Neurotransmitter and neuropathway imbalance hypotheses

These hypotheses can be traced back to about 6 decades ago when the important roles of several neurotransmitters serotonin (5HT), norepinephrine (NE), dopamine (DA) and acetylcholine (Ach) in mental disorders began to be discovered and reported widely in the literature. The symptoms of mania and depression appeared to be ‘directly opposite’ to each other, and it was therefore suspected that neuropathways/neurotransmitters with opposite or antagonistic functions dominated the depressed versus the manic states. A simple cholinergic−adrenergic hypothesis (Janowsky et al., Reference Janowsky, Davis, El-Yousef and Sekerke1972) was proposed to explain the contrasting states of mood disorders. This hypothesis depicted an imbalance between an adrenergic/noradrenergic for a high energy/mood state and a cholinergic (Ach) circuit for a calm or sedated state. With later research showing the importance of DA in the regulation of mood, as well as its important role in the mechanism of action of many psychotropic drugs, the early simple hypothesis was then replaced by the catecholaminergic-cholinergic hypothesis (Salvadore et al., Reference Salvadore, Quiroz, Machado-Vieira, Henter, Manji and Zarate2010; van Enkhuizen et al., Reference van Enkhuizen, Janowsky, Olivier, van Enkhuizen, Janowsky, Olivier, Minassian, Perry, Young and Geyer2015; Ashok et al., Reference Ashok, Marques, Jauhar, Nour, Goodwin, Young and Howes2017). This neurotransmitter out of balance hypothesis is comparable to the DA-Ach balance hypothesis in Parkinson’s disease (PD) (McKinley et al., Reference McKinley, Shi, Kawikova, Hur, Bamford, Sudarsana Devi, Vahedipour, Darvas and Bamford2019; Ztaou & Amalric, Reference Ztaou and Amalric2019; Myslivecek, Reference Myslivecek2021). In PD, the reciprocal control and balance between Ach and DA-containing neurons are lost with the death of DA-containing neurons. A simple introduction of anticholinergic drugs to restore the balance fell out of favour because of side effects and the introduction of novel treatment methodology (Ztaou & Amalric, Reference Ztaou and Amalric2019; Poppi et al., Reference Poppi, Ho-Nguyen, Shi, Daut and Tischfield2021).

The role of other neuropathways such as glutamine (Glx) has also been brought into this neurotransmitter imbalance concept in recent years. Patients with BD were shown to have significantly higher levels of Glx (Gigante et al., Reference Gigante, Bond, Lafer, Lam, Young and Yatham2012) in certain brain regions such as the anterior cingulate (Li et al., Reference Li, Xu, Zhang, Guan, Zhang, Xu, Shen, Xiao, Liang, Chen, Zhang and Wu2016). It was hypothesised that depressive and manic episodes may be characterised by modulation of the glutamine/glutamate ratio in opposite directions, possibly suggesting reduced versus elevated glutamate conversion to glutamine by glial cells, respectively (Yüksel & Öngür, Reference Yüksel and Öngür2010). Spectroscopy studies of the glutamate system and mitochondrial dysfunction in paediatric BD measurement of glutamate changes were proposed for the early detection of bipolar changes in paediatric patients (Kondo et al., Reference Kondo, Hellem, Shi, Sung, Prescot, Kim, Huber, Forrest and Renshaw2014). Similarly, higher GABA/creatinine levels were reported in euthymic BD outpatients compared to healthy controls (Brady et al., Reference Brady, McCarthy, Prescot, Jensen, Cooper, Cohen, Renshaw and Ongür2013), suggesting that a GABAergic dysfunction may also exist.

The interactions between neuropathways are dynamic, continuous and reciprocally adjusting. The sensitivity of neurotransmitter receptors, for example, may adjust or change over time. Chronic antidepressant drug treatment was shown decades ago to downregulate both 5HT and NE receptors (Tang et al., Reference Tang, Seeman and Kwan1981; Dumbrille-Ross & Tang, Reference Dumbrille-Ross and Tang1983; Helmeste & Tang, Reference Helmeste and Tang1983) and withdrawal may result in rebound hypersensitivity (Tang et al., Reference Tang, Helmeste and Stancer1979a, Reference Tang, Helmeste and Stancer1979b). Similarly, DA receptors may adjust with changes in neurotransmission. While the elevation of DA receptors may contribute to a hyperactive reward network in mania, secondary down-regulation of dopaminergic receptor sensitivity over time may shift the system into a depressive state. A repetition of the cycle may explain the cyclical nature of mood changes. A breakdown of DA receptor and transporter homeostasis might underlie the pathophysiology of unstable mood (Berk et al., Reference Berk, Dodd, Kauer-Sant’anna, Malhi, Bourin, Kapczinski and Norman2007; Ashok et al., Reference Ashok, Marques, Jauhar, Nour, Goodwin, Young and Howes2017). While the chronic antidepressant treatment-induced receptor subsensitivity and withdrawal rebound supersensitivity may explain the antidepressant-induced mood switching phenomenon, spontaneous mood switching in patients who are not on psychotropics may have a different mechanism.

The subsensitivity/rebound hypersensitivity switching may also be the mechanism behind the neuropathway oscillation model (Goldbeter, Reference Goldbeter2011, Reference Goldbeter2013) for explaining mood switching in BD. His hypothesis depicted the propensities to mania and depression as governed by the activities of two putative neural circuits that oscillate and self-inhibit each other. When mutual inhibition is sufficiently strong, the model predicts ‘bistability’, and lesser inhibition would result in a mixed bipolar state. About two-thirds of bipolar-depressed patients had concomitant manic symptoms (Henry et al., Reference Henry, M’Bailara, Lépine, Lajnef and Leboyer2010). While interesting, no experimental data is available to support the hypothesis and it may be difficult to use a variable strength reciprocal inhibiting dual neurocircuit model to explain the mixed symptoms in many bipolar states.

In summary, the translational aspect of the above hypothesis is that introduction of a psychotropic with potent action on one neurotransmitter pathway may upset a previously balanced mood state, or that the balance mood state may be lost over time with the development of neuropathway-receptor subsensitivity or supersensitivity, and drug−drug interactions through CYP enzyme inhibition or metabolic polymorphism. It will require a well-designed placebo-controlled on and off study of psychotropics with relatively targeted action on the specific neurotransmitter pathway in question to resolve this.

Circadian rhythm photoperiod length-induced neurocircuit changes

It is well known that changing daylight duration may induce a mood switch in some patients with affective disorders, exemplified in those with seasonal affective disorders (SAD). One of the proposals was the increased catecholaminergic expression during periods of high activity, changing over to increased somatostatin and corticotrophin-releasing factor during periods of low activity (Young & Dulcis, Reference Young and Dulcis2015). Perturbations of the circadian biological and social rhythms may also influence the expression of rapid cycling (Papadimitriou et al., Reference Papadimitriou, Calabrese, Dikeos and Christodoulou2005). Furthermore, associations of circadian gene polymorphisms, such as the CLOCK gene (OMIM 601851), with affective disorders have been reported. This model proposed a role of MAO-A inhibition with the decreasing sunlight effect, which leads to an increase in DA function leading to mania (Kripke et al., Reference Kripke, Nievergelt, Joo, Shekhtman and Kelsoe2009). While interesting, the efficacy of light therapy is only effective in a portion of patients with SAD (Pail et al., Reference Pail, Huf, Pjrek, Winkler, Willeit, Praschak-Rieder and Kasper2011) and thus can be considered as an adjunct treatment for selected patients.

For the selection of psychotropics for SAD, there have been few reports supporting differential efficacies of different types of antidepressant drugs on SAD. Bupropion is an example was once reported to be an effective preventive treatment (Westrin & Lam, Reference Westrin and Lam2007) but others did not find enough evidence to support the superior efficacy of any specific antidepressant agents for the treatment of SAD (Yildiz et al., Reference Yildiz, Batmaz, Songur and Oral2016; Pjrek et al., Reference Pjrek, Friedrich, Cambioli, Dold, Jäger, Komorowski, Lanzenberger, Kasper and Winkler2020).

Stress-induced neurobiological changes

Stressful life events are well known to trigger depression in previously well-maintained patients suffering from MD and BD. Negative life events do not seem to trigger mania, but life events involving goal attainment do appear to trigger manic symptoms (Johnson, Reference Johnson2005).

In animal models, experimental stress-induced both acute and long-term changes in the brain (McEwen & Gianaros, Reference McEwen and Gianaros2011). Changes in neurotransmitter functions and neurocircuits (Mahar et al., Reference Mahar, Bambico, Mechawar and Nobrega2014), neurogenesis (Lau et al., Reference Lau, Qiu, Helmeste, Lee, Tang, So and Tang2007; Qiu et al., Reference Qiu, Helmeste, Samaranayake, Lau, Lee, Tang and So2007), response to psychotropics (Hamidovic et al., Reference Hamidovic, Childs, Conrad, King and de Wit2010), receptor and gene expressions (Cattaneo & Riva, Reference Cattaneo and Riva2016) have all been reported in these models. Antidepressant drugs and physical exercises may protect the brain from the neurocircuit damaging effects of stress-induced cortisol elevation (Qiu et al., Reference Qiu, Helmeste, Samaranayake, Lau, Lee, Tang and So2007; Tang et al., Reference Tang, Chu, Hui, Helmeste and Law2008, Reference Tang, Helmeste and Leonard2012, Reference Tang, Tang and Leonard2017; Yau et al., Reference Yau, Lau, Tong, Wong, Ching, Qiu, Tang, Lee and So2011). Mood stabilisers, such as lithium and valproic acid (Wang et al., Reference Wang, Fessler and Chuang2011; Chiu et al., Reference Chiu, Wang, Hunsberger and Chuang2013) have been shown to protect the brain from stress-induced changes through glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase (Harwood & Agam, Reference Harwood and Agam2003).

It is important to caution that most of the data came from animal models, using various paradigms to model stress. In practice, antidepressant drugs and mood stabilisers are often adjusted in patients facing severe stressful life events. However, stressful life events as a trigger for depressive or manic symptoms still await further assessment within a longitudinal study (Johnson, Reference Johnson2005). When designing future studies, it would be important to define what constitutes ‘stress’ and how to quantify stress.

Episodic neuroinflammation

Inflammation has long been linked to affective disorders and suicide (Berk et al., Reference Berk, Williams, Jacka, O’Neil, Pasco, Moylan, Allen, Stuart, Hayley, Byrne and Maes2013; Franklin et al., Reference Franklin, Xu and Duman2018; Kageyama et al., Reference Kageyama, Kasahara, Kato, Sakai, Deguchi, Tani, Kuroda, Hattori, Yoshida, Goto, Kinoshita, Inoue and Kato2018; Leonard, Reference Leonard2018; Bergmans et al., Reference Bergmans, Kelly and Mezuk2019). There are several studies that have demonstrated an increase in proinflammatory cytokines in the blood of patients with BD (Bai et al., Reference Bai, Su, Tsai, Wen-Fei, Li, Pei-Chi and Mu-Hong2014). The proinflammatory cytokines are secreted from activated macrophages, which include microglia as well as T-lymphocytes and endothelial cells. This results in the activation of neutrophils, the proliferation of B cells, the synthesis of acute-phase proteins and vascular permeability is also increased. Other studies have concentrated on changes in the interleukins (IL’s), tumour necrosis factor, alpha (TNF) factor, the interferons and transforming growth factors. On accessing the CNS, the cytokines activate the microglia, astrocytes and oligodendroglia. In BD, the chronic activation of the glia changes the homeostatic balance of the glia to an inflammatory state, which contributes to neuronal damage (Watkins et al., Reference Watkins, Sawa and Pomper2014).

The most consistent change reported to occur in BD has been the elevation in the serum concentration of IL-6 (Remlinger-Molenda et al., Reference Remlinger-Molenda, Wójciak, Michalak and Rybakowski2012; Munkholm et al., Reference Munkholm, Weikop, Kessing and Vinberg2015). The concentration of IL-6 is reported to be higher during the manic phase than during the remission period while INF-gamma was higher during the acute depressive episode. The IL-6 concentration was correlated with the intensity of the manic state. By contrast, the concentration of the anti-inflammatory cytokine IL-10 was reported to be higher in the depressed phase during the remission period by Brietzke et al. (Reference Brietzke, Stertz, Fernandes, Kauer-Sant’anna, Mascarenhas, Escosteguy Vargas, Chies and Kapczinski2009), who also reported that the IL-6 levels were elevated in the depressive phase. The particular importance of IL-6 in BD relates to its pleiotropic properties, which result in the stimulation of T and B lymphocytes, and hepatocytes, which release acute-phase proteins such as C-reactive protein (CRP). Other investigators have confirmed an increase of IL-6, TNF-alpha (Kim et al., Reference Kim, Jung, Myint, Kim and Park2007) and IL-2 (Rapaport et al., Reference Rapaport, Guylai and Whybrow1999) in the manic phase and normalised after effective treatment. The anti-inflammatory cytokine, IL-4, was also found to be reduced during the manic phase and returned to normal on effective treatment (Kim et al., Reference Kim, Jung, Myint, Kim and Park2007). These studies confirm that there is an imbalance between pro- and anti-inflammatory cytokines in the two main phases of BPD.

The chronic elevation of the proinflammatory cytokines reduces the sensitivity of the glucocorticoid and insulin receptors thereby contributing to the increased incidence of metabolic syndrome (dyslipidaemia, diabetes, cardiovascular disease etc.) in BD patients (Goldstein et al., Reference Goldstein, Kemp, Soczynska and McIntyre2009).

In addition to the impact of the proinflammatory cytokines on the intermediary metabolism and ultimately on the integrity of the neuronal structure and function, they also disrupt monoamine neurotransmitter synthesis by reducing the availability of tetrahydrobiopterin, the key factor in monoamine synthesis (Felger & Miller, Reference Felger and Miller2012). Monoamine signalling is further disrupted by the increase in the expression of the serotonin and DA transporter proteins. Glutamate signalling is also affected as the proinflammatory cytokines increase the activity of indoleamine-2,3-dihydrogenase. This leads to the synthesis of the neurotoxic N-methyl-D-aspartate agonist quinolinic acid which potentiates excitotoxicity (Myint, Reference Myint2012). However, despite the evidence that the neuronal structure is affected by the inflammatory assault, there is evidence that BD is characterised by the glial pathology rather than neurodegenerative changes which characterise major depression (Rajkowska, Reference Rajkowska2002).

Recent meta-analyses implicate an increase in proinflammatory cytokines and a decrease in brain-derived neurotropic factor (BDNF) as crucial to the cellular pathology of BD, particularly during the manic phase of the episode. These markers appear to respond to the therapeutic effects of such mood stabilisers as lithium and valproate. However, despite the availability of data indicating changes in the manic and euthymic states, there appear to be no reports which would give an insight into specific changes associated with the switch process, or how this may induce a switch in mood states. Clearly, it is essential to undertake detailed studies, larger sample sizes, BD subtypes, family history and comorbidities to understand the immune complexity of BD (Muneer, Reference Muneer2016).

In summary, given the episodic nature of mood state switching, an ‘on and off’ neuro or systematic inflammatory process could possibly be one of the causes in some patients (Maletic & Raison, Reference Maletic and Raison2014; Fries et al., Reference Fries, Walss-Bass, Bauer and Teixeira2019). Genetic and systematic abnormalities in inflammatory factors have been reported to be associated with bipolar mood disorders (Sigitova et al., Reference Sigitova, Fišar, Hroudová, Cikánková and Raboch2017) and impulsivity (Kim et al., Reference Kim, Kang, Bahk, Jang, Hong and Baek2020). An association between low-grade inflammation and the clinical features of BD was also reported (Gan et al., Reference Gan, Wu, Liao, Wu, He, Yang and Zhang2019). Electroconvulsive treatment, an effective and safe treatment for all the states of severe and drug-resistant BD (Perugi et al., Reference Perugi, Medda, Toni, Mariani, Socci and Mauri2017), would cause an acute immuno-inflammatory response followed by a decrease in inflammation (Yrondi et al., Reference Yrondi, Sporer, Péran, Schmitt, Arbus and Sauvaget2018). However, neuroinflammation is non-specific to neuropathways (Goldstein et al., Reference Goldstein, Kemp, Soczynska and McIntyre2009; Tang et al., Reference Tang, Helmeste and Leonard2021) and has also been proposed to be associated with other brain disorders such as dementia. A hypothesis of episodic inflammation as the cause of mood state switching will require much more supporting evidence and a clear and unequivocal efficacy of anti-inflammatory agents with or without concomitant antidepressant drugs needs to be demonstrated. At this point, consideration of adjunctive anti-inflammatory agents may be useful in patients with unstable and hard-to-stabilise mood states who showed abnormal inflammatory markers.

Though anti-inflammatory agents have been and are being tested for their antidepressant effects, direct or indirect modulation of inflammatory response also has the potential to be tested as novel therapeutic approaches for patients with unstable moods or problematic mood switching (Pereira et al., Reference Pereira, Oliveira, Silva, Madeira, Pereira and Cruz2021).

Of the anti-inflammatory drugs investigated as adjunctive treatments for major depression and for BD, the cyclooxygenase-2 inhibitor, celecoxib, has received particular attention (Husain et al., Reference Husain, Strawbridge, Stokes and Young2017). Celecoxib is a non-steroidal anti-inflammatory which inhibits the formation of proinflammatory prostaglandins from arachidonic acid. As a consequence, arachidonic acid is shunted into a pathway leading to the synthesis of anti-inflammatory eicosanoids (Strauss, Reference Strauss2008) of which the omega-3 fatty acid, eicosapentaenoic acid has anti-inflammatory and possible antidepressant activity, as indicated by the behavioural, neurotransmitter and immune changes in the olfactory bulbectomised rat model of depression. The arachidonic cascade hypothesis has been advanced to explain the anti-manic actions of mood-stabilising drugs such as lithium, valproate and lamotrigine, all of which have been shown to downregulate the turnover of brain phospholipids. Clinical studies have demonstrated that the combination of antidepressants with celecoxib enhances the antidepressant action in the treatment of bipolar depression (Halaris et al., Reference Halaris, Cantos, Johnson, Hakimi and Sinacore2020) while Edberg et al. (Reference Edberg, Hoppensteadt, Walborn, Fareed, Sinacore and Halaris2018) demonstrated that the adjunctive celecoxib treatment also reduced the concentration of CRP concomitant with the antidepressant effect in BPD.

Clearly more extensive clinical studies need to be undertaken to validate the usefulness of the arachidonic acid cascade hypothesis in the development of potential mood-stabilising drugs. Presently there is no experimental or clinical evidence that the eicosanoids are specifically involved in the switch mechanism. However, an experimental study by Rapoport et al. (Reference Rapoport, Basselin, Kim and Rao2009) that antidepressants shown to switch patients into the manic phase also upregulate the arachidonic acid cascade. This further emphasises the need to clarify and extend these studies, both experimental and clinically, to target the metabolism of arachidonic acid in the two main phases of BD and in the switch process.

BDNF and thyroid hormone imbalance

A wealth of data supports a major role of BDNF in affective disorders. Antidepressant treatment and exercise (Tang et al., Reference Tang, Chu, Hui, Helmeste and Law2008) also elevate BDNF. Altered activity of BDNF has been proposed as a possible cause of mood instability (Tsai, Reference Tsai2004). A possible association between BDNF Val66Met polymorphism and BD has been reported (Neves-Pereira et al., Reference Neves-Pereira, Mundo, Muglia, King, Macciardi and Kennedy2002) but later found to be complex and inconsistent (Kanazawa et al., Reference Kanazawa, Glatt, Kia-Keating, Yoneda and Tsuang2007; Wang et al., Reference Wang, Li, Gao and Fang2014, González-Castro et al., Reference González-Castro, Nicolini, Lanzagorta, López-Narváez, Genis, Pool García and Tovilla-Zárate2015). Whether changes in brain BDNF is an important factor in mood shift or unstable mood in affective disorders still requires much further research.

Reports on thyroid dysfunction in bipolar patients date back to the 1990s, with Grade I (Bauer et al., Reference Bauer, Whybrow and Winokur1990), II, III (Kusalic, Reference Kusalic1992) hypothyroidism reported in rapid cyclers. However, the findings were not consistent, as no significant differences in thyroid function indices between rapid- and non-rapid-cycling cases were also reported (Valle et al., Reference Valle, Ayuso-Gutierrez, Abril and Ayuso-Mateos1999). As thyroxine is an important ‘activating’ hormone in energy metabolism, it is natural to question whether changes in thyroid function may trigger a switch in mood state. The literature reviewed argued that there were some clues that thyroxine (T3) could augment and accelerate treatment response with antidepressants and lithium and that it might protect against rapid-cycling BD, as well as against relapse (Parmentier & Sienaert, Reference Parmentier and Sienaert2018). Another double-blinded control study showed the benefit of adjunctive L-T₄ in alleviating resistant depression, reducing time in mixed states and increasing time euthymic and adjunctive T₃ did not show statistically significant evidence of benefit over placebo in reducing the time spent in disturbed mood states (Walshaw et al., Reference Walshaw, Gyulai, Bauer, Bauer, Calimlim, Sugar and Whybrow2018). Again, the thyroxine factor is likely to be only present in some patients with unstable mood and not a general phenomenon in all patients with mood switching.

Genetic susceptibility

There has been great progress in the application of pharmacogenomics in diagnosis and treatment (Fortinguerra et al., Reference Fortinguerra, Sorrenti, Giusti, Zusso and Buriani2019) and genetic susceptibility is an important factor. The genetic basis of BD appears to be complex. Earlier reports of simpler gene abnormalities are replacing by more complex ones. For example, not only coding but non-coding RNA been hypothesised to underlie the pathology of BD (Luykx et al., Reference Luykx, Giuliani, Giuliani and Veldink2019) more meta-analyses of both bipolar and unipolar mood patients suggested the risk of antidepressant-associated mood elevations in bipolar II disorder was intermediate between bipolar I and major depression (Bond et al., Reference Bond, Noronha, Kauer-Sant’Anna, Lam and Yatham2008). The risk of mania switch was more frequent with than without antidepressants, and in bipolar as compared to unipolar patients (Tondo et al., Reference Tondo, Vázquez and Baldessarini2010). The 5HT transporter gene promoter polymorphism has been suspected to underline the susceptibility to antidepressant-induced mania but more research is needed (Biernacka et al., Reference Biernacka, McElroy, Crow, Sharp, Benitez, Veldic, Kung, Cunningham, Post, Mrazek and Frye2012). A functional variant in the 5HT receptor 7 gene (HTR7) was shown to be associated with good response to SSRIs in bipolar and unipolar depression (Fortinguerra et al., Reference Fortinguerra, Sorrenti, Giusti, Zusso and Buriani2019; Wei et al., Reference Wei, McCarthy, Ren, Carrillo-Roa, Shekhtman, DeModena, Liu, Leckband, Mors, Rietschel, Henigsberg, Cattaneo, Binder, Aitchison and Kelsoe2020). The genetic factor, therefore, is unlikely to be a major factor behind mood state switching.

The mitochondria hypothesis of energy abnormality in mood disorders

It is well known that mitochondria are the powerhouse of the body and energy defects are a prominent symptom of depression while excessive energy is an important diagnostic symptom of mania. Reports supporting energy metabolism abnormalities in subjects with affective disorders dated back to the early 1990s and altered expressions of mitochondria-related genes were reported (Kasahara & Kato, Reference Kasahara and Kato2018). Additionally, environmental factors for these disorders, such as stresses, have been suggested to induce mitochondrial abnormalities. Moreover, animal studies have suggested that interactions of altered expression of mitochondria-related genes and environmental factors might be involved in mental disorders.

Mitochondrial dysfunction in affective disorders was organised into a hypothesis (Kato, Reference Kato2017; Allen et al., Reference Allen, Romay-Tallon, Brymer, Caruncho and Kalynchuk2018; Caruso et al., Reference Caruso, Benatti, Blom, Caraci and Tascedda2019). A 16–21% prevalence of BD was reported in mitochondrial diseases by several groups (Fattal et al., Reference Fattal, Budur, Vaughan and Franco2006; Mancuso et al., Reference Mancuso, Ricci, Choub, Filosto, DiMauro, Davidzon, Tessa, Santorelli, Murri and Siciliano2008; Inczedy-Farkas et al., Reference Inczedy-Farkas, Trampush, Perczel Forintos, Beech, Andrejkovics, Varga, Remenyi, Bereznai, Gal and Molnar2014), which is about 20 times higher than the general population. This suggests that having a mitochondrial disease is a strong risk factor for BD. Using an Induced pluripotent stem cells model for human BD, mitochondrial abnormalities were found in young neurons from patients with BD (Mertens et al., Reference Mertens, Wang, Kim, Yu, Pham, Yang, Zheng, Diffenderfer, Zhang, Soltani, Eames, Schafer, Boyer, Marchetto, Nurnberger, Calabrese, Ødegaard, McCarthy, Zandi, Alda, Nievergelt, Mi, Brennand, Kelsoe, Gage and Yao2015). All these findings regarding mitochondria defects raise the possibility of developing new bipolar drugs targeting mitochondria (Pereira et al., Reference Pereira, Chavarria, Vian, Ashton, Berk, Marx and Dean2018). The mitochondria hypothesis certainly offers an important conceptual framework to study the episodic or fluctuating energy phenomenon in mood disorders. How episodic mitochondrial changes can be used to explain the unstable and episodic changes in mood awaits further investigation. At this point, there is no pharmacotherapy targeting the mitochondria resulting in the stabilisation of mood.