Current therapies for schizophrenia mostly focus on treatment with antipsychotics, the prolonged use of which is prone to cause severe extrapyramidal side effects, such as parkinsonism or tardive dyskinesia [27]. In addition, long-term administration of typical antipsychotics decreases antioxidant enzyme levels, thus perhaps participating in the exacerbation of oxidative events [28]. Therefore, the search for new approaches is of great importance. In this regard, the likely involvement of oxidative stress and inflammation in the pathophysiology of schizophrenia has supported the use of curcumin in various preclinical and clinical studies.

On the preclinical side, we only found two studies. In the first one, curcumin-loaded nanoparticles (30 mg/kg, i.p.) were administered to ketamine-treated rats, achieving a reduction in metalloproteases (MMP), adenosine triphosphate (ATP), and mitochondrial enzyme complex II activity in cerebellar mitochondria, along with a reduction in the over-increased locomotor activities in the side-to-side rocking and neck arcing tests [29]. In the second one, published in 2021, the administration of curcumin (30 mg/kg, i.p.) to ketamine-treated mice induced a reduction in oxidative stress biomarkers in the brain, and a reduction in anxiety and depression-like behaviors [30].

On the clinical arena, five studies and trials have been conducted. The first one is an OLS (NCT01875822) in which 17 schizophrenic patients received 1 or 4 g of curcumin or placebo for 16 weeks. However, to our knowledge, there are no published results to date. In 2017, the first randomized, double-blind, placebo-controlled study reporting the effects of curcumin on brain-derived neurotrophic factor (BDNF), a neurotrophin involved in neuroprotection, neuroregeneration and cell survival among other functions, and cognition in 36 patients with schizophrenia and inpatients was published [31]. Patients receiving curcumin (360 mg/day for 8 weeks) showed an increased in BDNF levels relative to baseline and compared to placebo. However, the study failed to find any effect on cognition or other clinical symptoms. In contrast, the three most recent studies showed more promising results as an add-on to antipsychotics in the treatment of negative symptoms (NCT02298985, NCT02476708) or both positive and negative symptoms [32]. The first study, an 8-week randomized, double-blind, placebo-controlled, parallel, fixed-dose pilot clinical trial in 12 patients with schizophrenia, showed that 300 mg of curcumin add-on to conventional medication significantly improved working memory and reduced interleukin-6 (IL-6) levels [33]. The second study, also a randomized, double-blind, placebo-controlled, add-on clinical trial reported an improvement in negative symptoms in 20 patients receiving curcumin (3 g/day, for 24 weeks) compared to 18 patients receiving placebo [34]. Finally, in the third randomized, double-blind, placebo-controlled clinical trial, curcumin (160 mg/day, for 16 weeks) plus usual antipsychotic medication was administered to 28 patients with chronic schizophrenia (28 additional patients received a placebo). Curcumin-treated patients showed an improvement on the negative and positive subscales, the general psychopathology subscale, total Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), and Clinical Global Impressions (CGI-I) scores in comparison with the control group [32].

Therefore, the schizophrenia picture shows an unbalanced proportion of preclinical and clinical studies, biased towards the clinical ones. In all cases, curcumin was well-tolerated and, overall, an improvement of clinical symptoms was observed, especially in negative symptomatology. However, the heterogeneity of doses and curcumin formulations used precludes drawing more robust conclusions.

Pathophysiology and aetiology of major depression disorder (MDD) are heterogeneous, and traditional antidepressant treatments have some limitations in terms of efficacy, symptom improvement, and side effects. Although the pathological mechanisms are not fully understood, oxidative stress and inflammation seem to play an important role in the pathogenesis of depression, probably through increased inflammatory factors in the central nervous system. In this regard, curcumin has been used and demonstrated to be an effective adjuvant treatment for MDD in several studies.

On the preclinical side, we found a total of 57 studies, 19 of which were performed in mice and 38 in rats. The dose of curcumin ranged from 1 to 300 mg/Kg. The duration of treatment varied from a single intake to a 5-week treatment with curcumin. Regarding the route of administration, 36 used oral administration (23 in the drinking water or food and 13 by gavage), 19 used intraperitoneal administration, and two of them reported no information on the route of administration. In addition, several models of MDD were used, most of them (21) based on a stress-induced model, such as Chronic Unpredictable Mild Stress (CUMS), Single Prolonged Stress (SPS), Chronic Unpredictable Stress (CUS), or Chronic Mild Stress (CMS), while eight of them were induced by surgery (olfactory bulbectomy, ovarectomy, chronic constriction injury or middle cerebral artery occlusion), nine were induced by the administration of reserpine or corticosterone (CORT), and the remaining 19 were induced by other models of MDD.

The antidepressant efficacy of curcumin in modulating depressive behavior in different animal models has been shown in a large number of behavioral studies. Most of the studies reported improved performance in the forced swimming test [35,36,37,38,39,40,41,42,43,44,45,46,47,48], increased locomotor activity in the open field test [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64], decreased anxiety in the elevated plus maze test [57,59,64,65,66], improved anhedonia in the sucrose preference test [51,52,54,56,58,62,67,68,69,70,71,72,73,74,75,76], improved short and long-term memory in the passive avoidance test [49,50,55] and water maze test [54,60,77], reduced escape response in the shuttle-box test [78], attenuated the effort-related abnormalities in a choice procedure test [79], and reduced stress in the tail suspension test [50,64,66,69,80,81,82,83,84,85,86,87,88]. Only one study found no improvements in anxiety, as measured by the open field and elevated plus maze tests, nor in “depressive-like” states, as measured by the forced swimming test [89]. Another study found no improvements in anhedonia, as measured by the sucrose preference test [86].

The administration of curcumin has been shown to regulate serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels. Twenty studies reported an increment of 5-HT levels in the hippocampus, striatum or frontal cortex, which may be due to the interaction found between curcumin and 5-HT/cAMP/PKA/CREB/BDNF-signaling pathway or 5-HT_1A/1B and 5-HT_2C receptors [35,40,80,83,85,90]. Besides, fifteen studies reported an increased level of DA [38,41,42,44,45,46,48,49,55,72,77,81,87,91]. NA was also incremented in five studies [46,49,55,63,86]. In addition, curcumin has been claimed to present beneficial effects on reducing inflammatory cytokines (IL-1β, IL-6) [60,63,69,70,71,76,77,91], reducing the NF-κB-iNOS-COX-2-TNF-α inflammatory signaling pathway [39,51,52], and modulating the levels of antioxidant markers, such as monoamine oxidase (MAO), malondialdehyde (MDA), CAT, or SOD [43,56,57,62,65,66,82,84,88]. Furthermore, the BDNF is incremented by curcumin treatment [36,39,47,51,54,58,66,67,77,78,90]. Other effects of curcumin have been described in different animal models of depression, such as an interaction with glutamate N-Methyl-D-Aspartate (NMDA) receptors [37], an inhibition of Ca⁺² channels [74], an increased level of corticosterol and cortisone in plasma [64], or an altered lipid metabolism [75], or an upregulation of the insulin receptor IRS-1 and protein kinase-B (PKB) in the liver [73]. In contrast, only one study reported no effects of curcumin, regarding its interaction with the benzodiazepine site on gamma-aminobutyric acid (GABA) receptor [89].

Only two neuroimaging studies have evaluated the effect of curcumin on brain morphometry and glucose metabolism in an animal model of depression, showing improvements such as a reduction in hippocampal atrophy [50] and an activation of the metabolism of the amygdala in a positron emission tomography (PET) imaging study after curcumin treatment [53].

In the clinical setting, one OLS and eight clinical trials were performed. In 2013, two trials were conducted, one in India (NCT01022632) [92] and one in Israel (NCT01750359) [93]. In the first one, a randomized, active controlled, parallel group trial, curcumin (1000 mg/day) or fluoxetine (20 mg/day) were administered to patients with MDD for 6 weeks (17 patients on fluoxetine alone, 16 patients on curcumin, and 18 patients on fluoxetine/curcumin), which showed no biological effects on depressive symptoms, as measured by the Hamilton Depression Rating Scale (HDRS). In the second study, a randomized, double-blind, placebo-controlled, pilot clinical trial, curcumin (1000 mg/day, for 8 weeks) was administered to 19 patients (27 patients on placebo), showing no improvement in the MDD symptoms measured by the HDRS and the Montgomery–Asberg Depression Rating (MADRS) scales.

In contrast, the remaining trials conducted from 2014 until now showed better results. In 2014, two randomized, double-blind, placebo-controlled trials were conducted in Australia in 25 patients with MDD receiving curcumin (1000 mg/day, for 8 weeks) and 25–27 patients receiving placebo [94,95]. Both studies showed an improvement in MDD symptomatology (IDS-SR30 total score), and the second one also found an increase in some depression-related biomarkers, such as urinary Thromboxane B2 (TBX-B2) and substance-P (SUB-P), and plasma endothelin-1 (ET-1) and leptin levels. Thus, higher levels of these biomarkers were associated with greater reductions in IDS-S30 total scores.

In 2015, one OLS in Iran [96] and a randomized, double-blind, placebo-controlled trial in China were conducted [97]. In the first study, curcumin (1000 mg/day, for 6 weeks) was administered to 61 patients with MDD (50 patients on placebo), showing a decrease in anxiety levels as measured by the Hospital Anxiety and Depression Scale (HADS) and reductions in MDD symptomatology as measured by the Beck Depression Inventory II (BDI-II) scale [96]. Of note, piperine (10 mg/day) was used to increase the bioavailability of curcumin. In the second trial, curcumin (1000 mg/day, for 6 weeks) was administered to 50 patients with MDD (50 patients on placebo), showing an improvement in the HDRS and MADRS scales [97].

In 2017, another randomized, double-blind, placebo-controlled clinical trial was conducted in Australia [98]. The effects of two different doses of curcumin (500 mg/day or 1000 mg/day, for 12 weeks) was evaluated in 28 and 33 patients with MDD, respectively. Both doses induced improvements in symptomatology and anxiety measured by IDS-SR30 and State-Trait Anxiety Inventory (STAI) scales, with no difference between the doses used. In 2018, a randomized, double-blind, placebo controlled trial was performed in 30 patients with MDD treated with an increasing dose of curcumin (500 mg/day to 1500 mg/day with increments of 250 mg/week, for 12 weeks) and 31 on placebo [99]. This escalating medication dosage induced an improvement in the severity of depression on the MADRS scale. Despite this behavioral improvement, no significant effects were found in blood chemistry and electrocardiogram measurements.

Finally, a randomized, placebo-controlled trial is currently in the recruiting phase (NCT04744545 2021). The study estimates to recruit 60 patients with MDD, with curcumin (1500 mg/day) as an adjuvant treatment for MDD.

Although the etiology of this disorder is largely unknown, oxidative stress and inflammation have been hypothesized to be key factors in its occurrence, especially through an exacerbated increase in pro-inflammatory metalloproteases. In this sense, the anti-inflammatory and antioxidant potential of curcumin could be effective in alleviating this disorder.

So far, no clinical trials have been conducted in patients with ASD. On the preclinical field, only four studies have been performed in animal models, two in rats and two in mice. The first study used a model based on the intracerebroventricular injection of propanoic acid (PPA) in Sprague-Dawley rats. After the PPA injection, curcumin was orally administered for 4 weeks at different doses (50/100/200 mg/kg). The treatment restored many behavioral defects in PPA rats, such as social interaction, anxiety, depression, and repetitive behaviors. In addition, curcumin reduced the levels of MMP-9 and Thiobarbituric Acid Reactive Substances (TBARs), increased the activity of GSH, CAT, and SOD, and restored normal function of mitochondrial enzyme complex 1 [100]. In 2017, another study, based on prenatal valproic acid (VPA) exposure to fetal Wistar rats, proposed early postnatal administration of curcumin (first seven days after birth). This approach was reported to restore oxidative stress deficits and the abnormal body and brain weight values [101]. Two subsequent studies were performed in the BTBRT⁺ltpr3^tf/J (BTBRT) mouse model. The first one, in which curcumin (20 mg/kg) was administered from PND 6 to 8, reported enhanced neural stem cell proliferation, along with increased sociability and improved short-term memory [102]. The second study evaluated three different doses of curcumin (25/50/100 mg/kg), showing restoration of different oxidative stress markers in the hippocampus and cerebellum, along with a dose-dependent increase in sociability in curcumin-treated mice [103].

Taken together, these results suggest that curcumin could be effective in preventing some autistic behavioral and biochemical traits, but the lack of clinical trials do not allow for drawing solid conclusions.

The etiology of OCD is not fully understood either, but it has been hypothesized that it is a result of the existence of a deficit of monoamines in specific brain regions such as the orbitofrontal cortex and the anterior cingulate gyrus. In this regard, the potential of curcumin as an inhibitor of MAO-A and MAO-B, both of which are involved in monoamines degradation [97], led researchers to test its efficacy as an adjuvant treatment in this disorder.

Only two preclinical studies have been conducted to date. The first, carried out in 2010 by Jithendra and Murthy, evaluated the potential of orally administered curcumin (5 or 10 mg/kg) as a therapeutic approach to reduce obsessive-compulsive signs in the quinpirole-induced OCD rat model. Following treatment with both doses, a reduction in brain DA levels, together with an increase in serotonin levels, was observed in curcumin-treated pathological rats. In addition, an improvement in obsessive-compulsive symptoms together with a protective effect on the water maze memory task at both doses was reported [97]. The second study was recently conducted, in 2021, by Mishra et al. In this work, they intraperitoneally administered ethanolic extract of curcumin (10, 15, 25, or 40 mg/kg) to Swiss albino mice that had poor performance in the marble-burying behavior (MBB) and motor activity (MA) tests. The treatment at the dose of 40 mg/kg resulted in improved performance in the MBB test, but not in the MA [98].

From a clinical point of view, no OLS or trials have been conducted to date. However, a case report was announced in 2018. In this case, a 3-year-old child with a diagnosis of OCD and tics was treated with a combination of N-acetylcysteine (dose increase from 600 to 1800 mg/day) and curcumin (90 mg/day). After 7 days, a complete remission of tics and OCD symptoms was observed. Finally, after 3 weeks, symptoms remitted completely, together with a drastic reduction in Children’s Yale–Brown Obsessive Compulsive (CY-BOCS) and Yale Global Tic Severity (YGTSS) total scores [99].

Taken together, these data do not shed enough light to conclude whether curcumin is an effective compound for the treatment of OCD, especially in the case report, in which the observed positive effect could also be attributed to the administration of NAC.