Three studies have examined the effectiveness of valproic acid in children at familial risk for BD. The first one [36] showed “much” or “very much” improvement in clinical symptoms, evaluated with Clinical Global Impression-Improvement (CGI-I), while the other two RCTs [37,38] showed no particular effectiveness regarding severity of depressive symptoms in youths treated with valproate. In addition, when valproate was combined with paroxetine [38], the onset of manic symptoms or suicidality in over half of the nine patients enrolled caused the discontinuation of the study.

The efficacy of lithium on depressed offspring of BD-affected parents was highlighted in a review that showed lithium may be well tolerated and effective in reducing suicidal ideation and depressive symptoms [39]. In agreement with these results, Nogueira-Lima [40] reported a single child case-report in which lithium monotherapy, in addition to parental psychoeducation, improved depressive symptoms and suicidal behavior.

On the other hand, a six-week, double-blind, placebo-controlled RCT was performed in 30 prepubescent depressed children with family history predictors of BD to evaluate the efficacy of lithium [41]. In this trial, no differences in depressive symptoms were found between the placebo and lithium-treated group, but some of participants dropped out of the study due to adverse effects after lithium consumption.

Quetiapine was evaluated in only one single-blind study. A sample of 15 adolescent patients, treated with a mean of 460 mg/daily of quetiapine, showed statistically significant improvement in both manic and depressive symptoms and showed low side effects (moderate weight gain, no sedation or other adverse events) [42].

Even if lurasidone has not been approved for the treatment of depressive symptoms in high-risk populations, its good profile of efficacy and tolerability in BD patients could make it an interesting option. Lurasidone-induced mania has been reported infrequently, and it is mostly related to lower doses. In fact, a lower dosage of lurasidone (20 to 60 mg/day) is associated with a greater serotoninergic effect that could be risky in BD, while at higher dosages (80–120 mg/day), antidopaminergic effects are prevalent [43,44].

The Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder present strong advice against the use of antidepressants in monotherapy in the treatment of bipolar depression and recommend adequate education of patients and caregivers regarding early warning symptoms of mood switching [25]. No antidepressants are approved for at-risk stages of BD.

The Food and Drug Administration (FDA) has approved certain antidepressants for the treatment of major depressive disorder in children and teenagers: fluoxetine up to eight years old and escitalopram up to age of 12. An olanzapine and fluoxetine combination is the only pharmacological treatment approved for bipolar depression in children and adolescents. Nevertheless, its use is burdened by a significant weight gain and development of metabolic symptoms. It has not been tested in a high-risk population [45]. Antidepressants, especially Selective Serotonin Reuptake Inhibitors (SSRIs), are widely used, after or in combination with psychotherapy, for the treatment of depressive symptoms in youth, regardless of family history. No clear efficacy and safety have been demonstrated regarding the use of antidepressants in the case of prodromes of BD. Their use is associated with the risk of anticipating the development of a full-blown illness, while the efficacy on depressive symptoms seems to be lower than in major depressive disorder [37]. In children at high risk for BD who present hyperactivation, antidepressants could result in the worsening of behavioral problems, impulsivity and aggressivity as well as a greater probability of medication discontinuation [46].

The rate of antidepressant-induced activation is nearly 50% in children and youth at high risk for BD [46], while a retrospective study found that up to 83% of patients that switched to mania were previously treated with SSRIs [47]. This increased risk of conversion was confirmed in a recent naturalistic RCT that included 93 bipolar offspring with anxiety or depressive symptoms treated with antidepressants [48]. In this work, 68% of at-risk patients who met full criteria for major depressive disorder, hypomania or mania, had been previously treated with antidepressants. The odds ratio for switching to mania associated with antidepressant use during follow-up was 7.9.

If an antidepressant treatment is needed due to severity of symptoms, it should be cautiously selected and titrated and should include careful monitoring of any treatment-emergent adverse events. Tricyclics are less tolerated than SSRIs [49], and higher rates of switching to mania are associated with nortriptyline [50]. Yamaguchi presented a series of clinical cases that demonstrate the relative better safety profile of escitalopram among SSRIs. Escitalopram-induced mania is most likely linked to an higher dosage (20 mg/daily or more) and appears shortly after reaching the maximum dosage, so it can be easily monitored [51]. Apart from escitalopram, fluoxetine has the best efficacy/safety profile and is approved for use in children and adolescents [52], while venlafaxine is associated with a high risk of switching to mania [49].

FFT is a psychoeducation family intervention that enhances communication and problem-solving strategies to reduce intrafamilial stress, conflict and affective arousal as criticism, hostility or emotional over-involvement in caregivers. FFT has already shown good results for schizophrenia [55], major depression, prodromal psychosis, and bipolar I and II illness [54,56,57].

In 2011, Miklowitz and colleagues designed an adapted FFT for family of children at high risk for BD (FFT-high risk version: FFT-HR) that has as its principal aim to assist the youth and family members in recognition and acceptance of early signs of prodromal symptoms and prevention of mood escalation. In addition to pharmacotherapy as needed, FFT-HR has demonstrated better efficacy than educational control in preventing, delaying and reducing depressive symptoms (significant improvements in Children’s Depression Rating Scale) [53]. Two other subsequent randomized trials conducted by the same authors confirm that FFT in high-risk populations, in combination with pharmacotherapy, resulted in effective mitigation of mood symptoms prior to full BD as well as delaying recurrences and improving global functioning at the early phases of the illness [23,54].

CBT is recommended by the international guidelines for both high-risk patients for psychosis and for early stages of BD due to its effectiveness in reducing symptomatology and its lower incidence of adverse events [58]. In 2020, an early specific CBT (“Cognitive-behavioral therapy applied early in the potential developmental course of bipolar disorder—EarlyCBT”) was proposed to at-risk patients for BD to evaluate its efficacy and safety [24].

The theory of this model was adapted on the basis of the principles for stress management and problem solving described in previous works “BEsT (be)for(e) Bipolar” by C. Marx, Leopold and Pfennig, 2009, “Cognitive behavioral treatment manual for bipolar disorders” by Meyer and Hautzinger [59] and a psychotherapy model described by Bechdolf and Juckel [60]. The sessions included psychoeducation about BD, early warning signs and crisis management and offer cognitive strategies for prevention of and sensitization to mood episodes. The CBT group was compared to a control group that received non-directive psychotherapy. The results were controversial. In fact, the whole sample manifested an improvement in depressive symptoms, but no differences were found between the CBT group and the control group in the Hamilton Rating Scale for Depression (HAMD) and the Bipolar Prodrome Symptom Scale-Prospective (BPSS-P).

A recent review evidenced the efficacy of psychoeducation in reducing global symptom severity (one study reported), depressive symptom severity (three studies reported) and manic symptom severity (five studies reported), especially in BD patients with a lower number of previous mood episodes (less than 10 episodes) [61]. Thanks to promising results, more studies should be carried out on psychoeducation as a possible prevention strategy, even in at-risk populations.

In the last few decades, the role of Polyunsaturated Fatty Acids (PUFAs) in the prevention of psychiatric disorders has received significant attention. Omega-3 PUFAs take part in neuronal growth, development and function, acting as a neurotrophic factor [62]. EPA and DHA are the major components of omega-3 fatty acids. They seem to play a role in reducing the neuroinflammation and autoimmune effects linked to the development of depressive symptoms [63]. Severe n-3 PUFA deficiency causes an imbalance in dopaminergic and serotonergic pathways, which could be linked to symptoms such as lack of motivation, decreased response to reward, and impairment in intellectual abilities [64]. Moreover, lower levels of EPA and DHA in peripheral tissues (plasma, serum, and red blood cells) are common in subjects with a diagnosis of depressive or bipolar disorder [65,66]. A series of reviews [62,67,68] and meta-analyses [69,70] investigated the efficacy and tolerability of omega-3 fatty acids (DHA and EPA) on depressive symptoms in major depressive disorder, BD and high-risk states for psychosis, while no data could be found about high-risk conditions to develop BD. The most recent review [62] reported good results in major depressive disorder treated with supplementation of n-3 PUFAs (ranging from 0.4 to 6.2 g/day of EPA and from 0.2 to 3.4 g/day of DHA) in combination with antidepressants. Regarding BD, two studies and four reviews showed an improvement of depressive symptoms in patients treated with a combination of mood stabilizers and supplementation of PUFAs. While another recent metanalysis [71], which included 31 RCTs on the effects of omega-3, omega-6 or total PUFAs on depression and anxiety, showed little or no effect in terms of prevention against depressive or anxiety symptoms in BD.

NAC is a precursor of endogenous antioxidant glutathione and has antioxidant, anti-inflammatory, and neuroprotective properties [72]. No studies about the use of NAC on high-risk patients for BD have been carried out, but it has previously been investigated in the prevention and treatment of psychosis [73] and in the treatment of depressive disorder and BD, showing heterogeneous effects in a clinical setting.

Folate assumption has been studied specifically for the prevention of mood episodes in a familial risk population for BD.

A meta-analysis showed a significant relationship between low folate levels and risk for depression [74]. Folate deficiency is associated with accumulation of homocysteine, which, in excess, can promote nerve cell death. In a randomized, double-blind, placebo-controlled trial, Sharpley and colleagues [75] hypothesized that folic acid supplementation given to young people at increased familial risk of mood disorder may convey a neuroprotective effect and could prevent the first mood episodes. A dosage of 2.5 mg daily showed mild evidence that folate may delay the onset of an episode of mood disorder and make it clinically milder.

Positive results have been associated with use of coenzyme Q10 on depressive symptoms in BD. Two studies [76,77] showed an improvement in depressive symptoms and functioning in BD patients at the end of the treatment (respectively 8 and 20 weeks after the beginning of the treatment). The efficacy, the good tolerance and lack of adverse effects could make coenzyme Q10 an interesting option for future studies in high-risk BD populations.

Benzodiazepines (BZDs) provide fast relief in the reduction of comorbid anxiety and are approved by Canadian Network for Mood and Anxiety Treatments as symptomatic drugs in the short-term treatment in BD; however, the appropriateness of their use in at-risk patients for BD is debated. Two recent works [79,90] asserted that prolonged use of BZDs in at-risk populations may extend the duration of untreated illness up to four years, delaying the administration of an adequate psychopharmacological treatment and an appropriate medical follow-up. The risk of drug misuse and dependence in BD patients appears higher than in other patients. The yearly incidence of dependence and abuse reaches 6.3% in those using clonazepam, alprazolam, and multiple benzodiazepines alone or in combination with Z-drug treatments [91]. Thus, BZDs should be prescribed at the lowest possible dose for the shortest period possible, with a maximum of four weeks. Furthermore, BZD users having BD are more vulnerable to develop paradox effects, such as harmful depressogenic effects [92,93], worsening anxiety symptoms and rapid mood relapses [85].

As previously discussed, antidepressants, which are commonly used to treat anxiety disorders in the young, are poorly tolerated in at-risk BD patients and may accelerate the onset of mania [46]. Studies on children and adolescents with depression or anxiety disorders have reported high rates of agitation or anxiety-like symptoms in offspring of BD parents during antidepressant treatment [85]. The introduction of antidepressants should be limited to more severe cases and should be carefully monitored for emergence of agitation or manic symptoms.

Mood stabilization accompanies the reduction of anxious symptoms in co-occurring anxiety and BD. Valproic acid, carbamazepine, quetiapine and olanzapine may have specific anxiolytic properties. However, not all of these have been tested in at-risk populations and some are associated with important side effects. A familial history of anxiety disorder is a predictor of response to lamotrigine in patients with BD [94,95]; thus, it could be an interesting field for future trials.

Pregabalin is effective, well tolerated and is not associated with a risk of mood destabilization. It has not been tested in BD with co-morbid anxiety, but it could be an appropriate option in clinical practice [25].

CBT is the first line of intervention for the management of anxiety in children and adolescents with mood disorders [25,46]. Common CBT models, which have shown effectiveness for depressive symptoms, seem to be also effective for anxiety symptoms [61] in young patients with BD.

Mindfulness-based cognitive therapy for children (MBCT-C) is a manualized group psychotherapeutic intervention proposed by Cotton and colleagues for young patients at familial risk for BD, with the aim of enhancing attention and emotion regulation processes. It consists of 12 sessions that incorporate cognitive behavioral principles and mindfulness skills based on acceptance and non-judgmental awareness of thoughts [29]. MBCT-C was associated with improvements in clinician- and self-rated anxiety (seven points means improvement on a symptom scale) and emotional regulation [18,96,97].

Among nutraceutical agents, only PUFAs have been investigated in the management of anxiety, though they have not been tested for anxiety that occurs in patients with clinical or familial risk for the development of BD. Thanks to promising results among people with mental disorders, PUFAs could be an interesting option for the reduction of anxious symptoms, even in at-risk populations. Observational research suggests correlations between low omega-3 and a high omega-6/omega-3 ratio—in particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—and both depression [98,99] and anxiety scores [100]. A Spanish cohort study that included 7903 participants with a prospective two-year follow-up analysis suggested an initial beneficial effect of moderate intake of omega-3 fatty acids (a mean of 83.3–112 g/day) on comorbid anxiety [101]; the result was not confirmed in the final models. Three recent randomized clinical trials [102,103] reported an inverse association between high doses of DHA and EPA (ranging from 300 to 3360 mg/d of EPA plus DHA) and the severity of anxiety symptoms and anger.

Pharmacological treatment of sleep symptoms usually includes early adoption of hypnotic BZDs and hypnotics. Therefore, as mentioned above [91], these drugs are associated with several adverse effects in high-risk BD populations. In addition, BD has high association rates with pharmacophilia and substance misuse. Given the risk of abuse in this population, certain classes of FDA-approved insomnia medications, such as BZDs and hypnotics, should be avoided [114,115].

Sleep-promoting antidepressants (such as mirtazapine, trazodone and agomelatine) are commonly used in the treatment of insomnia as an alternative to BZDs and non-benzodiazepine hypnotics, thanks to the possibility of being used for a prolonged time and the low risk of dependence.

At the moment, data about the efficacy and safety of sleep-promoting antidepressants in high-risk people for BD are insufficient.

The literature regarding their use in BD raises concern about the risk of switching to mania. In 2015, Wichiniak and colleagues collected a series of clinical cases about the risk of switching to mania associated with trazodone, mirtazapine, and agomelatine. In agreement with previous works [116,117], the risk of switching was confirmed but seemed to be mostly associated with an early stage of treatment and a higher dosage (drugs were used at an antidepressant dosage); no cases were reported in the case of association with concomitant mood-stabilizer therapy. On the other hand, trazodone, mirtazapine and agomelatine provide hypnotic or sedative effects even at low dosages (up to 100 mg/day for trazodone, 3.75–15 mg/day for mirtazapine and up to 25 mg/day for agomelatine), which seem to be safe in patients with BD [118].

IPSRT helps to stabilize the sleep-wake rhythm and daily routine and has provided good results in delaying BD recurrence in adults. In 2014, Goldstein conducted an open trial of IPSRT, planned on the basis of “IPSRT—A treatment manual for youth with BD” [119]. The intervention was targeted at adolescents at risk for BD (decreased treatment length, interpersonal problem session focused on the adolescent’s feelings about having a parent or sibling with BD).

Data from the pilot study suggested a significant improvement in sleep patterns, with less oversleeping, but minimal or no difference in preventing or improving mood symptoms. In addition, the low numerosity of the initial sample (thirteen adolescents) and non-completion of the whole program by many of the participants constituted important limits of this study [27]. In 2018, the same study group conducted a pilot randomized trial of IPSRT plus data-informed referral (DIR), a referral for psychiatric community treatment, versus DIR alone for adolescents with familial risk of BD. The 42 adolescents in the study had a BP parent and had to wear an actigraph to measure sleep/wake patterns for seven days at baseline and at six months. Participants that received IPSRT + DIR, as compared with DIR alone, were significantly improved regarding continuity of sleep. The better quality of sleep was also linked to a reduction in manic and hypomanic subthreshold symptoms [28].

The efficacy of cognitive behavior therapy for insomnia (CBT-I) is supported by multiple meta-analyses and works [114,120]. The American College of Physicians recommend it as first line of treatment prior to pharmacotherapy [121] in both short-term and long-term perspectives on BD [122]. The core of cognitive behavior therapy for insomnia (CBT-I) includes several sessions focused on sleep restriction therapy, psychoeducation about sleep, stimulus control and perception of sleep. CBT-I for BD has not been evaluated in at-risk populations, but results demonstrate an improvement in sleep and circadian disturbance and also show benefits in mood symptoms during the treatment and during the follow-up period [123]. CBT-I for BD includes elements of IPSRT [124], Motivational Interviewing and Chronotherapy [125] and has a particular focus on correcting sleep state misperception [122]. Three trial protocols evaluating CBT-I in BD [122,126] and in multiple psychiatric disorders [123] are ongoing.

Chronotherapeutic intervention is a recognized treatment for bipolar depression based on the effect of light and dark and on the control of sleeping times on the regularization of wake-sleep rhythm. It includes bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP). Even though no results are available for its use in at-risk populations, it has provided good results in improving mood symptoms and sleep disturbances associated with BD, [114,127] and it seems safe even in children and adolescents. All chronotherapeutic interventions seem to prevent the relapse of maniac episodes via regularizing the dysregulated sleep patterns that appear early in the development of a mood episode [128]; thus, it could be an interesting option in the prevention of the illness. The International Society of Bipolar Disorders (ISBD) task force on chronobiology and chronotherapy recently published a systematic review of the literature about the use of the five classes of chronotherapy [126]. This work presents important limitations due to the heterogeneity of methods and objectives of the papers included. Nevertheless, the sum of the results suggests that LT and SD are both efficacious in the relief from depressive symptoms, cuing circadian rhythm, improving subjective sleep quality and decreasing excessive sleep in depressive phases of BD [114,127]. The results are concordant with a previous metanalysis that showed that LT reduces disease severity by regularizing the circadian rhythm [129]. DT as a blue-blocking regime could rapidly block the escalation of sleep symptoms associated with mania, acting on reduction in total sleep, reduction in motor activity during sleep intervals, and increased regularity of sleep intervals [126].

Melatonin is a neurohormone that is synthesized by the pineal gland during dark periods and regularizes the sleep-wake rhythm [108]. Immediate-release melatonin supplements have provided solid evidence in regularizing circadian rhythm alterations [130], in combination or without BZD assumption. Melatonin elicited an increasing interest as a result of neurobiological studies that found a higher suppression of melatonin in response to light in patients with BD [131]. Studies have shown that patients with BD exhibit a relative lack of endogenous melatonin due to impaired activity of the enzyme that converts serotonin into melatonin (acetyl serotonin O-methyltransferase—ASMT). Even in patients at risk for BD, ASMT showed several mutations that cause imbalances in melatonin levels and in the expression of melatonin receptors in the central nervous system [113,132,133,134].

RCTs regarding the use of melatonin in the treatment of sleep disorders in BD are lacking and heterogeneous; no studies have been conducted on high-risk subjects for BD. Further studies and larger samples are needed to make clear recommendations on the use of melatonin receptor agonists in sleep disturbances in patients at risk of BD or in the early phases of BD [135].

The Early CBT model adapted to at-risk patients (“cognitive-behavioral therapy applied early in the potential developmental course of bipolar disorder”), developed by Leopold and colleagues [24], has been proposed for at-risk patients for BD for the prevention and management of early hypomanic subthreshold symptoms. Final results were moderate: the severity of manic symptomatology at YMRS was slightly but significantly decreased in the intervention group, while no significant difference was found in the change of manic features, evaluated by the Bipolar Prodrome Symptom Scale-Prospective (BPSS-P), between the control and treatment group [24]. The literature about the efficacy of CBT on hypomanic symptoms in BD (at-risk and full-blown BD) provides scarce results. In 2016, Yu Ye completed a meta-analysis that found that the improvement in the Young Mania Rating Score (YMRS) during CBT rapidly decreased after three and six months of follow-up. On the other hand, all but one of the nine studies included in the meta-analysis that used YMRS [59] showed no difference between baseline and post-treatment symptoms [157].

As mentioned above, in 2018, Goldstein performed a larger scale RCT pilot study on the evaluation of efficacy of IPRST plus data-informed referral (DIR) on a sample of youths at risk of BD [28]. Contrary to the previous work [27], in which no differences were found on preventing or improving mood symptoms, in this work, the IPRST group showed improvement not only in sleep patterns but also in the severity of subthreshold hypomania symptoms over the follow-up period. In addition, subthreshold hypomania symptoms were present for less time. This pilot RCT demonstrates that a better quality of sleep may be beneficial in delaying or preventing subthreshold hypomanic symptoms among at-risk youths, even if further studies are needed to confirm these promising results.

The use of FFT was widely investigated for both depressive and manic symptoms. Seven randomized clinical trials of adult and pediatric populations investigated the efficacy of FFT in bipolar disorder. Five of these indicated stronger effects of FFT on depressive symptoms than manic or hypomanic symptoms [17,53,54,158,159], whereas two indicated stronger effects of FFT on manic or hypomanic symptoms [160,161]. FFT seems indifferent about the reduction of the risk of conversions to BD [23].

Miklowitz et al. performed a series of randomized controlled trials using a modified version of FFT adapted on patients at high risk for BD (FFT—High Risk Version). Families of the subjects received 12 sessions of adapted FFT over four months, in combination with psychotropic medications. Regarding hypomanic symptoms that were present prior to the development of a real BD, more rapid recovery, more weeks in remission and better YMRS scores were found in patients who participated in FFT sessions [53,55]. This benefit persists after one year of follow-up. In 2020, the same working group performed an extension of previous studies with a larger sample and a longer follow-up period (average of two years). The most relevant result was the prolongation of well intervals during the maintenance phase of treatment, while the recovery from mood symptoms showed no significative improvement.

The explanation of these results can be found in an additional study exploring areas of brain activation [162], using nine participants from the above-mentioned pilot RCT on the use of FFT in populations at risk of BD [53]. In parallel to a reduction of mania scores from pre- to post-treatment, FFT determined changes in activation in the dorsolateral prefrontal cortex and decreased activation in the amygdala, which is augmented during manic states [30,162].

Studies on addiction of omega-3 fatty acids have shown a scarcity of results on manic symptoms in BD [62,68], and only two RCTs have reported positive results. The first one [163] found a large score decrease on the YMRS in children who displayed mixed, manic, or hypomanic symptoms and were treated with high doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acids, while the second [164] reported significant improvements on the YMRS in adult BD treated with a supplement of 1000 mg of omega-3.

Initial studies about the efficacy of amino acid–enriched drinks have been carried for BD patients due to promising results and the lack of side effects. In agreement with the hypothesis that imbalances in the production of catecholamines, as a precursor of dopamine, play a role in the onset of manic symptoms [165], consumption of tryptophan-depleted, tyrosine-depleted and branched-chain amino acid–enriched drinks have been shown to have rapid antimanic effects (great improvement on YMRS within 6 h after the consumption) [166,167]. Nevertheless, the reliability of these results has to be confirmed with further studies.

Other nutraceuticals, used as additions to standard therapy, have been tested for hypomanic symptoms in full-blown BD; however, results appeared scarce or contrasting. Slight or no differences have been found for NAC assumption [33,72,166,167,168,169,170], and results have not confirmed improvements for folic acids [171].