Social Psychopharmacology: Novel Approaches to Treat Deficits in Social Motivation in Schizophrenia

Anya K Bershad; Harriet de Wit

doi:10.1093/schbul/sbad094

. 2023 Jun 26;49(5):1161–1173. doi: 10.1093/schbul/sbad094

Social Psychopharmacology: Novel Approaches to Treat Deficits in Social Motivation in Schizophrenia

Anya K Bershad ^1,^✉, Harriet de Wit ²

PMCID: PMC10483474 PMID: 37358825

Abstract

Background and Hypothesis

Diminished social motivation is a negative symptom of schizophrenia and leads to severe functional consequences for many patients suffering from the illness. However, there are no effective medications available to treat this symptom. Despite the lack of approved treatments for patients, there is a growing body of literature on the effects of several classes of drugs on social motivation in healthy volunteers that may be relevant to patients. The aim of this review is to synthesize these results in an effort to identify novel directions for the development of medications to treat reduced social motivation in schizophrenia.

Study Design

In this article, we review pharmacologic challenge studies addressing the acute effects of psychoactive drugs on social motivation in healthy volunteers and consider how these findings may be applied to deficits in social motivation in schizophrenia. We include studies testing amphetamines and 3,4-methylenedioxymethamphetamine (MDMA), opioids, cannabis, serotonergic psychedelics, antidepressants, benzodiazepines, and neuropeptides.

Study Results

We report that amphetamines, MDMA, and some opioid medications enhance social motivation in healthy adults and may represent promising avenues of investigation in schizophrenia.

Conclusions

Given the acute effects of these drugs on behavioral and performance-based measures of social motivation in healthy volunteers, they may be particularly beneficial as an adjunct to psychosocial training programs in patient populations. It remains to be determined how these medications affect patients with deficits in social motivation, and in which contexts they may be most effectively administered.

Keywords: Amotivation, approach and avoidance, human behavioral pharmacology

Introduction

Asociality, or impaired social motivation, is a negative symptom of schizophrenia and a major contributor to functional impairment in this population.^1,2 Social motivation refers to the drive to spend time with and form lasting relationships with others. Diminishment of this drive has severe functional consequences for those suffering from the illness including deficits in independent living, work, and maintenance of relationships.^3,4 Deficits in social motivation in schizophrenia do not respond to antipsychotic medications, and asociality remains a common, debilitating symptom of the disease.^5,6 Some patients benefit from social skills training, but the effects are modest, and low social motivation may further limit effectiveness of such interventions.⁷ Thus, there is currently no effective treatment for impaired social motivation.

Few psychopharmacology studies have targeted impairments in social motivation in patients with schizophrenia. However, there is evidence that certain psychoactive drugs can enhance social motivation in healthy volunteers, and these may be worth investigating in patients. Medications may enhance social motivation in their own right, or they may enable patients to benefit from psychosocial training by ameliorating social motivational deficits. Here we review acute effects of psychoactive drugs on social motivation in healthy volunteers and speculate on how these drugs may also treat impairments in patients. We will not discuss antipsychotic drugs because, despite their value in treatment of schizophrenia, they have little effect on clinician ratings of social motivation, and to the best of our knowledge there are no acute challenge studies.

Fulford et al.¹ note that patients with schizophrenia exhibit deficits in both social cognition and social motivation. We focus this discussion on indices of social motivation, distinct from other social deficits. Fulford et al. further distinguishes between deficits that are related to diminished approach to positive social stimuli and deficits that result from heightened avoidance of perceived negative social stimuli. This distinction is important in that these categories of motivation may have distinct underlying neural substrates; reward circuitry is important for approach deficits, whereas fear circuitry may underlie avoidance. As a result, different therapeutic interventions may be required to target each component of motivation. Consistent with this distinction, we review 7 classes of drugs—amphetamines/3,4-methylenedioxymethamphetamine (MDMA), opioids, cannabis, serotonergic psychedelics, antidepressants, benzodiazepines, and neuropeptides/neurosteroids—and consider how each might increase the pleasurable aspects of social stimuli and/or decrease the avoidance of perceived aversive aspects of social stimuli (Table 1). These classes of drugs have been selected on the basis of there being at least some available literature investigating their effects on social motivation. While the cholinergic neurotransmitter system is of particular interest in schizophrenia and in cognitive processes, this system has been less studied in the context of social motivation, and to the best of our knowledge, no studies have been conducted directly assessing the effects of cholinergic medications on these measures.

Table 1.

Drug Effects on Measures of Social Motivation in Healthy Volunteers.

Measure of Approach Motivation	Description	Drug Effects	References
Subjective ratings	Self-report ratings of sociability, friendliness, desire to socialize	MDMA↑ d-amphetamine↑ methamphetamine↑	Tancer et al.¹⁵ Van Wel et al.¹⁶ Kirkpatrick et al.¹⁷
Memory of positive social cues	Memory for spacial location of emotional face cues	Buprenorphine↑	Syal et al.⁵⁹
Autobiographical Memory Task	Positivity ratings of recalled social memories	Oxytocin↑	Cardoso et al.¹⁴
Affective responses to social stimuli
Emotional images
Ratings	Ratings of positivity	MDMA ↑ (for social content) D-amphetamine ↑ (for all images) Buprenorphine ↑ (for social content)	Wardle and de Wit²⁰ Wardle et al.²¹ Bershad et al.¹⁴
Facial EMG	Physiological emotional reactivity to positive faces	MDMA↑	Wardle and de Wit²⁰
Emotional faces
Facial EMG	Physiological emotional reactivity to positive faces	MDMA↑	Wardle and de Wit²⁰
fMRI	Striatal responses to happy faces	MDMA↑ Oxytocin↑ Mirtazapine↑	Bedi et al.⁴¹ Norbury et al.¹¹⁵ Lieberz et al.¹³⁵ Rawlings et al.¹¹³
Attractive faces	Ratings of and desire to view images of faces	Morphine↑	Chelnokova et al.⁵⁵
Multifaceted Empathy Test	Ratings of “feeling for” others in emotional images	MDMA↑ d-amphetamine↑	Schmid et al.²² Dolder et al.²³ Hysek et al.²⁴ Kuypers et al.²⁵
Welfare Tradeoff Task	Prosocial resource allocation	MDMA↑	Kirkpatrick et al.³³
Prisoner’s Dilemma Task	Cooperative behavior	MDMA↑	Gabay et al.³²
Speech
Quantity	Number of words spoken	Methamphetamine ↑ d-amphetamine↑	Wardle et al.²¹ Marrone et al.³⁵ Ward et al.³⁶ Griffiths et al.³⁷
Fluency	Measured by the number of pauses of disfluencies during speech	Methamphetamine ↑ MDMA↓	Marrone et al.³⁵
Content	Use of specific types of words/concepts (e.g., positive, social)	MDMA↑	Baggott et al.³⁸ Bedi et al.³⁹ Agurto et al.⁴⁰ Wardle and de Wit²⁰
Attention bias to social stimuli	Initial orienting toward positive faces, visual exploration of eyes	MDMA↑ Morphine↑ Oxytocin↑	Bershad et al.⁶⁴ Chelnokova et al.⁵⁶ Domes et al.²⁴ Bradley et al.¹⁴⁵
Affective responses to touch	Ratings of pleasantness	MDMA↑	Bershad et al.⁶⁴
Measure of avoidance motivation
Subjective ratings	Self-report ratings of social anxiety	MDMA↓	Baggott et al.¹⁹
Affective responses to emotional faces (fMRI)	Amygdala responses to threatening faces	MDMA↓ Oxytocin↓ Propranolol↓ SSRIs, Mirtazapine↓	Bedi et al.. 2010 Spengler et al.¹⁷ Hurlemann et al.¹²⁰ Murphy et al.¹²² Rawlings et al.¹¹³
Cyberball	Responses to simulated social exclusion	Buprenorphine↓ MDMA↓	Bershad et al.¹⁴, Frye et al.⁴⁷
Trier Social Stress Test (TSST)	Responses to a stressful public speaking task	Buprenorphine↓ Hydromorphone↓ Propranolol↓	Bershad et al.^63,64 MacCormack et al.¹¹⁹
Attention bias to social stimuli	Initial orienting toward negative faces	Buprenorphine↓	Bershad et al.¹⁴

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Note: ↑, increase; ↓, decrease; EMG, electromyography; fMRI, functional magnetic resonance imaging.

Measures of social motivation reviewed here include self-reported and clinician-rated affiliative tendencies as well as performance-based tasks assessing social motivation. Some studies examine psychophysiological responses and neural responses to social stimuli using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). It is worth mentioning there is a developing literature on drug effects on preclinical models of social motivation in schizophrenia, but we will limit our discussion here to human studies. We review evidence from studies with healthy volunteers to identify processes that may enhance function in patients with schizophrenia.

Amphetamines and 3,4-Methylenedioxymethamphetamine

Approach Motivation

As a class, amphetamines represent some of the most promising medications to enhance approach motivation. Before exploring the possible benefits of this class of medications, we address 2 clinical concerns about amphetamines: (1) that they may exacerbate positive symptoms of schizophrenia, and (2) that they have potential for abuse. With regard to the first, several studies have shown that low to moderate doses of amphetamines are safe.^8,9 It has been shown that most (if not all) of the potential adverse effects of these agents in patients with schizophrenia can be prevented with concurrent antipsychotic treatment.^10,11 With regard to the second, stimulant drugs have been prescribed safely for attention deficit hyperactivity disorder for decades with little evidence for abuse when the drugs are used orally as prescribed.¹² MDMA has shown promise as an adjunct to psychotherapy in the treatment of post-traumatic stress disorder (PTSD),¹³ perhaps by facilitating social engagement during the therapeutic session. MDMA has not yet been tested in patients with schizophrenia, and few studies have directly compared social motivation effects of MDMA to those of other stimulants.¹⁴

Both amphetamines (d-amphetamine, methamphetamine) and MDMA increase several dimensions of sociability including subjective ratings and affective responses to social stimuli. Both increase subjective ratings of sociable emotions, including how talkative, friendly, and social individuals report feeling.^15–19 MDMA enhances ratings of positivity for images with social content,²⁰ while d-amphetamine enhances positive ratings of images, regardless of social content.²¹ Several studies have investigated the effects of amphetamines and MDMA on empathy. Both MDMA and d-amphetamine increase emotional empathy for positive situations,^22,23 and MDMA may increase empathy for negative situations as well.^24–26

One laboratory study has used a less traditional measure of social reactivity, that is, the subjective ratings of the pleasantness of social touch.²⁷ Social touch is a fundamental psychosocial process that acts via well-characterized physiological circuits.^28–30 Although therapeutic touch is not used in most modern psychotherapy, it has recently been reintroduced as a component of psychedelic-assisted psychotherapy.³¹ The processes through which touch may facilitate the therapeutic experience (e.g., through grounding, reducing anxiety, and facilitating social connection) are unknown. While the above-referenced study did not specifically investigate processes that could be of value in psychotherapy, it shows that acute doses of MDMA, but not methamphetamine, enhance pleasantness of touch in healthy volunteers. While fully recognizing potential ethical complexities that arise with the use of touch in psychotherapy, the role of social touch in treatment of psychiatric disorders, including schizophrenia, remains an understudied area.

In addition to the above effects, MDMA also enhances prosocial behavior. It increases cooperative behavior during a Prisoner’s Dilemma Task³² and increases generosity toward friends on a Welfare Tradeoff Task,³³ suggesting MDMA may motivate prosocial resource allocation. Another important behavioral measure of social motivation is speech. Speech may reflect a continuous effort to connect during a social interaction, and thus is a form of social motivation.³⁴ Both methamphetamine and d-amphetamine increase speech quantity,^21,35–37 and methamphetamine increases fluency.³⁵ MDMA specifically increases the use of social words and concepts.^38–40 Additionally, MDMA, but not methamphetamine, increases initial orienting to positive facial expressions.²⁷

Other studies have examined the effects of amphetamines and MDMA on physiological and neural measures of affective reactivity to social stimuli. MDMA enhances positive psychophysiological responses to emotional faces,²⁰ which may indicate increased reward during a positive social encounter. MDMA also enhances ventral striatal responses to positive faces.⁴¹ Although these studies have been done in healthy controls, the findings suggest that amphetamines in general, and particularly MDMA, may show promise in improving social motivation in schizophrenia.

Avoidance Motivation

While both MDMA and amphetamines appear to enhance approach motivation, only MDMA also dampens responses to negative social interactions. Clinical trials with MDMA suggest that the drug can reduce social anxiety or recall of emotionally intense memories.^19,42–44 In line with this idea, MDMA reduces amygdalar responses to threatening faces,⁴¹ and increases the threshold of reactivity to negative facial expressions.^{20,22,24,45,46} One study showed that MDMA reduces affective responses to social rejection in the simulated social rejection paradigm Cyberball.⁴⁷

Neither amphetamines, nor MDMA, seem to dampen subjective or physiological responses to a laboratory model of acute social stress.^48,49 MDMA has paradoxical effects on anxiety: It induces anxiety in some contexts,¹⁹ but may also ameliorate social anxiety and fear of negative evaluation in social settings specifically.^19,43 The contexts in which MDMA induces vs. ameliorates anxiety is a topic for future investigation.

Opioids

Approach Motivation

The opioid system plays a key role in social behavior of humans and other species. Receptors in both the mu-opioid systems and the kappa-opioid systems are important in social function, although in different ways. Mu-opioid system activation appears to mediate affiliative motivation in preclinical animal models and in humans.^50–53 Conversely, for the kappa-opioid system it is antagonism of the receptors that favors prosociality, and kappa-opioid system antagonists decrease anxiety and responses to social stress across species.⁵⁴ Thus, the systems appear to act in opposite directions.

Studies in healthy volunteers have suggested that mu-opioid activation favors approach motivation. One study investigated the effects of the opioid agonist morphine on “liking” and “wanting” of attractive faces. “Liking” was measured by ratings of attractiveness, and “wanting” was measured by participants changing the viewing time to continue viewing each face or to move to the next one. For the most attractive faces, morphine increases both ratings of attractiveness and time spent viewing the faces, suggesting an increase in both “wanting” and “liking” for a high-value social reward.⁵⁵ On another behavioral measure of social motivation, visual attention to social stimuli, morphine increases visual exploration of faces and eyes.⁵⁶ The effects of morphine on pleasantness ratings of social touch have also been investigated, though, unlike MDMA, morphine does not appear to affect this measure.⁵⁷

While morphine is a pure mu-agonist, buprenorphine is a partial agonist at the mu-opioid system but antagonist at the kappa-opioid system. Buprenorphine has shown promise for patients with social deficits. Low doses of buprenorphine selectively increase ratings of positivity of images with social content, suggesting the drug may enhance the pleasantness of social experiences.⁵⁸ Furthermore, it boosts memory for positive social cues,⁵⁹ suggesting it may enhance approach motivation.

Given the effects of a kappa antagonist, it is potentially informative to consider the effects of a kappa agonist. Salvinorin A is an agonist at the kappa-opioid receptor and is considered an “atypical dissociative hallucinogen.” To the best of our knowledge, no studies have directly assessed the effects of the drug on social motivation, but studies suggest salvinorin A alters the experience of one's self, which may indirectly affect social experiences.^60,61

Avoidance Motivation

Both mu-agonists and kappa-antagonists also reduce certain dimensions of avoidance motivation in humans and other species. Social avoidance motivation is often assessed using the Trier Social Stress Test (TSST).⁶² in which participants present a speech in front of a panel of nonreactive strangers. It provides both subjective measures (threat appraisal, anxiety) and physiological measures (heart rate, blood pressure, and cortisol). During this task, buprenorphine reduces how threatened participants feel even before they give the speech, and reduces cortisol responses to the task.⁶³ The mu-agonist hydromorphone also reduces cortisol responses to the task, but does not affect subjective threat appraisals.⁶⁴ The compound mu- and kappa- actions of buprenorphine may account for the drugs’ differential effects.

Beyond reducing responses to acute social stress, opioids also dampen responses to negative facial expressions and reduce feelings of social rejection. Morphine reduces perceived anger from ambiguous facial expressions.⁶⁵ Buprenorphine reduces negative affective responses to rejection during Cyberball⁵⁸ and reduces responses to faces expressing negative emotions.^58,66 Buprenorphine has also shown promise in the treatment of suicidality, possibly in part due to its effects on social behavior.⁶⁷

While there is no selective kappa antagonist available for use in humans, preclinical evidence suggests kappa-antagonists reduce social distress. In rodents, kappa antagonists^54,68–70 reduce effects of social defeat stress, and buprenorphine reverses stress-induced social interaction deficits.⁷¹ These results are in line with evidence that buprenorphine, acting as both a mu-agonist and kappa antagonist, reduces avoidance motivation in healthy human volunteers, perhaps more than its pure mu-opioid analogs.

One final medication that should be mentioned in a discussion of opioids and social motivation is the opioid antagonist, naltrexone, which appears to inhibit social motivation. Naltrexone acts as an antagonist of both the kappa receptor (which may favor increased social motivation), and the mu receptor (which may counteract beneficial effects). In healthy volunteers, naltrexone inhibits social bonding,⁷² self-disclosure,⁷³ feelings of warmth during social interactions,⁷⁴ and reduces ventral striatal responses to images of close social contacts.⁷⁵

Overall, the findings described above indicate that opioid agonists at the mu receptor and antagonists at the kappa receptor may have promise in enhancing approach motivation and reducing avoidance motivation in clinical populations.

Cannabis

Approach Motivation

The effects of cannabis or its primary active constituent delta-9-tetrahydrocannabinol (THC) on the perceived value of positive social interactions are mixed. One popular idea is that cannabis produces “amotivational” states that decrease motivation in general, including social motivation.⁷⁶ However, the evidence that cannabinoids either increase or decrease the value of positive social interactions is mixed.⁷⁷ Early studies conducted with cannabis users in a residential laboratory found that cannabis does not increase either time spent in a social area or time spent talking.⁷⁸ There is some evidence that THC reduces the willingness to exert effort to earn points redeemable for money in healthy volunteers,⁷⁹ but willingness to work for a social reward has not been studied. Cannabis and THC have little effect on other indices of social motivation, such as self-reported sociability, reactivity to positive facial emotions or amount of time spent talking.^80–82 Only one study found that cannabis increases social and verbal interaction, but this occurred only in cannabis users who had high baseline levels of interaction.^83,84 The evidence thus far does not strongly support the idea that cannabis might increase the motivation to engage in positive social interaction.

Many patients with schizophrenia use cannabis, for reasons that vary widely.⁸⁵ These include reasons related to affect (depression, happiness), relaxation, socialization, physical effects (euphoria, energy, tiredness, etc.), treating symptoms (e.g. paranoia, suspiciousness, confusion)and treating side effects of antipsychotic medication (e.g. restlessness). Although the category of socialization suggests an effect on social motivation, it is also possible that cannabis use simply provides an opportunity to engage with others. Overall, there is little evidence that cannabis or related drugs increase the motivation to engage in positive social interactions.

Avoidance Motivation

The effects of cannabis on perceived negative effects of social interactions have received little attention, and the findings are mixed.⁸⁶ A low dose of THC dampens anticipatory anxiety on the trier social stress test (TSST), but a higher dose increases response to stress.⁸⁷ Imaging studies suggest that low doses of THC (7.5 mg) reduce amygdala reactivity to angry and fearful faces.^88–90 THC has mixed effects on measures of attentional bias to negative emotional faces: One study reports that THC impairs recognition of fear and anger emotions in faces,⁹¹ but another shows that THC increases attention to negatively valenced stimuli,⁸² suggesting that it could heighten responses to negative social situations in patients. There has been concern that THC administration can induce psychotic, negative, and other psychiatric symptoms with large effect sizes, and the small, mixed effects of the drug on social motivation may not be enough to warrant the risk.⁹² Although one of the constituents of the cannabis plant, cannabidiol, has received much attention as a possible medication to decrease social anxiety, or to dampen anxiogenic effects of THC,^93,94 this idea is not supported by a comprehensive recent review.⁹⁵ It is possible that some of the positive reports about cannabidiol are related to positive expectancies.⁹⁶

Serotonergic Psychedelics

Approach Motivation

Serotonergic psychedelics, or “classic psychedelics,” have garnered interest in clinical psychiatry in the treatment of depression and other conditions. These substances act as 5HT2A agonists, and include psilocybin, dimethyltryptamine (the active ingredient in ayahuasca), and lysergic acid diethylamide (LSD). Psychedelic drugs present an unusual category of potential medications for deficits in social motivation. Unlike most psychiatric medications, these drugs are typically administered in a single, controlled session, at relatively high doses, and their therapeutic effects are usually assessed well after the drug experience. Beyond this dosing strategy, there has been an interest in “microdosing” regimens, in which individuals take very low doses of the substance at 2–3 day intervals. Despite promising anecdotal reports of the clinical effectiveness of microdosing to improve mood and cognition, controlled studies have shown very small effects.^97–99 Few studies have examined the effects of psychedelic drugs specifically on social motivation. Psychedelics reportedly affect the sense of self, including a loosening of self-boundaries, oneness, unity, or ego dissolution.¹⁰⁰ Such effects might influence future social interactions, including social motivation by helping patients to regain pleasure from social interaction. As with stimulant drugs, a common concern is that these drugs might worsen symptoms, especially because they can induce experiences that resemble symptoms of schizophrenia.¹⁰¹ Nevertheless, it has been proposed that psychedelic drugs may have a role in schizophrenia treatment, and the potential benefits remain to be determined.¹⁰² It is not known whether psychedelic drugs enhance social motivation in healthy adults, using tasks specifically designed to assess this construct (eg, social incentive delay task or willingness to exert effort to obtain a social reward).

Avoidance Motivation

Few studies have examined the effects of psychedelic drugs on avoidance of social interactions. While several studies have explored the effects of this class of drugs on anxiety in general, few have specifically investigated social anxiety. One recent study administered ayahuasca to 17 volunteers with social anxiety disorder and assessed the effects of the drug on performance on the TSST. The authors report the drug increases self-assessment of performance, but does not dampen social anxiety related to the task.¹⁰³ As noted above, the potential therapeutic effects of these drugs are typically assessed well after the acute effects have dissipated, distinguishing them from other typical psychiatric medications. It is possible that psychedelic drugs have lasting psychological effects that enhance social motivation, for example by decreasing sensitivity to negative emotional stimuli. This is an important future topic for research. It is notable that psychedelics such as ayahuasca and psilocybin have shown promise in the treatment of psychiatric disorders such as PTSD and depression,^104–107 which are also characterized by social withdrawal, raising the possibility that these drugs have some place in treatment of social avoidance in patients with schizophrenia.

Antidepressants

Approach Motivation

Antidepressants are a heterogenous category of medications that include drugs with different mechanisms of action which, in addition to their efficacy in treating symptoms of depression, also affect other behaviors. Serotonergic antidepressant drugs may increase motivation for positive social interactions by modifying processing of emotional stimuli.^108–111 Harmer et al. have argued that antidepressant drugs acutely (within hours) enhance the processing of positive emotional information, relieving the negative processing bias associated with depression. This acute effect ultimately leads to a change in social behavior that is thought to contribute to the longer-term clinical effectiveness of the medications through cognitive restructuring and learning.¹⁰⁹ Harmer and her colleagues have demonstrated, using functional neuroimaging, that a range of antidepressant drugs (from selective serotonin reuptake inhibitors [SSRIs], to serotonin norepinephrine reuptake inhibitors [SNRIs], and to mirtazapine) both acutely (hours after administration)^112,113 and subacutely (after 7 days of treatment)¹¹⁴ alter fronto-limbic and extra-striatal circuitry in ways that affect processing of affective stimuli. In this way, these classes of medications may modify evaluation of self, the world, and the future, in patients with depression, and perhaps also in schizophrenia. Antidepressant drugs such as citalopram, fluoxetine, duloxetine, and reboxetine, even after acute administration, positively bias responses to social cues,¹¹¹ and they modulate amygdalar responses to images of emotional faces.¹¹⁵ Serotonergic antidepressants have shown some benefit in treating the negative symptoms of schizophrenia in clinical trials, suggesting they may act to enhance social motivation.^116,117

Avoidance Motivation

Antidepressant drugs may affect not only the perceived value of positive social encounters (above), but may also affect the avoidance of perceived negative social interactions. That is, antidepressants may counter deficits in social motivation by lessening the perceived negativity of social stimuli. In a review of studies of acute administration of antidepressants, Harmer et al. describe this negative processing bias: “Depression is associated with the tendency to perceive social cues as more negative, to preferentially attend to aversive information, and to recall negative more than positive information concerning oneself.”^109,111 Thus, the authors conclude that antidepressant drugs like citalopram, fluoxetine, duloxetine, and reboxetinetypically reduce neural and behavioral responses to negative facial expressions, consistent with a decreased avoidance of negative social encounters. This suggests that they may have the potential to relieve the avoidance of negative social encounters experienced by some patients with schizophrenia.

Beyond SSRI and SNRIs, the beta-adrenergic antagonist propranolol is another drug that has been studied in the treatment of anxiety and PTSD.¹¹⁸ Several studies have shown propranolol decreases physiological and subjective responses to the TSST,¹¹⁹ suggesting the drug may reduce avoidance motivation. The effects of propranolol may not be specific to social avoidance, or even social processes more generally, however. One study showed that propranolol reduces amygdalar responses to faces expressing all types of emotion.¹²⁰ In fact, propranolol may reduce the salience of social cues. Another study used a learning paradigm that involves both social trials (happy vs. angry faces) and nonsocial trials (red vs. green colors). Under placebo, participants acquire associations with social cues more quickly than nonsocial cues, but, propranolol abolishes this distinction.¹²¹ Therefore, while the drug may reduce avoidance motivation, it may reduce the salience of social signals overall, which may be a detrimental effect in clinical contexts.

Benzodiazepines

Approach Motivation

To the best of our knowledge, the effects of benzodiazepines on the motivation to engage in positive social interactions have not been tested. Typical benzodiazepines such as diazepam and lorazepam have little effect on measures of facial emotion recognition effect,^122,123 especially on recognition of happy expressions that might predict increased social motivation.

Avoidance Motivation

Benzodiazepines may facilitate engagement in social interaction by decreasing social anxiety. However, they have mixed effects on the Trier Social Stress Test. Both diazepam and alprazolam reduce physiological indicators of stress, but fail to decrease self-report ratings of anxiety during this paradigm.^124–126 On emotion recognition tasks,¹²⁷ diazepam reduces attention toward emotional faces and decreases overall startle reactivity, but does not significantly affect facial expression recognition.¹²² Lorazepam dampens amygdalar reactivity to faces expressing both positive and negative emotions.¹²⁸ While benzodiazepines may ameliorate autonomic hyperreactivity associated with increased avoidance motivation, these effects are inconsistent. Therefore this class of medications shows limited promise as treatment of social anxiety that might inhibit engagement in social interactions.

Neuropeptides and Neurosteroids

Approach Motivation

The neuropeptide oxytocin is known to mediate social motivation in humans and other animals (reviewed in¹²⁹). In healthy volunteers, intranasal oxytocin may either enhance approach in positive social contexts, or enhance avoidance in potentially threatening social contexts.^130–135 This paradoxical effect has led to the “social salience” hypothesis, according to which oxytocin increases the salience of social stimuli, regardless of valence.¹³⁶ In the realm of approach, intranasal oxytocin increases the positivity of memories of social interactions in healthy volunteers.¹³⁷ It also enhances gazes toward positive, but not negative, social stimuli,¹³⁸ and toward socially salient eyes and faces in social images.^139,140 These effects on eye gaze have led to the study of intranasal oxytocin in the treatment of autism.^141–143

Oxytocin is one of the few drugs that have been tested to improve social motivation in schizophrenia. Intranasal oxytocin has been assessed in relation to several symptoms of schizophrenia, including deficits in social cognition and social motivation. However, the results are mixed.¹⁴⁴ Paralleling the autism literature, intranasal oxytocin increases time spent looking at the eye region of faces in patients with schizophrenia.¹⁴⁵ Oxytocin also increases motivation for the social reward of winning on an auction task in patients with schizophrenia,¹⁴⁶ though it does not enhance the motivating effects of social encouragement.¹⁴⁷ To identify neural changes underlying possible effects of oxytocin on social motivation, one study used EEG to measure mu-suppression. Mu-suppression refers to suppression of oscillations in the 8–12 Hz range over central electrodes in response to social stimuli, and is thought to be an index of mirror neuron activity.¹⁴⁸ This study investigated a range of 8 doses of oxytocin, reporting that two mid-range doses (36 and 48 International Units) of oxytocin enhance mu-suppression in patients.¹⁴⁹ This study was unique in that it included a full range of doses, while other studies may have failed to show effects because they tested only 1 or 2 doses. Thus the findings with oxytocin are difficult to interpret, perhaps because of the heterogeneity of measures used or the limited doses tested.

Despite promising findings after acute doses of oxytocin, longer-term clinical trials of oxytocin for social deficits in schizophrenia have been disappointing. Although few studies have examined social motivation in particular, several clinical trials have examined effects of oxytocin alone and in combination with social cognitive training on social cognition and negative symptoms over 6–12 weeks. Daily intranasal oxytocin improves social cognition¹⁵⁰ and decreases negative symptoms in some studies.^150,151 But another trial reports only minor improvements in social symptoms on one subscale of the interpersonal reactivity index.¹⁵² Oxytocin has also been tested as an adjunct to social cognitive skills training, but not as a treatment for social motivation. One study suggests oxytocin combined with social cognitive training enhances empathic accuracy,¹⁵³ but another study reports no effect on measures of social cognition or symptom ratings.^154–156 There are numerous technical challenges with intranasal oxytocin administration, including large variability in effects of oxytocin at different doses,¹⁵⁷ questions about incomplete absorption,¹⁵⁸ issues related to assay measurement,¹⁵⁹ and different effects for acute vs. chronic administration.¹⁶⁰ A primary issue is that absorption of oxytocin by the intranasal route is controversial. It may be absorbed directly into the brain, peripherally by crossing the blood-brain barrier, or by influencing vagal projections. One study attempted to dissect these considerations in relation to observed effects on social motivation by comparing lingual oxytocin spray to intranasal oxytocin. They show that the two routes of administration lead to very different, sometimes opposing effects; oral oxytocin, for instance, increases amygdalar responses to faces, while intranasal oxytocin decreases such responses.¹⁶¹ Further work is needed to determine the exact contexts in which oxytocin may act on social motivation.

Beyond oxytocin, a handful of other hormonal treatments have been considered in the treatment of social motivation deficits. The neuropeptide arginine vasopressin promotes both aggressive and affiliative behaviors in different social contexts, and has been tested as a treatment of social deficits in autism.¹⁶² However, the one trial assessing the effects of intranasal arginine vasopressin on cooperative behavior in schizophrenia reported no effect.¹⁶³ Although there has been interest in the use of pregnenolone and estrogen to treat negative symptoms of schizophrenia,^164,165 the evidence for acute effects on social motivation is limited. Overall, there is limited evidence that neuropeptides and neurosteroids modulate social motivation in schizophrenia, but factors such as dosing, sex, and social context remain to be explored.

Avoidance Motivation

Beyond its well-studied role in social approach motivation, oxytocin has also been implicated in avoidance motivation, but the findings are mixed.¹⁶⁶ Some studies report that it reduces anxiety and avoidance in healthy volunteers,^167,168 while others indicate that it increases avoidance, facilitating withdrawal from potentially dangerous situations.^133,134 The effects of oxytocin on avoidance motivation may be different in healthy adults vs. in patients with schizophrenia. One fMRI study showed that intranasal oxytocin administration decreases amygdalar reactivity to emotional faces in patients with schizophrenia, but increases it in healthy controls.¹⁶⁹

Arginine vasopressin appears to enhance avoidance motivation in some contexts, although to the best of our knowledge, no studies have examined patients with schizophrenia.¹⁷⁰ Other hormones such as pregnenolone and estrogen have not been investigated.

Conclusions and Future Directions

In conclusion, several drugs show promise in both enhancing approach and reducing avoidance motivation. MDMA reliably enhances approach motivation and reduces avoidance motivation in healthy volunteers, but has not been tested in schizophrenia. Certain opioid drugs that activate the mu-opioid system and deactivate the kappa-opioid system, such as buprenorphine, may also dampen emotional responses to negative social stimuli and boost reward responses to positive social stimuli. SSRIs, SNRIs, and mirtazapine may facilitate a favorable social motivation profile by positively biasing social cognition. Amphetamines may increase approach motivation, but do not reduce avoidance motivation. The effects of other categories of drugs on social motivation are mixed.

Drugs may improve social motivation either through their direct effects or as an adjunct to a psychosocial treatment. In the case of the former, drugs would be taken daily to improve social interactions. In the case of the latter, the drugs would be taken a limited number of times during social training or psychotherapy. Amphetamines, MDMA, and opioid medications may be best administered in a controlled setting to enhance psychosocial treatments. More work should be done investigating these medications as adjuncts to such interventions in patient populations.

This review illustrates some of the challenges in defining and measuring the construct of social motivation. Although diminished social motivation is recognized as an important feature in schizophrenia, it is typically assessed clinically as part of a broader cluster of negative symptoms using clinician-rated interviews¹⁷¹ in which patients report on their social activities during their normal daily lives. In contrast, controlled studies typically assess effects of drugs on social motivation using tasks that target core deficits of social motivation. Even farther removed from clinical trials are studies using preclinical models of social motivation, which have the advantage of tightly controlled experimental design, but are limited by their relevance to human experience. It is difficult to apply the knowledge gained from the preclinical and human laboratory setting to the clinical setting, or vice versa. Moreover, it is not known whether effects of acute drug administration on tasks would provide a good index of patients’ willingness to form and maintain social relationships in their normal daily environments.¹ Therefore, we recommend that future clinical trials investigating pharmacologic treatments for deficits in social motivation in schizophrenia include behavioral and performance-based measures of social motivation that are comparable to those used with healthy volunteers, such as visual attention to social cues, social decision-making paradigms, and effort expenditure tasks.

Contributor Information

Anya K Bershad, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.

Harriet de Wit, Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.

Conflicts of Interest

HdW is on the Board of Directors of PharmAla Biotech and consultant to Awakn Life Sciences and Gilgamesh Pharmaceuticals. These are unrelated to this manuscript.

Funding

HdW is supported by a grant from the National Institute on Drug Abuse (DA02812).

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PERMALINK

Social Psychopharmacology: Novel Approaches to Treat Deficits in Social Motivation in Schizophrenia

Anya K Bershad

Harriet de Wit

Abstract

Background and Hypothesis

Study Design

Study Results

Conclusions

Introduction

Table 1.

Amphetamines and 3,4-Methylenedioxymethamphetamine

Approach Motivation

Avoidance Motivation

Opioids

Approach Motivation

Avoidance Motivation

Cannabis

Approach Motivation

Avoidance Motivation

Serotonergic Psychedelics

Approach Motivation

Avoidance Motivation

Antidepressants

Approach Motivation

Avoidance Motivation

Benzodiazepines

Approach Motivation

Avoidance Motivation

Neuropeptides and Neurosteroids

Approach Motivation

Avoidance Motivation

Conclusions and Future Directions

Contributor Information

Conflicts of Interest

Funding

References

ACTIONS

PERMALINK

RESOURCES

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