• Lower Case Switcher Serial Season 3

Get Grammarly In General, Can You Capitalize Seasons?The seasons—winter, spring, summer and fall—do not require capitalization. Some people think these words are proper nouns and capitalize them using the capitalization rule for proper nouns. But seasons are general nouns, so they follow the capitalization rules that apply to other general nouns.Does that seem unfair? We capitalize Monday and February, so why not summer?

It’s a valid question. But then again, if we were to always capitalize the names we give to specific periods of time, wouldn’t we then also have to capitalize afternoon or morning? You can debate this as much as you’d like (and please do in the comment section), but as things stand right now, seasons are common nouns, so no capital letters for them. When Can You Capitalize the Names of Seasons?There’s one exception that you’ve probably already thought of: when the name of a season is the first word of a sentence, you should capitalize it. Likewise, capitalize seasons when they are part of a proper name or a title, like the Summer Olympics.

If your name is Summer, which is great because it’s a lovely name, there’s no reason not to capitalize your own name.If you’re a poetic soul and you like to think about seasons as if they were people, you can also capitalize their names. If you want to write a verse that describes how summer is caressing you with his warm arms, go ahead and capitalize that “s.” But when you’re done with the poem, remember to switch back to lowercase in your everyday correspondence.A quick summary:. The general rule says that seasons should not be capitalized. They are common nouns, not proper nouns. But there are a few exceptions that call for capitalization. Capitalize the name of a season when it’s the first word of a sentence or part of a proper noun.

If the season is being personified, you can capitalize it then, too.ExamplesThis fall, you can cozy up in military-style outerwear, throw on a tartan coat, try out a sweeping cape, or keep the chill at bay with an elevated version of the workaday puffer jacket.—Southern California is having its smoggiest summer in nearly a decade and hospitals report an increase of people with breathing problems.—You could say Rob Connolly’s competent but slight thriller “Edge of Winter” is about extreme roughing it.—Only at the end of spring did they rise above average, the Woodland Trust said.—.

ObjectiveThe singular phenomenon of switching from depression to its opposite state of mania or hypomania, and vice versa, distinguishes bipolar disorder (BPD) from all other psychiatric disorders. Despite the fact that it is a core aspect of the clinical presentation of BPD, the neurobiology of the switch process is still poorly understood. In this review we summarize the clinical evidence regarding somatic interventions associated with switching, with a particular focus on the biological underpinnings presumably involved in the switch process. Data SynthesisConverging evidence suggests that certain pharmacological and non-pharmacological interventions with very different mechanisms of action, such as sleep deprivation, exogenous corticosteroids, and dopaminergic agonists, can trigger mood episode switches in patients with BPD.

The switch-inducing potential of antidepressants is unclear, although tricyclic antidepressants (TCAs), which confer higher risk of switching than other classes of antidepressants, are a possible exception. Several neurobiological factors appear to be associated with both spontaneous and treatment-emergent mood episode switches; these include abnormalities in catecholamine levels, upregulation of neurotrophic and neuroplastic factors, HPA-axis hyperactivity, and circadian rhythms. IntroductionThe singular phenomenon of switching from depression to its opposite state of mania or hypomania, and vice versa, distinguishes bipolar disorder (BPD) from all other psychiatric disorders. Although symptoms such as depressed mood, insomnia, paranoid ideation, anxiety, and appetite changes are experienced across many psychiatric disorders, the process of switching from depression to a state of mania or hypomania is a unique and core feature of BPD.

Currently, no uniform definition exists to describe the switch phenomenon; herein, we have defined it as a sudden transition from a mood episode to another episode of the opposite polarity. Clinical predictors of switch and their significanceFew studies have tried to characterize the clinical characteristics of the switch process in BPD or its prognostic significance. To study the clinical and prognostic correlates of the phenomenon of switching in patients with BPD, Maj and colleagues prospectively compared a group of patients who experienced a mood switch (defined as a sudden transition from a mood episode to another episode of the opposite polarity with an intervening period of no more than one month) to a comparison group of subjects who did not experience any switches during an observational period of at least three years. The study found that switchers were more likely to have a greater number of hospitalizations previous to their study index episode and to need more time to recover from their index episode. Furthermore, the time to 50% probability of recovery was significantly longer for patients who experienced more than one switch (i.e., those having a polyphasic episode) during their index episode (44 weeks) compared to patients who had only one switch (i.e., those having a biphasic episode) (12 weeks) or to non-switchers (seven weeks).

Likewise, patients with more than one switch spent more time in mood episodes during the observational period following the index episode than the other two groups. In this study, switching from depression to mania/hypomania was associated with a poorer prognosis as well as an increased risk of switching during subsequent episodes than switching from mania/hypomania to depression. In addition, switchers were more likely to show psychomotor retardation than non-switchers.

However, neither gender, a positive family history of BPD, nor age at recruitment were significant predictors of switching.Another retrospective study found that the presence of mixed symptoms during a depressive episode was associated with an increased risk of having a manic switch. In another study, Zarate and colleagues found that a mixed manic presentation was a strong predictor of switch from mania to depression. They investigated clinical and demographic predictors of switch from mania to depression in 28 switchers and 148 non-switchers.

In this study, switching from mania to depression was not associated with a longer time to recovery or earlier time to relapse during the 24-month follow-up period. In these two studies the treatment status at the time of switching was not controlled for, as the patients were undergoing uncontrolled treatment with multiple classes of drugs.

A recent observational study that investigated the switch from mania to depression noted that a history of previous depressive episodes, substance abuse, greater overall severity on the Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP), and benzodiazepine use all increased the risk of this type of switch. Conversely, the authors also identified factors associated with lower switch rates from mania to depression, including atypical antipsychotic use, lower Young Mania Rating Scale (YMRS) severity, and higher CGI-BP depression scores.Several clinical variables have been studied specifically as potential predictors of TEAS, including gender, diagnosis, age, number of previous episodes of mania, previous history of TEAS, and polarity of onset episode. Some studies have found that switchers have a higher number of past manic episodes, while others found more past manic episodes in non-switchers, and still others found no differences between switchers and non-switchers on this variable. Serretti and colleagues found an association between TEAS and depressive polarity of illness onset, but this was not replicated in subsequent studies,. Two studies reported that switchers were older at intake, but the opposite association (i.e., earlier age at intake) was reported in a more recent study.

Also, a positive past history for TEAS was found to predict current TEAS in some but not all studies,. A positive history of rapid cycling has also been associated with TEAS,. However, gender, family history, age of onset, and substance abuse have not been found to predict TEAS,.In addition, a number of studies have focused specifically on clinical predictors of TEAS when antidepressants are administered. Data from the Systematic Treatment Enhancement Program for Bipolar Disorder suggest that a past history of multiple antidepressant trials is associated with TEAS. A history of past TEAS also seems to be associated with the development of chronic dysphoria following antidepressant administration.

Another important question is whether patients with BPD-I and BPD-II differ in their risk for TEAS; while some studies detected an increased likelihood of switch in patients with BPD-I, others reported no difference, or increased risk for subjects with BPD-II. However, a recent meta-analysis that combined results from nine different studies assessing TEAS rates in patients with BPD-I and BPD-II noted that patients with BPD-I had a significantly higher risk of TEAS (14.2 vs 7.1%, respectively). Abbreviations: AD: antidepressant; CGI-BP: Clinical Global Impressions Scale for Bipolar Disorder; DSM: Diagnostic and Statistical Manual of Mental Disorders; RDC: research diagnostic criteria; RCT: randomized controlled trial; sx: symptoms; tx: treatment; YMRS: Young Mania Rating Scale.Another critical issue is the uncertainty regarding switch rates in unmedicated patients; for instance, retrospective data obtained from patients hospitalized between 1920 and 1959 found a rate of 29% for spontaneous switching from depression to hypomania. Without a clear benchmark estimating the rate at which patients are likely to switch spontaneously, it can be difficult to assess the degree to which antidepressants increase that risk. Relatedly, the fact that most patients with BPD receive antidepressants concomitantly with mood stabilizers makes switch rates even more difficult to estimate accurately.Despite these limitations, results from clinical trials may provide important clues to understanding the neurobiology of the switch process by analyzing switch rates for antidepressants that target different neurotransmitter systems (for an excellent and extensive recent review of this topic, see ).

Below, we review what is known about the various classes of antidepressants and their propensity to cause TEAS in individuals with BPD. 3.1 TEAS associated with the use of various classes of antidepressantsTricyclic antidepressants (TCAs) have consistently been associated with a high risk of TEAS compared to other antidepressants; naturalistic and retrospective studies have reported TEAS incidence rates ranging from 9% to 69% –. Because much of this knowledge has been previously and extensively reviewed by others and is already familiar to the reader, we offer here only a brief discussion of the evidence concerning the mood-elevating potential of TCAs; when possible, we also include data from randomized controlled trials in bipolar depression.Bunney and colleagues reviewed 80 studies involving 3923 patients mostly treated with TCAs for depression and found that the incidence of TEAS into mania or hypomania was 9.5%. A later study by Wehr and Goodwin of 26 patients with BPD-I and II found that 18 experienced manic or hypomanic switches while on TCAs after an average of 21 days for those with BPD-I and 35 days for those with BPD-II. Pooled data have similarly shown that mood switches are considerably more frequent with TCAs (11.2%) than with selective serotonin reuptake inhibitors (SSRIs) (3.7%) or placebo (4.2%). Bottlender and colleagues evaluated the incidence of mania and hypomania in 158 patients with BPD-I treated for depression. They describe switch rates of 34% for patients receiving TCAs.

Similar switch rates were reported in a naturalistic study by Boerlin and colleagues, who found that both TCAs and monoamine oxidase inhibitors (MAOIs) were associated with higher switch rates than the SSRI fluoxetine (32%, 35%, and 12%, respectively). The TCA imipramine has also been associated with TEAS (rates between 6.6 and 17.8%) in four studies –. These rates are considerably lower than those obtained from naturalistic and retrospective studies, but the enrollment of patients with milder forms of BPD in clinical trials compared to observational/naturalistic studies might explain this difference.Evidence from a clinical trial in bipolar depression suggests that use of the TCA desipramine, which is a selective inhibitor of norepinephrine reuptake, was associated with a high frequency of switches into mania or hypomania (30%). However, no definitive conclusions can be drawn from this study, as few patients were enrolled (n= 10); furthermore, there have been no studies evaluating desipramine’s propensity to cause TEAS since 1994. One case report noted that reboxetine, another norepinephrine reuptake inhibitor (though not available in the U.S.), induces hypomania.Only three randomized clinical trials have evaluated TEAS in monoamine oxidase inhibitors (MAOIs).

In the first trial, 3.7% of patients experienced manic/hypomanic symptoms leading to study withdrawal. Also, a YMRS score ≥ 10 was described in 9.3% of all patients taking moclobemide. In the second study, the MAOI tranylcypromine caused manic or hypomanic switches in 11% of patients. Finally, Nolen and colleagues reported no manic switches in eight patients with BPD openly randomized to tranylcypromine for 10 weeks as an add-on to mood stabilizers. Interestingly, a recent retrospective analysis of STEP-BD data suggests that TEAS is less likely to occur when MAOIs are administered in conjunction with mood stabilizers compared to other classes of antidepressants.Bupropion, a norepinephrine and dopamine reuptake inhibitor (NDRI), is associated with low TEAS potential, and its lower mood-elevating potential compared to TCAs has been described since the 1980s,. Five clinical trials have evaluated its switch-inducing potential in patients with bipolar depression, with a frequency of mood episode switches ranging from 0 to 17.9%,. Notably, all the patients enrolled in bupropion trials were concomitantly treated with mood stabilizers, a factor that may have contributed to the low TEAS rates observed.

Lower Case Switcher Serial Season 3

3.2 The role of the serotonergic, catecholaminergic, noradrenergic, and dopaminergic systems in the switch processAs the preceding section emphasized, antidepressants targeting the serotonergic, noradrenergic, and dopaminergic systems have been associated with various degrees of propensity to induce TEAS, providing valuable clues regarding the underlying mechanisms of the switch process.Data from genetic studies that investigated polymorphisms involved in the homeostasis of the serotonergic system suggest it has a negligible role in the switch process, with one exception. Mundo and colleagues found that the short allele polymorphism of the serotonin transporter (5HTTLPR) was overrepresented in patients who developed treatment-emergent hypomania/mania after receiving SSRIs. However, this association was not confirmed in a subsequent study that applied both a broad and a narrow definition of TEAS; failure to replicate the association between the switch pattern and the short variant of the serotonin transporter might be due to higher age of onset in the second study compared to the first. Another study investigated other potential candidate genes that regulate serotonergic system homeostasis and switch, such as 5HTTLPR, 5-HT 2a, and tryptophan hydroxylase, but no association was found. Tryptophan depletion, a procedure that depletes serotonin, does not generally cause mood changes in lithium-treated euthymic patients with BPD, while catecholamine depletion evokes a rebound hypomania in patients with BPD (see below).The role of the noradrenergic and dopaminergic systems in the switch process is not clearly defined or well-studied. Some historical studies tried to investigate the potential role of the noradrenergic and dopaminergic systems in TEAS in BPD by measuring peripheral metabolites of monoaminergic systems activity.

Most of these case reports or case series were carefully conducted with inpatients studied across sequential episodes of switches. With the exception of three studies, all other reports described here are single case studies of patients with rapid- or ultra-rapid cycling. The data summarized here generally refer to drug-free patients, with few exceptions,. Higher urinary cyclic adenosine 3’5’monophosphate (cAMP), urinary norepinephrine, and dopamine, have all been associated with mania and, more relevant to the present discussion, the switch to mania. Increased urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) has also been described in this context,. Increased post-synaptic receptor sensitivity interacting with high levels of catecholamines has also been hypothesized to trigger manic switches in some patients with BPD,.Several genetic polymorphisms in the catecholaminergic system (D4 receptor, D2 receptor, Catechol- O-methyl transferase COMT, MAO-A) have been proposed as putative risk factors for TEAS in BPD, but no polymorphism was specifically found to be associated with the switch process.

Interestingly, this study analyzed genetic polymorphisms that had previously been associated with antidepressant response, thus suggesting that the process associated with spontaneous switching might have a very different mechanism from that associated with antidepressant response.Evidence from rodent studies further supports a putative role for the catecholaminergic system in the switch process. Drugs that deplete norepinephrine in the CNS (reserpine-like drugs) produce depression-like symptoms (e.g., locomotor hypoactivity) in animal models, whereas drugs that increase norepinephrine levels, such as MAOIs and TCAs, are associated with antidepressant-like effects. One hypothesis is that these antidepressant-like effects may occur through delayed postsynaptic receptor desensitization, leading to increased receptor responsivity. This is theorized to be a critical physiological protective mechanism against acute and chronic receptor overstimulation that, in turn, might be associated with an increased risk for switching in BPD. Also, receptor supersensitivity, altered internalization of cell surface receptors, and changes in critical mRNA expression might result in altered monoaminergic activity in the prefrontal areas, leading to manic-like behavioral changes. The glutamatergic system and switchAbundant evidence now implicates glutamatergic system dysfunction in the pathophysiology and treatment of unipolar depression and BPD (reviewed in ). For instance, animal models of BPD suggest that the glutamatergic system plays a major role in manic-like behaviors.

Du and colleagues found that inhibition of glutamate receptor type 1/2 (GluR1/2) subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor significantly attenuates amphetamine-induced hyperactivity in rodents. In addition, disruption of GluR6, a subunit of the kainate receptor (kainate receptors, along with AMPA receptors, are glutamatergic non-N-methyl D-aspartate (NMDA) ionotropic receptors), produces a complex set of symptoms in mice that resemble the behavioral symptoms of mania, including increased risk-taking behaviors and aggressiveness, hyperactivity, and less despair-type manifestations. Whether and how these findings might be related to the switch process will need to be addressed in future studies.Although the study of glutamatergic drugs in the treatment of mood disorders is still in its infancy, preliminary evidence from small trials and case reports suggests that drugs that modulate the glutamatergic system have low risk of inducing TEAS. For example, lamotrigine—an FDA-approved mood stabilizer that inhibits glutamate release through sodium and calcium channel blockage —is not associated with significant risk of switch in patients with bipolar depression. In another study of 14 patients with bipolar depression, riluzole, another inhibitor of glutamate release, was not associated with increased risk of switching; in that eight-week study, patients received riluzole as an add-on to lithium.The switch-inducing potential of glutamatergic drugs that act by blocking NMDA receptors (i.e., ketamine, memantine) is essentially unknown, as the clinical evidence for their use in BPD is small. Studies in healthy volunteers found that individuals who received intravenously-administered ketamine showed significantly more euphoria than those who received amphetamine or placebo, possibly indicating some switch-inducing potential. However, it is unclear whether ketamine or memantine elicit core manic symptoms in BPD patients, and not only euphoria.

Clinical trials conducted with these agents have not noted any increased risk of switch associated with their use. While no conclusions can yet be drawn about the propensity of these agents to induce mood switches in BPD, this is nevertheless an important new avenue of research that will undoubtedly further our understanding of the molecular underpinnings of the switch process. Dopaminergic agonists (psychostimulants) and switchSelective dopaminergic drugs, such as psychostimulants, have long been associated with high rates of TEAS, and have been empirically tested in preclinical studies. Murphy and colleagues studied the effects of L-dopa, and L-dopa + peripheral decarboxylase inhibitor alpha-methyl dopa hydrazine (MK-485) in a double-blind, randomized, placebo-controlled study in bipolar depression. Six out of seven subjects treated with L-dopa developed hypomanic symptoms after an average of 7.8 days.

Interestingly, the symptoms decreased within 24–48 hours of discontinuing L-dopa. These results suggest that, at least for some patients, the switch into mania or hypomania is associated with increased functional brain norepinephrine and dopamine.Similarly, amphetamines that promote dopamine release and inhibit its reuptake have been shown to either precipitate hypomania in patients with BPD or induce a “hypomanic-like” state in healthy subjects,. Consistent with these findings, a chart review of depressed, medically ill patients found several cases of hypomania one to five days after d-amphetamine was initiated at doses as low as 5–10 mg/day.

Another study found a significant increase in subjective measures of thought processing speed and irritability in healthy volunteers who received 25 mg oral dextro-amphetamine, two symptoms often associated with mania. However, whether amphetamine can trigger other core manic symptoms (e.g., grandiosity, aggressive behaviors, pressured speech) has yet to be demonstrated. Amphetamine has been shown to trigger euphoria in healthy volunteers, mostly due to increased dopamine levels in the anteroventral striatum.

Polymorphisms in the dopamine (DAT1) and norepinephrine (SLC6A2) transporters are known to modulate the mood-elevating effects of amphetamine,.Pharmacological evidence supports the notion that manipulating the dopaminergic system can mimic the symptoms of BPD. Investigators have used a catecholamine depletion strategy employing the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT) in lithium-treated, euthymic patients with BPD to study the pathophysiology of the disorder. Intriguingly, AMPT was not associated with any mood-lowering effects, but was associated with “rebound” hypomanic symptoms.

Although preliminary, these results are compatible with the theory of a dysregulated signaling system wherein the compensatory adaptation to catecholamine depletion results in an “overshoot” due to impaired homeostatic mechanisms. Most recently, McTavish and colleagues found that a tyrosine-free mixture lowered both subjective and objective measures of the psychostimulant effects of methamphetamine or amphetamine, as well as manic symptom scores. These preliminary findings suggest that decreased tyrosine availability to the brain attenuates pathological increases in dopaminergic neurotransmission following methamphetamine administration and, putatively, in mania.Evidence from animal models shows that decreased dopaminergic activity and receptor binding in the mesolimbic cortex and nucleus accumbens is associated with depression-like states that can be reversed by diverse antidepressants that potentiate dopaminergic activity –. In contrast, stimulants with dopaminergic properties (such as amphetamine and cocaine), lead to both manic-like effects and increased sensitization in diverse animal models of BPD. Intriguingly, quinpirole, a D2/D3 agonist, induces a biphasic motor activity response, characterized by initial inhibition followed by hyperactivity, which resembles the switch process in BPD,.Furthermore, psychostimulants exert opposite effects than mood stabilizers on major intracellular signaling cascades, which might also be relevant for the switch process.

For example, increased striatal dopaminergic activity—either in dopaminergic transporter knock-out mice or following amphetamine administration—is mediated by the activation of glycogen-synthase kinase 3 (GSK-3) α and β, whose inhibition is pivotal for the therapeutic actions of lithium and valproate. Psychostimulants also activate protein kinase C (PKC), a family of enzymes that have been associated with the pathophysiology of BPD (reviewed in ). Recent evidence shows that the integrity of the PKC pathway is critical for amphetamine-induced behavioral responses and that PKC inhibition has robust antimanic effects in patients with BPD,.These data are intriguing, as they show converging evidence from clinical and preclinical models regarding the major involvement of the dopaminergic system in mania and mood stabilization. However, whether activation of GSK-3 and PKC pathways is necessary for producing mood switching in patients with BPD is a topic that requires further investigation.

The Hypothalamic-Pituitary-Adrenal Axis (HPA) and switchSince the early 1950s, the administration of HPA exogenous hormones has been reported to produce psychiatric symptoms in some patients with no pre-existing psychiatric disorders. In particular, adrenocorticotropic hormone (ACTH) and cortisone have been associated with mood elevation,. A review of the literature prior to 1983 reported that the incidence of psychiatric symptoms in patients receiving corticosteroids ranged from 5.7 to 27.6% in uncontrolled studies, and 6.3 to 32% in controlled studies. All of these cases were medically ill patients whose onset of psychiatric symptoms occurred within one day to several weeks of initiating treatment with glucocorticoids, and most of the patients developed mania/psychosis. These psychiatric symptoms were clearly induced in a dose-response fashion, with a higher proportion of manic symptoms occurring in patients who received higher doses (80 mg/day). Recent studies have also confirmed this association between corticosteroid administration and psychiatric symptoms. For example, glucocorticoids elevate mood in patients with multiple sclerosis, ophthalmologic diseases, asthma, and also in healthy volunteers.

Notably, higher rates of BPD-like symptoms were usually associated with a positive personal or family history of psychiatric disorders,.Patients suffering from BPD are particularly susceptible to developing hypomanic/manic symptoms after receiving steroids. A recent study reviewing clinical charts from patients referred for a psychiatric consultation found nine patients with BPD whose psychiatric symptoms were precipitated by the use of corticosteroids (prednisone, betamethasone, methylprednisolone); seven of the nine (77%) rapidly developed manic/hypomanic symptoms. Patients with BPD using a beclomethasone inhaler, as well as those using the androgen hormone dehydroepiandrosterone (DHEA), also developed mania. In addition, the single administration of triamcinolone in a celiac plexus block produced manic episodes in two patients with BPD, confirming that susceptible patients can develop manic symptoms after the administration of even a single dose of glucocorticoids, and within a short period of time. This relationship between the administration of glucocorticoids and the switch process is more striking when one considers that the administration of prednisone 40–60 mg on alternate days (in an on–off fashion) induced rapid-cycling symptoms in three patients.

These patients developed manic symptoms on the days they received prednisone; the opposite—a relapse into depression—occurred on the days they did not receive the drug.In addition, hyperactivity of the HPA axis is one of the most replicated biological finding in major depression. Although the evidence for HPA dysfunction in BPD is not as well-validated, several authors have reported abnormalities in urinary and cerebrospinal fluid (CSF) cortisol levels and decreased dexamethasone test suppression in patients with BPD (see for a review). In contrast, this finding is not observed in pure mania,. However, this association does not necessarily implicate a causal relationship, as HPA axis hyperactivity might be an epiphenomenon of mounting mood elevation.Converging evidence from small studies with rapid cyclers or ultra-rapid cyclers in patients with BPD suggest that HPA hyperactivity is critical for the switch from mania to depression in most of these patients, –; however, the role of the HPA axis in switching from depression to mania is more controversial. Notably, transgenic mice overexpressing glucocorticoid receptors in the forebrain displayed enhanced depressive-like behaviors and increased sensitization to cocaine and antidepressants. They also had a wider range of reactivity to stimuli that trigger both negative and positive emotional responses, which might be relevant for the neurobiology of the switch process in BPD.

Findings from other rodent studies, albeit not always consistent, further support the role of glucocorticoid receptors in affective-like behaviors (reviewed in ). Sleep deprivation and switchSleep deprivation has historically been proposed as a final common pathway prior to the onset of mania, and it can be triggered by diverse environmental, psychological, interpersonal, or pharmacological factors associated with the onset of mania. Studies have consistently shown that sleep deprivation produces an acute antidepressant response in as many as 80% of subjects with bipolar depression and 60% of patients with unipolar depression. Spontaneous switch rates after sleep deprivation vary from 10% to 30%, across studies, and this wide range is likely due to sample heterogeneity and the different treatment status of the patients. The fact that sleep deprivation acts quickly makes it an ideal tool to study the molecular basis of the switch process.

However, it remains unclear why sleep deprivation causes temporary recovery in some patients, but triggers manic switches in others, and whether these two phenomena share the same neurobiological mechanism.Sleep deprivation produces several behaviors in rats that suggest it may be a useful model for mania, including insomnia, hyperactivity, irritability, aggressive behavior, novelty seeking preference, and hypersexuality. Moreover, rats exposed to serial sleep deprivation display behavioral sensitization, with worse manic-like symptoms emerging over repetition of the procedure, which parallels clinical findings of increased severity of illness over cumulative relapses in patients with BPD. Sleep deprivation induces few effects at adrenergic or serotonergic receptors, but directly regulates brain dopaminergic receptor sensitivity. Increased plasma norepinephrine and norepinephrine metabolites have also been found in responders to sleep deprivation,. Decreased MHPG levels have also been found in the CSF of sleep deprivation responders compared to nonresponders,. More recent studies have demonstrated that the expression of selected critical genes varies dramatically during sleep and waking, which likely plays a major role in regulating long-term neuroplastic events related to the antidepressant effects of sleep deprivation.

Other neurobiological factors implicated in the switch process: role of circadian rhythmsObservational studies conducted as early as the 1970s hypothesized that a disruption in circadian rhythms in BPD was a core feature of this illness. For example, an early report of patients hospitalized at the National Institute of Mental Health (NIMH) showed that switches into mania were more likely to happen in the morning than at night, suggesting a possible role for circadian factors in this process. Marked alterations in body temperature, sleep patterns, cortisol secretion, thyroid-stimulating hormone (TSH) secretion, and motor activity have been described during episodes of BPD (reviewed in ). Increased motor activity and decreased REM sleep, in particular, were found to strongly predict an imminent manic switch,. According to some researchers, sleep loss might be the final common pathway triggering switches into mania. According to this model, the interaction between sleep reduction and a sleep-sensitive circadian phase interval could promote switches from depression. However, sleep disruption might also be the sign that the manic process is already mounting, rather than the specific trigger.Both genetic and environmental factors might act as susceptibility factors through circadian rhythm regulation, increasing the desynchronization between the central pacemaker (i.e., the suprachiasmatic nucleus) and other internal oscillators.

Increased external desynchronization between the timing of body rhythms and the light-dark cycle has been also hypothesized as a predisposing factor for mood episodes. Interestingly, different mood stabilizers modulate the circadian clock, controlling the expression of genes involved in circadian rhythm regulation. For example, the mood stabilizer lithium inhibits GSK-3, and through this mechanism increases circadian period length,. Studies conducted in Drosophila have shown that the orthologue of GSK-3, a protein called SHAGGY, is an important regulator of circadian cycles. However, studies that have investigated GSK-3 polymorphisms as a putative susceptibility gene for BPD have produced conflicting results –.The CLOCK gene is another major determinant of circadian cycles and might be involved in the switch to mania in patients with BPD; indeed, such evidence has arisen in animal models of BPD. Disruption of the CLOCK gene produces manic-like behaviors in mice, such as hyperactivity, increased reward-value for cocaine and sucrose, and medial forebrain bundle stimulation. In humans, CLOCK gene polymorphisms were shown to be associated with illness recurrence but not with diurnal variation in individuals with BPD.

Thus, it appears that polymorphisms in genes that regulate the circadian clock (e.g., CLOCK), along with sleep disruption and consequent increase in neuroplastic factor expression (pCREB, TrkB, BDNF) might have a substantial impact on mood destabilization leading to manic switch. Conclusions and future perspectivesDespite the fact that the switch phenomenon is a core aspect of the clinical presentation of BPD, as well as fundamentally relevant to its therapeutics, it is still poorly understood. The studies conducted on this issue are unfortunately associated with several methodological limitations, and are often retrospective in nature, or the result of secondary analyses. For example, different definitions of TEAS have been used throughout these studies and may produce dramatically different results in terms of both clinical and biological findings. In order for a systematic study of this topic to be successful, the criteria and threshold of rating scales used will need to be uniform across studies.

Agreement is also needed regarding how long after the beginning of drug treatment a manic episode should be considered as TEAS. Another major limitation in our understanding of the switch process is the lack of appropriate animal models for manic behaviors; preliminary evidence linking glutamate receptor abnormalities with manic-like behaviors in rodents are encouraging in this sense and might provide new evidence about the role of the glutamatergic system in the switch process.For these reasons, results from clinical trials that have investigated the switch potential of different classes of antidepressants are difficult to interpret and subject to controversy among researchers. Even considering these caveats, it appears that drugs that “perturbate” more than one monoaminergic system, such as TCAs and, possibly, venlafaxine, confer a higher risk for TEAS than SSRIs or other second-generation antidepressants. A putative role for the monoaminergic system in the switch process has been suggested by clinical, and preclinical studies, but needs further systematic investigation. Increased catecholamine levels lead to upregulation of factors involved in neuroplasticity cascades and to increased post-synaptic receptor sensitivity, which might ultimately increase the liability to switch (see ). Neurobiology of the switch process: a comprehensive overview of the current evidenceSeveral factors have been associated with the switch process in BPD, but little is known about how these neurobiological variables are interconnected. Psychostimulants, TCAs, SNRIs and sleep deprivation, three interventions that trigger manic switches in a significant proportion of individuals with BPD, are all known to increase catecholamine levels.

Increased catecholamine levels lead to upregulation of factors involved in neuroplasticity cascades and to increased post-synaptic receptor sensitivity, which might ultimately increase the liability to switch. Psychostimulants also act by activating GSK-3 and PKC, two major proteins whose inhibition is important in the mechanism of action of mood stabilizers.Other major determinants of this complex phenomenon include glucocorticoids, which increase cellular vulnerability to different physiological stressors (e.g., glutamatergic-mediated excitoxicity), abnormal glutamatergic transmission, and circadian rhythm instability.