A complex clinical challenge revolves around accurately differentiating substance-induced psychosis from a primary psychotic disorder or a psychotic disorder co-occurring with substance use. This poses a nuanced dilemma and an opportunity for thorough investigation, gaining significance when determining the optimal therapeutic approach for patients. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) ^[4] more accurately describes the substance/medication-induced psychotic disorder as a psychiatric condition characterized by delusions and/or hallucinations that arise during or shortly following the intoxication or withdrawal from a substance.

Additionally, the symptoms of a non-substance-induced psychotic disorder are not yet fully understood. Nevertheless, in this context, a particular definition has been formulated utilizing the diagnostic classification of “substance-related exogenous psychosis (SREP)”. This concept refers to a range of psychotic symptoms that are temporary or enduring and are associated with substance use. These include changes in consciousness; feelings of being persecuted; disorders affecting sensory perception, like visual and bodily hallucinations; impulsive behavior, self- or other-directed aggression, and psychomotor restlessness; fluctuations in mood; negative affects, such as indifference, lack of motivation, and inability to feel pleasure; an overwhelming feeling of being detached from reality; and maintained self-awareness ^[1].

The occurrence of drug-induced psychosis appears to be associated with various pathogenetic mechanisms: (a) elevated levels of central dopamine, particularly for hallucinogens or psychedelic substances, stimulants, and cathinone derivatives; (b) activity as an agonist at cannabinoid CB1 receptors, particularly in substances related to cannabis; (c) agonist activity at 5-HT_2A receptors in hallucinogenic plants, newer phenethylamines, and tryptamine derivatives; (d) activity as an antagonist at NMDA receptors (n-methyl-D-aspartate receptors), seen in substances like ketamine and methoxetamine; and (e) activation of k-opioid receptors in plants, such as Salvia divinorum [6]^[5].

2. Third-Generation Antipsychotics and Lurasidone in Substance-Induced Psychoses Treatment 

2.1. Aripiprazole

Aripiprazole, classified as a partial agonist within the antipsychotic drug category, exhibits lower intrinsic activity at receptors compared to full agonists [24]^[6]. Its partial agonism at dopamine D₂ receptors leads to (1) functional antagonism in the mesolimbic dopamine pathway, reducing positive symptoms caused by excessive dopamine activity, and (2) agonist activity in the mesocortical pathway, addressing negative symptoms and cognitive impairment due to reduced dopamine activity [25,26,27]^[7][8][9]. This dual effect contributes to significant improvements in both positive and negative psychotic symptoms. Moreover, aripiprazole avoids the complete blockade of the nigrostriatal or tuberoinfundibular pathways, thereby preserving the avoidance of extrapyramidal symptoms and hyperprolactinemia [24]^[6]. It also demonstrates a favorable cardiac safety profile, preventing QTc prolongation and causing minimal weight gain or sedation. Focusing on substance use, aripiprazole shows promise in animal models, where acute administration prevented increased locomotion induced by stimulants, like amphetamine, cocaine, and methylphenidate, and attenuated their reinforcing properties without interfering with spontaneous motor activity [26]^[8]. It reversed amphetamine-associated anhedonia and prevented the reinstatement of cocaine-seeking behavior [27]^[9], suggesting its potential in alleviating withdrawal symptoms linked to dopamine depletion and maintaining balanced dopamine neurotransmission in drug-dependent behavior [28,29,30]^[10][11][12].

2.2. Cariprazine

Cariprazine, a third-generation antipsychotic drug approved for schizophrenia [39]^[13], is notable for its partial agonism toward D₂ receptors. Distinguishing itself from other second-generation antipsychotics (SGAs), it demonstrates a lower intrinsic activity at the D₂ receptor compared to aripiprazole and brexpiprazole, approximately 0.15. This positioning suggests a minimized capacity to activate the D₂ receptor, offering an intermediary profile between aripiprazole and traditional receptor antagonists with zero intrinsic activity [39,40,41,42]^{[13][14][15][16]}. The reduced intrinsic activity of cariprazine is associated with a decreased likelihood of side effects, such as restlessness and akathisia, commonly observed with aripiprazole [40]^[14]. Cariprazine’s primary distinction lies in its high affinity for the dopaminergic D₃ receptor, exceeding that of endogenous dopamine. This high D₃ affinity is significant, considering that most antipsychotics have a lower affinity for this receptor, leading to inadequate D₃ receptor occupancy in the brain. This unique affinity is crucial for cariprazine’s clinical efficacy, as indicated by PET studies on schizophrenic patients, demonstrating a stronger effect on the D₃ receptor compared to the D₂ receptor [41,42,43,44,45,46,47]^{[15][16][17][18][19][20][21]}. Cariprazine also exhibits significant serotonergic activity, with high affinity for the 5-HT2B receptor and moderate affinity for the 5-HT_2A and 5-HT_1A receptors. This receptor profile is somewhat distinct from those of many SGAs, which tend to have high affinities for the 5-HT_2A receptor. The 5-HT_2A/D₂ affinity ratio of cariprazine is lower than those of other antipsychotic drugs. Additionally, it has low affinity for the 5-HT7 and 5-HT2C receptors as well as the noradrenaline α1A and α1C receptors. Its interactions with the 5-HT6, α1a, and α2b receptors and other potential targets are minimal in therapeutic activity [42,43]^[16][17]. When comparing cariprazine with other partial agonists, such as blonanserin [48,49]^[22][23], an antagonist of dopaminergic D₂ and D₃ receptors, its D₃/D₂ affinity ratio is notably higher. This suggests a potential influence on negative symptoms, a theory supported by its unique receptor action. In contrast, brexpiprazole shows higher 5-HT_2A/D₂ and 5-HT_1A/D₂ ratios. The combined dopaminergic and serotonergic receptor activities of these drugs modulate specific brain circuits and neurotransmitter release, as observed in increased dopamine release in the prefrontal cortex with olanzapine and lurasidone, enhancing cognitive functions [50]^[24]. In conclusion, the receptor profile of cariprazine provides significant insights into cariprazine’s mechanism of action and ability to modulate various neurotransmitter systems. Unlike other antipsychotics, cariprazine’s efficacy is based on not only its receptor profile but also its capacity to modulate intracellular mechanisms downstream of these receptors [51,52]^[25][26]. Its dual action as a partial agonist at both D₂ and D₃ receptors, with a stronger effect on the latter, is particularly effective in improving negative symptoms, setting it apart from other SGAs [53]^[27]. Another intriguing facet of cariprazine pertains to its activity in the context of substance abuse. Experimental studies have illustrated cariprazine’s capacity to mitigate the stimulating effects of cocaine and forestall relapses associated with the abused substance. This observed activity seems to correlate with its partial agonism for dopamine receptors D₂ and D₃ [54]^[28].

2.3. Brexpiprazole

Brexpiprazole, an atypical antipsychotic, received FDA approval in July 2015 for treating schizophrenia and as an adjunct therapy for managing major depressive disorder (MDD). Acting as a partial agonist at 5-HT_1A and D₂ neuroreceptors, brexpiprazole also engages with noradrenergic receptors, although the clinical significance of this interaction is not fully understood. The safety and efficacy of brexpiprazole were evaluated in four finished placebo-controlled Phase III trials—two targeting major depressive disorder (MDD) as an add-on to antidepressants and two for schizophrenia. These studies showed that brexpiprazole was more effective than a placebo at certain dosages for both disorders [62,63,64]^[29][30][31]. For schizophrenia, the recommended initiation is 1 mg once daily, titrating to a target dose from 2 mg to 4 mg daily. As an adjunct therapy for MDD, the initiation dose is advised at 0.5 mg or 1 mg once daily, with a weekly increase to a target dose of 2 mg. Contraindications include prior hypersensitivity reactions to similar medications. Common adverse reactions involve weight gain and akathisia, with additional associations with metabolic changes, like dyslipidemia and hyperglycemia. Precautions and warnings for this medication include cerebrovascular adverse reactions in elderly patients with dementia-related psychosis, the risk of neuroleptic malignant syndrome, tardive dyskinesia, leukopenia, orthostatic hypotension, and seizures. A prominent black box warning highlights the increased risk of mortality in elderly patients with dementia-related psychosis, as well as the potential for suicidal thoughts and behaviors in children, adolescents, and young adults. Additionally, its use during pregnancy is cautioned against owing to the risk of extrapyramidal and/or withdrawal symptoms in neonates exposed during the third trimester. Brexpiprazole is metabolized by hepatic enzymes, and dose adjustments are necessary if the CYP2D6 or CYP3A4 superfamilies of enzymes are impacted [65]^[32]. Brexpiprazole functions as a partial agonist at dopamine D₂ and serotonin 5-HT_1A receptors and a potent antagonist at serotonin 5-HT_2A, α_1B, and α_2C adrenergic receptors. In contrast to aripiprazole, brexpiprazole exhibits significantly greater potency at these three receptors: 5-HT_2A, 5HT_1A, and α_1B. Despite commonly reported side effects, such as EPS and akathisia, the strong affinity of brexpiprazole to these receptors may contribute to a reduction in the occurrence of these symptoms. Brexpiprazole exhibits a higher intrinsic activity at the serotonin 5-HT_2A receptor and a lower intrinsic activity at the dopamine D₂ receptor along with a stronger affinity for the norepinephrine transporter [66]^[33]. Hyperprolactinemia, an often-undesirable side effect of many antipsychotics, is largely due to the blockade of dopamine D₂ receptors, which interrupts the dopaminergic inhibition of the prolactin release. In a detailed evaluation, brexpiprazole shows moderate antagonist activity at dopamine D₃ and serotonin 5-HT_2B and 5-HT₇ receptors, as well as α_1A and α_1D receptors. It also has moderate affinity for histamine H₁ receptors and low affinity for muscarinic cholinergic M₁ receptors. This pharmacodynamic profile not only enhances brexpiprazole’s efficacy but also positions brexpiprazole as a potentially preferred alternative based on patient tolerability and therapy goals [67]^[34]. Brexpiprazole undergoes primary metabolism by the enzymes CYP3A4 and CYP2D6. The major metabolite, DM-3411, constitutes between 23% and 48% of brexpiprazole’s exposure at a steady state, although it has not been demonstrated to contribute to any antipsychotic effects. Various factors influence the rate of brexpiprazole metabolism, subsequently impacting its overall exposure (AUC). Patients who use strong CYP3A4 inhibitors (like erythromycin or itraconazole) or potent CYP2D6 inhibitors (such as bupropion, fluoxetine, or paroxetine) may experience increased exposure to the drug. This heightened exposure is also seen in individuals who are poor metabolizers of CYP2D6. On the other hand, using potent CYP2D6 inducers (for instance, rifampicin or glucocorticoids) is likely to decrease the exposure to brexpiprazole. Brexpiprazole demonstrates efficacy in acute schizophrenia according to two studies [70,71]^[35][36]. Although the 2 mg dose showed inconsistent results, the recommended 4 mg dosage exhibited more consistent benefits. Higher brexpiprazole dosages, especially at 4 mg, significantly improved the PANSS-EC score and PANSS scores for negative symptoms, disorganized thought, and uncontrolled hostility/excitement. In a 52-week maintenance study, brexpiprazole outperformed the placebo, prolonging the time to exacerbation and showing significant benefits in psychosocial, occupational, and cognitive functioning, including attention/vigilance and visual learning [63]^[30]. Brexpiprazole also demonstrated cognitive improvement in animal models, distinguishing itself from aripiprazole in this regard. Short-term trials showed a good safety profile, with weight gain being the only common adverse event, and long-term studies indicated a decrease in the mean bodyweight change. Akathisia was dose-dependent but generally mild, with no treatment discontinuations [72]^[37]. Other adverse effects were comparable to those of the placebo, and minimal impacts on glucose, lipids, prolactin, and the QTc interval were observed.

2.4. Lurasidone

Lurasidone, like other second-generation antipsychotics, functions as a complete antagonist at dopamine D₂ and serotonin 5-HT_2A receptors, with binding affinities (Ki) of 1 nM and 0.5 nM, respectively. A distinctive feature of lurasidone is its high affinity for serotonin 5-HT₇ receptors (0.5 nM, on par with its affinity for dopamine D₂ and 5-HT_2A receptors) and its partial agonist activity at 5-HT_1A receptors (Ki, 6.4 nM). The serotonin 5-HT₇ receptor is of significant interest as it is linked to potential procognitive and antidepressant effects. The 5-HT_1A receptor is considered important in the treatment of major depressive disorder and schizophrenia. Notably, lurasidone lacks affinity for histamine H₁ and muscarinic M₁ receptors, contributing to its characteristics of low sedation, minimal weight gain, and limited interference with cognitive and functional assessments [75,76]^[38][39]. The pharmacokinetic characteristics of lurasidone support its suitability for once-daily administration, as it has an elimination half-life of 18 h [77,78]^[40][41]. When lurasidone was administered with food, both the mean Cmax and the area under the curve were approximately threefold and twofold greater, respectively, compared to those for administering lurasidone while fasting [79]^[42]. Based on these findings and clinical trial results, it is recommended to take lurasidone once daily in the evening, either with a meal or within 30 min after eating. Notably, lurasidone absorption remains unaffected by the fat content of the ingested food [79]^[42]. Lurasidone is primarily metabolized by the CYP3A4 enzyme system. Consequently, its use is contraindicated when there are strong inducers or inhibitors of CYP3A4 present. Within the category of psychotropic medications, notable examples of strong inhibitors of CYP3A4 include fluvoxamine and fluoxetine. On the other hand, a well-known strong inducer of CYP3A4 is carbamazepine. When moderate inhibitors of CYP3A4 are present, the suggested initial dose of lurasidone is 20 mg/day instead of 40 mg/day, and the highest recommended dose is 80 mg/day rather than 160 mg/day. Lurasidone’s pharmacokinetics do not interfere with those of other drugs, including lithium, valproate, or those metabolized by the CYP3A4 pathway [80]^[43]. In patients who have moderate or severe renal or hepatic impairment, the advised initial dosage of this medication is set at 20 mg per day. For those with moderate-to-severe renal impairment or moderate hepatic impairment, the maximum dosage should not surpass 80 mg per day. In cases of severe hepatic impairment, the dosage should be restricted to a maximum of 40 mg per day. Lurasidone demonstrated good tolerability, with consistent side effects observed in both short-term and long-term use. In trials spanning six weeks, the most frequently reported adverse reactions to lurasidone included drowsiness, restlessness, nausea, Parkinson-like symptoms, and sleeplessness [81]^[44]. Finally, lurasidone was associated with less weight gain and fewer metabolic disturbances than brexpiprazole [82,83]^[45][46].

3. Summary

Third-generation antipsychotics and lurasidone emerge as promising therapeutic strategies in the treatment of substance-induced psychoses. Aripiprazole has been effective in improving a wide range of psychotic symptoms, including both positive and negative aspects, as well as impacting substance use disorders positively. Its mode of action is unique; it is a partial agonist, meaning it does not stimulate receptors as strongly as full agonists. Its effectiveness lies in its dual role: it diminishes positive symptoms by antagonizing the mesolimbic dopamine pathway and improves negative symptoms and cognitive deficits by activating the mesocortical pathway. This selective mechanism helps aripiprazole to avoid severe side effects, like motor disorders and elevated prolactin levels, that are common for other antipsychotics. Additionally, it is known for its cardiac safety, causing negligible QTc prolongation and having a low risk of weight gain or sedation. In research with animals, aripiprazole has been observed to curb the heightened activity caused by stimulants, such as amphetamine, cocaine, and methylphenidate, and reduce their addictive qualities without hampering normal motor functions. It also reverses the lack of pleasure associated with amphetamine use and hinders the recurrence of cocaine-seeking behaviors. These findings indicate that aripiprazole might be effective in easing withdrawal symptoms associated with dopamine deficiency and, owing to its broad receptor activity, could represent a new strategy for achieving balanced dopamine levels in the treatment of drug addiction. Cariprazine’s receptor profile, particularly its high affinity for the D₃ receptor and reduced intrinsic activity at D₂ receptors, makes it an effective treatment for schizophrenia, improving both positive and negative symptoms. Its ability to modulate different neurotransmitter systems further highlights its potential as a distinct and effective antipsychotic medication. Cariprazine’s role in substance abuse treatment is noteworthy. Its effectiveness emerges in reducing the stimulating effects of substances, like cocaine, and mitigating cravings and relapses. This effect is possibly due to its partial agonism at D₂ and D₃ receptors. Case studies show cariprazine’s beneficial impact on schizophrenic patients with a history of substance abuse and its effectiveness in treating psychosis induced by substances, like methamphetamine. Brexpiprazole exhibits potential efficacy in the domain of substance abuse therapy. Primarily indicated for the management of schizophrenia and as an adjunctive treatment in major depressive disorder (MDD), its unique pharmacodynamic properties extend to the mitigation of substance-induced psychotic disorders. Operating as a partial agonist at the 5-HT_1A and D₂ neuroreceptors, brexpiprazole also engages with noradrenergic receptors. Consequently, albeit preliminary and limited in scope, research indicates its utility in addressing psychotic sequelae associated with cannabis consumption and in modulating dopaminergic activity in heroin-exposed rodents. Lurasidone has shown potential in treating psychopathological conditions related to substance abuse, although research in this area is limited. Known for its antagonistic action at dopamine D₂ and serotonin 5-HT_2A receptors and strong affinity for serotonin 5-HT₇ receptors, lurasidone is unique in its partial agonism at 5-HT_1A receptors. This receptor profile contributes to its low sedative effects and minimal impact on weight and cognitive functions, making it an appealing option in treating substance-induced psychoses. In the context of substance abuse, recent studies have shown lurasidone to be effective in treating young individuals with substance-induced psychosis, particularly from cannabis, improving various symptoms, including mood. It has also been beneficial for a complex case involving a young person with alcohol, cannabis, and LSD abuse along with behavioral and psychotic symptoms. It is important to consider that lurasidone is an approved medication for treating schizophrenia in individuals as young as 13, an age group particularly susceptible to substance use. Consequently, this could make it a feasible option for treatment in this younger demographic in the future.