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Medications for Mania & Bipolar Disorder

Medications for Mania & Bipolar Disorder


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Bipolar disorder is characterized by cycling mood changes: severe highs (mania) and lows (depression). Episodes may be predominantly manic or depressive, with normal mood between episodes. Mood swings may follow each other very closely, within days (rapid cycling), or may be separated by months to years. The “highs” and “lows” may vary in intensity and severity and can co-exist in “mixed” episodes.

When people are in a manic “high,” they may be overactive, overly talkative, have a great deal of energy, and have much less need for sleep than normal. They may switch quickly from one topic to another, as if they cannot get their thoughts out fast enough. Their attention span is often short, and they can be easily distracted. Sometimes people who are “high” are irritable or angry and have false or inflated ideas about their position or importance in the world. They may be very elated, and full of grand schemes that might range from business deals to romantic sprees. Often, they show poor judgment in these ventures. Mania, untreated, may worsen to a psychotic state.

In a depressive cycle the person may have a “low” mood with difficulty concentrating; lack of energy, with slowed thinking and movements; changes in eating and sleeping patterns (usually increases of both in bipolar depression); feelings of hopelessness, helplessness, sadness, worthlessness, guilt; and, sometimes, thoughts of suicide.

Lithium

The medication used most often to treat bipolar disorder is lithium. Lithium evens out mood swings in both directions – from mania to depression, and depression to mania – so it is used not just for manic attacks or flare-ups of the illness but also as an ongoing maintenance treatment for bipolar disorder.

Although lithium will reduce severe manic symptoms in about 5 to 14 days, it may be weeks to several months before the condition is fully controlled. Antipsychotic medications are sometimes used in the first several days of treatment to control manic symptoms until the lithium begins to take effect. Antidepressants may also be added to lithium during the depressive phase of bipolar disorder. If given in the absence of lithium or another mood stabilizer, antidepressants may provoke a switch into mania in people with bipolar disorder.

A person may have one episode of bipolar disorder and never have another, or be free of illness for several years. But for those who have more than one manic episode, doctors usually give serious consideration to maintenance (continuing) treatment with lithium.

Some people respond well to maintenance treatment and have no further episodes. Others may have moderate mood swings that lessen as treatment continues, or have less frequent or less severe episodes. Unfortunately, some people with bipolar disorder may not be helped at all by lithium. Response to treatment with lithium varies, and it cannot be determined beforehand who will or will not respond to treatment.

Regular blood tests are an important part of treatment with lithium. If too little is taken, lithium will not be effective. If too much is taken, a variety of side effects may occur. The range between an effective dose and a toxic one is small. Blood lithium levels are checked at the beginning of treatment to determine the best lithium dosage. Once a person is stable and on a maintenance dosage, the lithium level should be checked every few months. How much lithium people need to take may vary over time, depending on how ill they are, their body chemistry, and their physical condition.

Side effects of lithium

When people first take lithium, they may experience side effects such as drowsiness, weakness, nausea, fatigue, hand tremor, or increased thirst and urination. Some may disappear or decrease quickly, although hand tremor may persist. Weight gain may also occur. Dieting will help, but crash diets should be avoided because they may raise or lower the lithium level. Drinking low-calorie or no-calorie beverages, especially water, will help keep weight down. Kidney changes – increased urination and, in children, enuresis (bed wetting) – may develop during treatment. These changes are generally manageable and are reduced by lowering the dosage. Because lithium may cause the thyroid gland to become underactive (hypothyroidism) or sometimes enlarged (goiter), thyroid function monitoring is a part of the therapy. To restore normal thyroid function, thyroid hormone may be given along with lithium.

Because of possible complications, doctors either may not recommend lithium or may prescribe it with caution when a person has thyroid, kidney, or heart disorders, epilepsy, or brain damage. Women of childbearing age should be aware that lithium increases the risk of congenital malformations in babies. Special caution should be taken during the first 3 months of pregnancy.

Anything that lowers the level of sodium in the body – reduced intake of table salt, a switch to a low-salt diet, heavy sweating from an unusual amount of exercise or a very hot climate, fever, vomiting, or diarrhea – may cause a lithium buildup and lead to toxicity. It is important to be aware of conditions that lower sodium or cause dehydration and to tell the doctor if any of these conditions are present so the dose can be changed.

Lithium, when combined with certain other medications, can have unwanted effects. Some diuretics – substances that remove water from the body – increase the level of lithium and can cause toxicity. Other diuretics, like coffee and tea, can lower the level of lithium. Signs of lithium toxicity may include nausea, vomiting, drowsiness, mental dullness, slurred speech, blurred vision, confusion, dizziness, muscle twitching, irregular heartbeat, and, ultimately, seizures. A lithium overdose can be life-threatening. People who are taking lithium should tell every doctor who is treating them, including dentists, about all medications they are taking.

With regular monitoring, lithium is a safe and effective drug that enables many people, who otherwise would suffer from incapacitating mood swings, to lead normal lives.

Anticonvulsants

Some people with symptoms of mania who do not benefit from or would prefer to avoid lithium have been found to respond to anticonvulsant medications commonly prescribed to treat seizures.

The anticonvulsant valproic acid (Depakote, divalproex sodium) is the main alternative therapy for bipolar disorder. It is as effective in non-rapid-cycling bipolar disorder as lithium and appears to be superior to lithium in rapid-cycling bipolar disorder.2 Although valproic acid can cause gastrointestinal side effects, the incidence is low. Other adverse effects occasionally reported are headache, double vision, dizziness, anxiety, or confusion. Because in some cases valproic acid has caused liver dysfunction, liver function tests should be performed before therapy and at frequent intervals thereafter, particularly during the first 6 months of therapy.

Studies conducted in Finland in patients with epilepsy have shown that valproic acid may increase testosterone levels in teenage girls and produce polycystic ovary syndrome (POS) in women who began taking the medication before age 20.3,4 POS can cause obesity, hirsutism (body hair), and amenorrhea. Therefore, young female patients should be monitored carefully by a doctor.

Other Anticonvulsants

Other anticonvulsants used for bipolar disorder include carbamazepine (Tegretol), lamotrigine (Lamictal), gabapentin (Neurontin), and topiramate (Topamax). The evidence for anticonvulsant effectiveness is stronger for acute mania than for long-term maintenance of bipolar disorder. Some studies suggest particular efficacy of lamotrigine in bipolar depression. At present, the lack of formal FDA approval of anticonvulsants other than valproic acid for bipolar disorder may limit insurance coverage for these medications.

Most people who have bipolar disorder take more than one medication. Along with the mood stabilizer – lithium and/or an anticonvulsant – they may take a medication for accompanying agitation, anxiety, insomnia, or depression. It is important to continue taking the mood stabilizer when taking an antidepressant because research has shown that treatment with an antidepressant alone increases the risk that the patient will switch to mania or hypomania, or develop rapid cycling.5 Sometimes, when a bipolar patient is not responsive to other medications, an atypical antipsychotic medication is prescribed. Finding the best possible medication, or combination of medications, is of utmost importance to the patient and requires close monitoring by a doctor and strict adherence to the recommended treatment regimen.

Antidepressants for Bipolar Disorder

To treat depression in persons with bipolar disorder, psychiatrists may prescribe antidepressants. Generally, the use of antidepressants is limited to treatment during depressive episodes. Once the depressive episode has lifted, the antidepressant gradually is decreased.

One type of antidepressant drug works by affecting the level of serotonin in the brain. Serotonin helps regulate appetite, sexual behavior and emotions. Medications affecting serotonin levels include fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), bupropion (Wellbutrin), nefazodone (Serzone) or venlaflaxine (Effexor). SSRIs and Wellbutrin« may be less likely to induce mania and rapid cycling.

Another category of antidepressants is the monoamine oxidase inhibitor. Another type of drug, called tricyclic antidepressants, works by increasing the activity of norepinephrineùanother brain chemical essential for normal moods. They include amitriptyline (Elavil), desipramine (Norpramin, Pertofrane), imipramine (Tofranil), nortriptyline (Pamelor). These drugs, however, are more likely to cause side effects and have a greater risk of being lethal in an overdose.


Principles of Treatment of Bipolar Disorder?

Now that we know something about the illness and how it presents let’s move on to treatment. The treatment of bipolar I and II disorder is essentially the same. The goal of treatment in both cases is to stabilize mood, treat hypomania or mania, treat depression and for the long run prevent relapses back into depression or hypomania/mania. Another key component or goal in treatment is to restore normal functioning. It is not of much value if symptoms appear to have gone away and if the patient is not back to work or a normal life with family and friends.

Before we get to medications a word about therapy. Therapy is important for many reasons not least for ongoing stress management. This illness is very sensitive to stress and it must be kept at a low or at a manageable level. Diet, exercise and sleep are the key components. Diet is important for general wellbeing and to combat the tendency of some medications to induce weight gain. Exercise is important for the brain as it stimulates production of new neurons in key areas. In this it can help the brain to heal literally from the affective episode. Adequate sleep is vital. Sleep deprivation is another stressor. Additionally, it is a frequent culprit in triggering hypomania/mania.


Mental imagery as an emotional amplifier: application to bipolar disorder

Cognitions in the form of mental images have a more powerful impact on emotion than their verbal counterparts. This review synthesizes the cognitive science of imagery and emotion with transdiagnostic clinical research, yielding novel predictions for the basis of emotional volatility in bipolar disorder. Anxiety is extremely common in patients with bipolar disorder and is associated with increased dysfunction and suicidality, yet it is poorly understood and rarely treated. Mental imagery is a neglected aspect of bipolar anxiety although in anxiety disorders such as posttraumatic stress disorder and social phobia focusing on imagery has been crucial for the development of cognitive behavior therapy (CBT). In this review we present a cognitive model of imagery and emotion applied to bipolar disorder. Within this model mental imagery amplifies emotion, drawing on Clark's cyclical panic model [(1986). A cognitive approach to panic. Behaviour Research and Therapy, 24, 461-470]. We (1) emphasise imagery's amplification of anxiety (cycle one) (2) suggest that imagery amplifies the defining (hypo-) mania of bipolar disorder (cycle two), whereby the overly positive misinterpretation of triggers leads to mood elevation (escalated by imagery), increasing associated beliefs, goals, and action likelihood (all strengthened by imagery). Imagery suggests a unifying explanation for key unexplained features of bipolar disorder: ubiquitous anxiety, mood instability and creativity. Introducing imagery has novel implications for bipolar treatment innovation--an area where CBT improvements are much-needed.


Apps in Clinical Psychology

Other Apps of Interest

Up! Depression, Bipolar & Borderline Management: the app is a highly automated mood diary designed for individuals with bipolar disorder, rapid cycling or mixed episodes, borderline personality disorder, cyclothymia and recurrent depression. The UP! mood diary automatically keeps a journal of physical activity, work-life-balance, sleeping habits and social activity and implicitly implements psycho-educative and CBT approaches. Users' personal early warning signs for hypomania, mania or depression are automatically displayed when they report an unusually depressed or elevated mood, and the app also provides customizable reminders and reports. The app also has options to connect the user's profile with health professionals and/or friends for communication.

Mood Tools: this free app is designed for individuals struggling with clinical depression and provides six CBT-based tools to improve users' mood and functioning: (1) psychoeducation about depression (2) guided meditations and inspirational talks (3) a Thought Diary to guide users to observe and change problematic thinking patterns (4) an activities log with suggestions for increasing healthy behaviors (5) a mood tracker with an electronic version of the PHQ-9 test and (6) a safety planner that lets users store a set of resources should they find themselves in crisis.

iCBT: the app is designed to be used in conjunction with CBT treatment. The process begins with logging an event. The app prompts the users to describe what happened, to select their feelings from a list of options and then to rate the intensity of their feelings and to describe their negative thoughts. After doing so, users are asked to reappraise the event previously entered by identifying potential distortions from a list and then by typing their reappraised thought. Finally users are encouraged to ask themselves a series of challenge questions (e.g. “Am I positive this will happen?”) and then to log the intensity of their feelings again and to record the actual outcome of the event. All the contents are adopted from a CBT book ( Sank and Shaffer, 1984 . A Therapist's Manual for Cognitive Behavior Therapy in Groups.)


What are symptoms of bipolar mania?

  • Euphoria or irritability
  • Excessive talking racing thoughts
  • Inflated self-esteem
  • Grandiose thoughts
  • Unusual energy less need for sleep
  • Impulsiveness, a reckless pursuit of gratification -- shopping sprees, impetuous travel, more and sometimes promiscuous sex, high-risk business investments, fast driving and or delusions (psychotic features such as these may be involved in about one out of every two of cases of bipolar mania)

The bipolar prodrome

Danella M. Hafeman , Boris Birmaher , in Bipolar Disorder Vulnerability , 2018

Questionnaires/Assessments

Based on a growing knowledge base about the symptoms that predict new-onset bipolar disorder, several scales and instruments have been developed to characterize better this risk. Many of these were reviewed recently ( Ratheesh, Berk, Davey, McGorry, & Cotton, 2015 ) while a few of these questionnaires showed promise in a single study, e.g., the General Behavioral Inventory (GBI) and the Manic Symptom Subscale of the Child Behavioral Checklist (CBCL-MS), none was replicated in high-quality studies. Scales used to screen for bipolar disorder in youth, a closely related though not identical problem, have been evaluated elsewhere ( Youngstrom et al., 2004 ). These authors found that, in general, parent report of manic symptoms better distinguished youth with bipolar disorder from healthy controls than either youth or teacher reports. Here, we discuss scales and assessments that have been used in the attempt to predict onset of bipolar disorder. The list below is meant to be not a comprehensive review of questionnaires that could potentially predict bipolar disorder, but rather an overview of strategies that investigators have used to estimate the risk of conversion, and the degree to which these have been validated in prospective studies.

Child Behavior Checklist (CBCL) subscales (parent-report): One longitudinal study found that a high score on CBCL subscales of attention, aggression, and anxiety/depression predicted new-onset bipolar disorder in youth with ADHD ( Biederman et al., 2009 ) thus they termed this the pediatric bipolar disorder subscale. However, these authors and others found that high scores on this scale predicted not only bipolar disorder, but also other disorders such as depression and conduct disorder ( Diler et al., 2009 Meyer et al., 2009 ) the scale also predicted severity of disorder and poor function, and thus seems to be an indicator of general psychopathology. As such, it is now more often called the dysregulation profile ( Althoff, Verhulst, Rettew, Hudziak, & van der Ende, 2010 ). More recently, Papachristou et al. (2013) developed the CBCL mania scale (CBCL-MS), based on 19 items from the CBCL ( Table 1 ) the scale was found to have high internal consistency, and to discriminate between youth with BD-I and healthy controls (AUC = 0.64) ( Papachristou et al., 2013 ). Youth with BD-I also had higher scores on the CBCL-MS than youth with anxiety (P = .004) and major depressive disorder (P = .002), but not compared to youth with ODD or ADHD. In a longitudinal community study of Dutch adolescents, the authors found that those in mildly and highly symptomatic classes (based on their CBCL-MS scores at age 11) were at a twofold and fivefold risk, respectively, to develop new-onset bipolar disorder by the age of 19 ( Papachristou et al., 2017 ). After adjustment for confounders, this scale was not predictive of new-onset anxiety or depression, though those in the highly symptomatic class were more likely to have diagnoses of ADHD, oppositional defiant disorder (ODD), and conduct disorder.

Table 1 . Studies of bipolar disorder offspring with longitudinal follow-up

StudyParticipantsFollow-upRecruitment sourceAssessment toolsAt-risk vs healthy controlsPredictors of new-onset BD
Amish ( Egeland et al., 2003, 2012 Shaw et al., 2005 )115 at-risk 106 controls, 8 at-risk developed BD-I16 yearsCommunityCARE—Semistructured interview blindedCompared to control children, those with BD parent had more problems with attention, energy (high and low), sleep, and talkativenessThose who later developed BD had more “sensitive” temperament as preschool children, as well as more anxiety/worry later, lower mood, lower energy, and decreased sleep were evident in those who converted
Dutch ( Hillegers et al., 2005 Mesman et al., 2013 Mesman, Nolen, et al., 2017 )140 at-risk 4 with BD-I/II at intake, 8 developed over follow-up12 yearsSurvey + hospitalsKSADS GBI YSR CBCL not blindedDid not find increased CBCL scores relative to normative samples, but they did not recruit and follow a control sampleNew-onset bipolar disorder was mostly preceded by episode of depression depressive symptoms (as measured by the General Behavioral Inventory) predicted new-onset bipolar disorder subthreshold manic symptoms predicted bipolar onset in offspring with mood disorder
Ontario Cohort ( Duffy et al., 2007, 2014 , Duffy, Alda, Hajek, Sherry, &amp Grof, 2010 )229 at-risk (133 LiR, 96 LiNR) and 86 controls 8 with BD at intake, 31 lifetime BD16 yearsOutpatient clinicsKSADS blindedHigher risk for anxiety and mood disordersAnxiety disorders predicts mood disorders in general bipolar disorder generally debuts with a depressive episode
Pittsburgh Bipolar Offspring Study ( Axelson et al., 2015 Birmaher et al., 2013 Birmaher, Axelson, Monk, et al., 2009 Diler et al., 2011 Hafeman et al., 2016 Levenson et al., 2015, 2017 Sparks et al., 2014 )359 at-risk and 220 controls 33 had BD at baseline, 44 with new-onset12 yearsAdvertisements, research studies, outpatient clinicsKSADS CALS MFQ SCARED CBCL SSHS blindedMore mood lability, internalizing and externalizing symptoms in at-risk vs controls. Also higher rates of anxiety, disruptive behavioral disorders, ADHD, major depressive episodes (but not MDD)Diagnostic predictors of BD: subthreshold manic episode, major depression, disruptive behavior disorder. Dimensional predictors: subthreshold manic symptoms, anxiety/depression, mood lability. Sleep difficulties also predicted new-onset BP
Pittsburgh Bipolar Offspring Study—Preschool Study (2–5 years) ( Birmaher et al., 2010 Maoz, Goldstein, Axelson, et al., 2014 )122 at-risk, 102 controlsOngoing only baseline reportedAdvertisements, research studies, outpatient clinicsCBCL ECI-4 EASMore aggression, mood dysregulation, sleep disturbances, and somatic complaints higher rates of ADHDn/a
Australia Cohort ( Perich et al., 2015 )118 at-risk, 110 controlsOngoing only baseline reportedAdvertisements, research studies, outpatient clinics consumer organizationsK-SADS-PL DIGS v4 (for adults)Higher rates of depressive, anxiety, and behavioral disorders in at-riskn/a
Multisite NIMH-Funded Cohort ( Nurnberger Jr et al., 2011 )141 at-risk, 91 controlsOngoing only baseline reportedGenetic studiesK-SADS-PLHigher rates of affective disorders in general, and bipolar disorderRetrospective assessment: anxiety and externalizing disorders predicted major affective disorder, but only in at-risk offspring
( Radke-Yarrow et al., 1992 )44 at-risk, 72 controls (+ 82 offspring of mother with MDD)3 yearsDaycare centers, advertisements, outpatient clinicsCBCL CASHigher rates of depression, anxiety, and disruptive behavioral disorders in at-risk (also in offspring of MDD)n/a
( Hammen et al., 1987, 1990 )18 at-risk, 38 controls + offspring of mothers with MDD (n = 19) and medical illness (n = 18)3 yearsInpatient units, outpatient clinics, private referralsK-SADSHigher rates of mood d/o (67%) and MDD (22%) than controls (17% and 11%, respectively)n/a
( LaRoche et al., 1985, 1987 )39 at-risk3 yearsOutpatient clinicsChildren’s Psychiatric Rating Scale18% mood disorder 13% “cyclothymic traits”n/a

BD, Bipolar Disorder CARE, Child and Adolescent Research Evaluation CAS, Child Assessment Scale CBCL, Child Behavioral Checklist DIGS, Diagnostic Interview for Genetic Studies EAS, Emotionality Activity Sociability Survey ECI-4, Early Childhood Inventory-4 K-SADS-PL, Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Aged Children LiNR, Offspring of lithium-nonresponsive parent LiR, Offspring of lithium-responsive parent MD, Major Depressive Disorder.

Bipolar Prodrome Symptom Interview and Scale (BPSS clinician-administered): Correll et al. (2007) initially developed a retrospective version of this scale, which included 36 items that assessed subthreshold symptoms of mania, depression, and psychosis. In 52 individuals with child- or adolescent-onset mania, the authors found that all participants had experienced at least one moderately severe manic symptom prior to onset. While approximately half had an “insidious” onset (> 1 year of symptoms), most of the remainder had a “subacute” onset (1 month to 1 year) only a small minority (3.8%) had less than a month of symptoms prior to onset. Most common symptoms were subthreshold manic symptoms (irritability, racing thoughts, and increased energy) and depressed mood. The prospective version of this scale (BPSS-P) was developed more recently, and has also been shown to discriminate well between bipolar disorder, other psychopathology, and healthy controls, with expected correlations with other scales of mania and depression ( Correll, Olvet, et al., 2014 ). The prospective utility of this scale has not yet been evaluated.

General Behavioral Inventory (GBI), Revised (self-report and parent-report): This extensive inventory was developed to screen for bipolar disorder and unipolar depression ( Depue, Krauss, Spoont, & Arbisi, 1989 ) it consists of two subscales, assessing depression and hypomanic/biphasic symptoms. In the Dutch cohort of bipolar offspring, more severe scores on the depression subscale was found to predict future bipolar disorder (vs unipolar depression, nonmood disorders, and no disorder) in the next 5 years the hypomanic/biphasic scale was not predictive ( Reichart et al., 2005 ). The authors provide several explanations for this, including the low power (only nine conversions to bipolar disorder). Several scales have been developed based on the GBI, including shortened scales ( Mesman, Youngstrom, Juliana, Nolen, & Hillegers, 2017 ), a shortened parent-report of the GBI ( Youngstrom, Frazier, Demeter, Calabrese, & Findling, 2008 ), and self-report of the GBI in adolescents ( Danielson, Youngstrom, Findling, & Calabrese, 2003 ). While many of these adaptations have shown promise regarding screening and discrimination between disorders, they have not yet been evaluated in a longitudinal study to determine if high scores are predictive of new-onset bipolar disorder.

Hypomanic Personality Scale (self-report): This is a measure of an “overactive, gregarious style” of interacting with others ( Eckblad & Chapman, 1986 ) that was found to predict bipolar disorder at 13-year follow-up: 25% (9/36) with the highest scores developed bipolar disorder ( Kwapil et al., 2000 ) however, it was not predictive of bipolar disorder in another larger sample ( Klein, Lewinsohn, & Seeley, 1996 )

Bipolar At-Risk Criteria (clinician-administered): Building on previous findings about risk for bipolar disorder, Bechdolf and colleagues defined the Bipolar At-Risk (BAR) Criteria to be: (1) subthreshold manic symptoms (≥ 2 days, < 4 days) (2) depression (× 1 week) + cyclothymia or (3) depression (× 1 week) + family history of bipolar. They prospectively evaluated 35 adults who met this criteria, along with 35 controls, for 12 months while 5 in the BAR group converted, none in the non-BAR group developed bipolar disorder ( Bechdolf et al., 2014 ).

BIS/BAS (self-report): The Behavioral Approach System (BAS) is central to motivation to obtain and response to reward, and is thought to be hypersensitive in individuals with and at-risk for bipolar disorder. To test whether BAS hypersensitivity would predict new-onset bipolar disorder, Alloy and colleagues assessed community adolescents for reward sensitivity, using the BAS subscales of the BIS/BAS and the reward sensitivity subscale of the Sensitivity to Reward/Punishment Questionnaire). In a year of follow-up, 12.3% (21/171) of the adolescents in the High BAS group (highest 15th percentile on both scales) developed bipolar spectrum disorder vs 4.2% (5/119) in the Medium BAS group ( Alloy, Bender, et al., 2012 ). Thus the BIS/BAS, in combination with another measure of reward sensitivity, predicted bipolar disorder onset in adolescents.

CALS (self-report and parent-report): The Child Affective Lability Scale (CALS) was developed by Gerson et al. (1996) it includes both self- and parent-report versions that assess for sudden and intense changes in mood. Based on an analysis from the Pittsburgh Bipolar Offspring Study, the CALS has three factors (anxiety/depression, irritability, and mania), all of which were highest in offspring with bipolar disorder, intermediate in nonbipolar offspring of parents with bipolar disorder, and lowest in control offspring the irritability factor was most important ( Birmaher et al., 2013 ). The CALS score was also found to predict new-onset bipolar disorder over follow-up ( Hafeman et al., 2016 ).

In summary, many scales have been developed to assess part or all of the bipolar prodrome. While none has yet been replicated in high-quality prospective trials, many of these scales have been shown to predict new-onset bipolar disorder in at least one longitudinal study. A further consideration for the value of these scales is whether they are transportable to a community setting. Several of these scales are self- or parent-reports that are free and available for use, and can easily be integrated into a community psychiatry evaluation. The clinician-administered assessments are more laborious, and require training, but also represent potential tools for the clinician (and/or researcher) to assess bipolar disorder risk.


SIGNALING NETWORKS: THE CELLULAR COGWHEELS UNDERLYING LONG-TERM NEUROPLASTICITY

More recently, research into the pathophysiology and treatment of mood disorders has moved from a focus on neurotransmitters and cell surface receptors to intracellular signaling cascades.

Multicomponent, cellular signaling pathways interact at various levels, thereby forming complex signaling networks which allow the cell to receive, process, and respond to information (49-51). These networks facilitate the integration of signals across multiple time scales, the generation of distinct outputs depending on input strength and duration, and regulate intricate feed-forward and feedback loops (49- 51). Given their widespread and crucial role in the integration and fine-tuning of physiologic processes, it is not surprising that abnormalities in signaling pathways have now been identified in a variety of human diseases (2,52,53). Furthermore, signaling pathways represent major targets for a number of hormones, including glucocorticoids, thyroid hormones, and gonadal steroids (2,52). These biochemical effects may play a role in mediating certain clinical manifestations of altered hormonal levels in mood disorder subjects (e.g. the frequent onset of bipolar disorder in puberty, triggering of episodes in the postpartum period, association of depression and potentially rapid cycling with hypothyroidism, and triggering of affective episodes in response to exogenous glucocorticoids).

Complex signaling networks may be especially important in the CNS, where they 'weigh' and integrate diverse neuronal signals and then transmit these integrated signals to effectors, thereby forming the basis of a complex information processing network (49-51). The high degree of complexity generated by these signaling networks may be one mechanism by which neurons acquire the flexibility for generating the wide range of responses observed in the nervous system. These pathways are thus undoubtedly involved in regulating such diverse vegetative functions as mood, appetite and wakefulness and are therefore likely to be involved in the pathophysiology of BD. We now turn to a discussion of the direct and indirect evidence supporting a role for abnormalities in signaling pathways in the pathophysiology and treatment of BD.

The Gs/cAMP generating signaling pathway

Several independent laboratories have now reported abnormalities in G protein subunits in BD (54,55). Postmortem brain studies have reported increased levels of the stimulatory G protein (Gαs) accompanied by increases in post-receptor stimulated adenylyl cyclase (AC) activity in BD (55,56). Several studies have also found elevated Gαs protein levels and mRNA levels in peripheral circulating cells in BD, although the dependency on clinical state remains unclear (45,55,57-60). It should be emphasized, however, that there is at present no evidence to suggest that the alterations in the levels of Gαs are due to a mutation in the Gαs gene itself (61). There are numerous transcriptional and post-transcriptional mechanisms which regulate the levels of G protein subunits, and the elevated levels of Gαs could potentially represent the indirect sequelae of alterations in any one of these other biochemical pathways (54,55,57,62).

There is growing consensus that the ability of a 'simple' monovalent cation like lithium to treat multiple aspects of an illness as complex as BD arises from its major effects on intracellular signaling pathways, rather than on any single neurotransmitter system per se (9,44,60). Although it appears that the lithium ion (at therapeutic concentrations) does not directly affect G protein function, there is considerable evidence that chronic lithium administration affects that function (9,44). Although some studies have reported modest changes in the levels of G protein subunits, the preponderance of the data suggests that chronic lithium does not modify G protein levels per se, but rather modifies G protein function (62,63). Although speculative, it might be postulated that these G protein effects - which would theoretically attenuate excessive signaling through multiple pathways - likely contribute to lithium's long-term prophylactic efficacy in protecting susceptible individuals from spontaneous-, stress-, and drug (e.g. antidepressant, stimulant)- induced cyclic affective episodes.

The protein kinase C signaling pathway

Protein kinase C (PKC) exists as a family of closely related subspecies, has a heterogenous distribution in brain (with particularly high levels in presynaptic nerve terminals), and, together with other kinases, appears to play a crucial role in the regulation of synaptic plasticity and various forms of learning and memory (64-67). PKC is one of the major intracellular mediators of signals generated upon external stimulation of cells via a variety of neurotransmitter receptors (including muscarinic M1, M3, M5 receptors, noradrenergic 㬑 receptors, metabotropic glutamatergic receptors, and serotonergic 5-HT2A receptors), which induce the hydrolysis of various membrane phospholipids.

To date, there have only been a limited number of studies directly examining PKC in BD (68). Although undoubtedly an over-simplification, particulate (membrane) PKC is sometimes viewed as the more active form of PKC, and thus an examination of the subcellular partioning of this enzyme can be used as an index of the degree of activation. Friedman et al (69) investigated PKC activity and PKC translocation in response to serotonin in platelets obtained from BD subjects before and during lithium treatment. They reported that the ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. With respect to brain tissue, Wang and Friedman (70) measured PKC isozyme levels, activity and translocation in post-mortem brain tissue from BD patients they reported increased PKC activity and translocation in BD brains compared to controls, effects which were accompanied by elevated levels of selected PKC isozymes in cortices of BD subjects.

Evidence accumulating from various laboratories has clearly demonstrated that lithium, at therapeutically relevant concentrations, exerts major effects on the PKC signaling cascade. Currently available data suggest that chronic lithium attenuates PKC activity, and downregulates the expression of PKC isozymes α and ε in frontal cortex and hippocampus (62,71). Chronic lithium has also been demonstrated to dramatically reduce the hippocampal levels of a major PKC substrate, MARCKS (myristoylated alanine rich C kinase substrate), which has been implicated in regulating long-term neuroplastic events (62,71). Although these effects of lithium on PKC isozymes and MARCKS are striking, a major problem inherent in neuropharmacologic research is the difficulty in attributing therapeutic relevance to any observed biochemical finding. It is thus noteworthy that the structurally dissimilar antimanic agent VPA produces very similar effects as lithium on PKC α and ε isozymes and MARCKS protein (63,71). Interestingly, lithium and VPA appear to bring about their effects on the PKC signaling pathway by distinct mechanisms. These biochemical observations are consistent with the clinical observations that some patients show preferential response to one or other of the agents, and that one often observes additive therapeutic effects in patients when the two agents are co-administered.

In view of the pivotal role of the PKC signaling pathway in the regulation of neuronal excitability, neurotransmitter release, and long-term synaptic events (68,72), it was postulated that the attenuation of PKC activity may play a role in the antimanic effects of lithium and VPA. In a pilot study it was found that tamoxifen (a non-steroidal antie- strogen known to be a PKC inhibitor at higher concentrations (73)) may, indeed, possess antimanic efficacy (74). Clearly, these results have to be considered preliminary, due to the small sample size thus far. In view of the preliminary data suggesting the involvement of the PKC signaling system in the pathophysiology of BD, these results suggest that PKC inhibitors may be very useful agents in the treatment of mania. Larger double-blind placebo-controlled studies of tamoxifen and of novel selective PKC inhibitors in the treatment of mania are warranted.

Abnormalities of calcium signaling

Calcium ions play a critical role in regulating the synthesis and release of neurotransmitters, neuronal excitability, and long-term neuroplastic events, and it is thus not surprising that a number of studies have investigated intracellular Ca 2+ in peripheral cells in BD (54,75). These studies have consistently revealed elevations in both resting and stimulated intracellular Ca 2+ levels in platelets, lymphocytes and neutrophils of patients with BD. The regulation of free intracellular Ca 2+ is a complex, multi-faceted process, and the abnormalities observed in BD could arise from abnormalities at a variety of levels (54). Ongoing studies should serve to delineate the specific regulatory sites at which the impairment occurs in BD.


Treatment Options in Bipolar Disorder: Mood Stabilizers

Noncompliance is probably the single most common reason for the failure of Li therapy. The first year after starting Li is a particularly high-risk period for noncompliance. [3] Patients may miss the elevated mood and the good feelings that are part of the disorder. Poor adherence to the drug regimen can also arise as a result of confusion secondary to the illness itself, or even as a side effect of drug treatment. For example, altered cognition, perception, and mood can predispose to noncompliant behavior. Adverse drug effects are also a major reason for noncompliance. Because the impact of noncompliance can be as devastating as that of nontreatment, it is imperative to prevent noncompliance, and to recognize it and intervene when it occurs. [3,7,8]

Accurate diagnosis and aggressive pharmacotherapy are especially important for younger patients, to help them to avoid disruption of social development and compromise of educational and occupational opportunities. Younger patients tend to be less compliant than older patients. [3,7,9]

Since noncompliance is reversible, unlike poor therapeutic response, education and counseling can effect improvement in symptoms. Educating patients about the importance of adhering to an effective drug regimen and making sure they understand the implications of discontinuing therapy are essential. [1,2,3]

Psychological interventions are also necessary for helping patients cope with the potentially devastating changes in self-perception and, often, in their interpersonal relationships. [10,11] Moreover, patients frequently use different criteria to judge treatment success than clinicians do. Such criteria as fewer or no hospitalizations or less need for adjunctive neuroleptics/antidepressant agents or even mood stabilizers represent treatment success for patients. Clinicians, on the other hand, focus on comparative effects of 1 drug over another (eg, differences between Li and anticonvulsants) or on the differences between treated and untreated illness. Day-to-day problems can be as compelling in determining patients' feelings about medications as dramatic differences in symptoms. Whereas the clinician may conclude that a given medication has excellent efficacy, the patient who continues to experience disruptive and upsetting mood swings will interpret the same evidence much more equivocally. [1,2,3]

Psychotherapy is also indicated as an adjunct to medication to help patients understand their illness and the role temperament plays, and to help them deal with issues of control. [10,11] Supportive interventions range from a brief consult with the prescribing physician to formal (individual and/or group) psychotherapy sessions. Indeed, the therapeutic relationship between patient and prescribing physician is often key to the patient's continued adherence to the maintenance regimen. Self-help groups and family counseling are also useful modalities.

Patients must be alerted to the symptoms of impending episodes, such as altered sleep patterns that often precede, accompany, or precipitate mania. They should be counseled to avoid situations that are likely to disrupt sleep and should be encouraged to establish and maintain a regular rhythm for activities of daily living--including meals, exercise, sleeping, and waking. A single night of unexplainable sleep loss should be taken as an early warning of possible impending mania. Not only do patients need to be forewarned about early symptoms, they need to be able to recognize drug side effects in order to address them and consult with their physician about the most appropriate management plan. [1,2,3,7]


A profile approach to impulsivity in bipolar disorder: the key role of strong emotions

Sheri L. Johnson, Department of Psychology, 3210 Tolman Hall, University of California, Berkeley, CA 94720, USA.

Department of Psychology, University of Miami, Coral Gables, FL, USA

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

Department of Psychology, University of California, Berkeley, CA, USA

Department of Psychology, University of California, Berkeley, CA, USA

Sheri L. Johnson, Department of Psychology, 3210 Tolman Hall, University of California, Berkeley, CA 94720, USA.

Department of Psychology, University of Miami, Coral Gables, FL, USA

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

Abstract

Objective

Bipolar disorder has been associated with elevated impulsivity – a complex construct subsuming multiple facets. We aimed to compare specific facets of impulsivity in bipolar disorder, including those related to key psychological correlates of the illness: reward sensitivity and strong emotion.

Method

Ninety-one individuals diagnosed with bipolar I disorder (inter-episode period) and 80 controls completed several well-validated impulsivity measures, including those relevant to reward (Fun-seeking subscale of the Behavioral Activation System scale) and emotion (Positive Urgency and Negative Urgency scales).

Results

Bipolar participants reported higher impulsivity scores than did controls on all of the impulsivity measures, except the Fun-seeking subscale of the Behavioral Activation System scale. Positive Urgency – a measure assessing the tendency to act impulsively when experiencing strong positive emotion – yielded the largest group differences: F(1,170) = 78.69, P < 0.001, partial η 2 = 0.316. Positive Urgency was also associated with poorer psychosocial functioning in the bipolar group: ΔR 2 = 0.24, b = −0.45, P < 0.001.

Conclusion

Individuals with bipolar I disorder appear to be at particular risk of behaving impulsively when experiencing strong positive emotions. Findings provide an important first step toward developing a more refined understanding of impulsivity in bipolar disorder with the potential to inform targeted interventions.