 non-depressed paediatric patients with anxiety disorders who received fluvoxamine, two patients (5%) demonstrated apathy (Reinblatt & Riddle, Reference Reinblatt and Riddle2006): both presentations were characterised by lack of awareness, delayed onset, dose-dependency, and reversibility following reduction of dosage or discontinuation.

Reduction of crying and other emotional symptoms without emergence of apathy in SSRI-treated subjects

Previous data suggest that some MDD patients and healthy volunteers with emotional lability demonstrate SSRI-induced reduction of crying, but without suffering from concurrent apathy. Rapid improvement of excessive or inappropriate crying without concurrent apathy was initially reported in SSRI-treated depressed patients (Oleshansky & Labbate, Reference Oleshansky and Labbate1996). Subsequently, in a randomised, placebo-controlled trial, a single dose (20 mg) of paroxetine significantly inhibited the crying behaviour of 25 healthy, young females in response to emotional movies, without concurrent mood changes (van der Veen et al., Reference van der Veen, Jorritsma, Krijger and Vingerhoets2012).

Eight female MDD patients reported that after SSRI therapy they ceased to cry during moving film scenes, although their overall emotional experience was left intact (Vinar, Reference Vinar2000). Another case study explored the effect of SSRIs on ‘emotional lability’, that is, poor control of emotions manifested as tearfulness, weeping, and crying spells (Scoppetta et al., Reference Scoppetta, di Gennaro and Scoppetta2005): participants (3 MDD patients, 2 controls) received an SSRI for 5-day cycles and all reported total remission of emotional lability after a few days of pharmacotherapy. In another case report, all seven SSRI-treated patients demonstrated inability to cry soon after starting pharmacotherapy, although feelings of sadness and the urge to cry remained intact (Holguin-Lew & Bell, Reference Holguin-Lew and Bell2013). The different secondary pharmacological effects of the various SSRIs administered (fluvoxamine on sigma-1 receptors, sertraline on dopamine receptors, and citalopram and escitalopram on histamine receptors) led the authors to suggest that the amelioration of crying behaviour was probably due to their common serotoninergic effect.

Clinical conditions in which SSRIs might improve apathy

Some data suggest that SSRIs may improve apathy in patients with dementia. However, other reports do not support this notion (Azhar et al., Reference Azhar, Kusumo, Marotta, Lanctot and Herrmann2022). Thus, in non-depressed behaviourally disturbed patients with Alzheimer’s disease, administration of citalopram was associated with up to 60% reduction in scores of the Apathy subscale of the Neuropsychiatric Inventory (Siddique et al., Reference Siddique, Hynan and Weiner2009). Likewise, in a mix of patients with Alzheimer’s disease or vascular dementia, Nyth and Gottfries (Reference Nyth and Gottfries1990) reported a significant reduction in apathy in the citalopram group in at week 4 in comparison with baseline. However, this reduction in apathy was not significant when compared with placebo. Another study in patients with the same diagnoses as in the previous study did not show any effect of citalopram in apathy (Pollock et al., Reference Pollock, Mulsant, Rosen, Mazumdar, Bharucha, Marin, Jacob, Huber, Kastango and Chew2002).

Other medications that may induce apathy symptoms

Apathy manifestations may emerge as a consequence of treatment with antipsychotics. More precisely, antipsychotic medications – both typical and atypical – may induce a condition known as neuroleptic-induced deficit syndrome (NIDS) which includes apathy, lack of initiative, anhedonia, indifference, blunted affect, and reduced insight into disease. The concept of NIDS is well described in patients with schizophrenia. However, antipsychotics are widely used in patients with depressive or bipolar disorders. Thus, antipsychotics can make depression or bipolar disorder resemble other more refractory conditions and may lead clinicians to mistaken diagnoses and inappropriate treatments (Szmulewicz et al., Reference Szmulewicz, Samane, Caravotta, Martino, Igoa, Hidalgo-Mazzei, Colom and Strejilevich2016). Such cases have been already described in literature (Ueda et al., Reference Ueda, Sakayori, Omori, Fukuta, Kobayashi, Ishizaka, Saijo and Okubo2016). Moreover, it has been proposed that antipsychotic drugs do not extinguish psychotic symptoms, but rather they produce emotional detachment due to down-regulation of dopamine turn-over (Kapur, Reference Kapur2003). It also assumes that apathy and lack of initiative is an unwanted consequence of the same psychological mechanism that relieves psychotic symptoms (Kapur et al., Reference Kapur, Agid, Mizrahi and Li2006).

Data from healthy subjects and case reports suggest that lithium can induce an amotivational syndrome in healthy volunteers (e.g. Kropf & Muller-Oerlinghausen, Reference Kropf and Muller-Oerlinghausen1979) or in patients with bipolar disorders (e.g. Folstein et al., Reference Folstein, DePaulo and Trepp1982). This follows a dose-response pattern being more prominent in patients with higher lithium serum levels (Szmulewicz et al., Reference Szmulewicz, Samane, Caravotta, Martino, Igoa, Hidalgo-Mazzei, Colom and Strejilevich2016). Regarding anticonvulsant medications, as already mentioned, a case report suggests that carbamazepine-topiramate combination administered for epilepsy together with sertraline for depression was associated with emergence of significant apathy (Monga & Padala, Reference Monga and Padala2015).