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    {
        "text": "1. INTRODUCTION > Figure 1. > paragraph id: 1\n\n > Figure Caption: Hierarchical rankings of treatment recommendations: How were they arrived at? Figure 1. What are hierarchical rankings? Hierarchical rankings of treatment options are new to the 2018 Guidelines. They were created for first and second line treatment recommendations for acute mania, depression, and maintenance treatment of bipolar I disorder; and will further assist clinicians in making evidence based treatment decisions. These orders were created by considering the efficacy of each treatment across all phases, as well as acute and maintenance safety and tolerability and the risk for treatment emergent switch. Thus, for example if two treatments were shown to be similarly effective in acute mania, and if only one of these treatments has demonstrated efficacy for maintenance treatment, or had better safety or tolerability, that treatment would be placed higher in the hierarchical recommendation. When making treatment decisions, we recommend that agents listed higher in the hierarchy be tried first, unless there are patient-specific reasons for choosing an agent lower in the order (such as patient preference, prior treatment non/response, or clinical features which favor treatments lower in the ranking). \n",
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        "text": "4. ACUTE MANAGEMENT OF BIPOLAR DEPRESSION > 4.4. Pharmacological treatment for acute bipolar depression > 4.4.2. Step 2: initiate or optimize therapy and check adherence > First-line > Figure 2. > paragraph id: 2\n\n >  # Figure 2. Why are lithium and lamotrigine recommended as first-line agents for bipolar depression? Reconciling conflicting data ## Lithium \n\nIn the only large double blind placebo controlled trial conducted to date, lithium was not more effective than placebo for treating acute bipolar depression(254). So, how does one justify recommending lithium as a first-line agent? \n\n The mean serum lithium levels in this study was only 0.61 mEq/L and this may account for lack of efficacy as a previous study demonstrated that lithium monotherapy was as effective as lithium plus paroxetine in those with serum lithium levels of Š0.8 mEq/L (247).\n\nFurther, several small crossover trials demonstrated significantly higher response rates to lithium than placebo in patients with acute bipolar depression (245). As well, the STEP-BD study suggested that mood stabilizers which include lithium are as effective as mood stabilizers plus antidepressants in treating acute bipolar depression, although the durable recovery rate was modest, and there was no sub analysis focusing on lithium versus other antimanic drugs (246). Thus, the findings of these studies justify a Level 2 rating of efficacy for lithium. \n\n Given that lithium also has clearly demonstrated efficacy in preventing mood episodes and in treating acute mania, our hierarchical ranking thus justifies lithium as an important first-line agent for bipolar depression, and based on overall evaluation of available studies, it is our opinion that a trough lithium serum level of 0.8-1.2 mEq/L would be needed for clinical effectiveness. \n\n## Lamotrigine \n\n Lamotrigine monotherapy was not superior to placebo in four double blind placebo controlled trials of acute bipolar depression on the primary outcome (254). However, a meta-analysis conducted on the response rates from these studies as well as a BDII trial showed superiority of lamotrigine (248). Moreover, methodological issues with the trials likely led to the effect of lamotrigine being underestimated-including the relatively low final dose (200 mg in most trials, which is lower that usually used in clinical practice) (255) and short trial duration (8 weeks in most trials) which, coupled with the slow titration of lamotrigine, resulted in participants being on the final dose for only a short period (around two weeks). Further, lamotrigine was superior to placebo on Montgomery–Åsberg Depression Rating Scale (MADRS) in one of the studies (249), and changes in symptoms on this scale have since been used to demonstrate the efficacy of other agents for acute bipolar depression. Finally, the addition of lamotrigine to lithium (253) was superior to adding placebo to lithium and there was a trend for superiority of addition of lamotrigine to quetiapine vs placebo add on (252) in treating bipolar depression. It is likely that these beneficial effects are due to the direct effect of lamotrigine and not due to pharmacokinetic interaction between lamotrigine and concomitant medications. Furthermore, trial design issues, especially the fact that the six-week dose titration phase took up most of the 8 week trials, is likely to compromise efficacy signals. Lastly, the short and long-term tolerability of lamotrigine is a major benefit. Taken together, we believe these data justify at least a Level 2 rating for lamotrigine for acute bipolar depression. \n\n In addition to this Level 2 rating for bipolar depression, lamotrigine also has demonstrated efficacy in maintenance treatment and an excellent tolerability profile - features which qualify it to be a first-line treatment for bipolar depression. \n\nFigure Caption: Lithium and lamotrigine as first-line agents for bipolar I depression: Summary of evidence> [Colour figure can be viewed at http://wileyonlinelibrary.com]\n",
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        "text": "4. ACUTE MANAGEMENT OF BIPOLAR DEPRESSION > 4.4. Pharmacological treatment for acute bipolar depression > 4.4.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Figure 3. > paragraph id: 3\n\n >  # Figure 3. Why are armodafinil and modafinil third-line treatments for bipolar I depression? \n\n Armodafinil adjunctive therapy was assessed in three double blind randomized controlled trials. Of these, one was positive (270) but in the other two studies, it failed to separate from placebo on the primary efficacy measure (286, 287) although in one of the trials several secondary outcomes were positive (288). Furthermore, in a fourth trial, there was also suggestion of efficacy based on some secondary measures (289). Therefore, although two trials were negative on the primary efficacy measure, based on one positive trial and some positive secondary outcomes in two trials, this was given a Level 4 rating (expert opinion), and recommended as a third-line. \n\n Although modafinil has been shown to be efficacious in the only trial (269), it was also recommended a third-line in light of the three negative trials for armodafinil. \nFigure Caption: Armodafinil and modafinil as third-line agents for bipolar I depression: Summary of evidence [Colour figure can be viewed at http://wileyonlinelibrary.com]\n",
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            "headings": "4. ACUTE MANAGEMENT OF BIPOLAR DEPRESSION > 4.4. Pharmacological treatment for acute bipolar depression > 4.4.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Figure 3.",
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        "text": "5. MAINTENANCE THERAPY FOR BIPOLAR DISORDER > 5.5. Pharmacological treatments for maintenance therapy > 5.5.2. Step 2: initiate or optimize therapy and check adherence > First-line > Figure 4. > paragraph id: 4\n\n >  # Figure 4. Why is divalproex recommended as a first-line maintenance treatment for bipolar I disorder? \n\n In the only large double-blind placebo controlled RCT of divalproex monotherapy (373), it was not more effective than placebo in preventing relapse of mood episodes i.e. time to any mood episode. However, in this trial, lithium which has been shown in many other studies to be effective in relapse prevention, was also found to be no more effective than placebo. Thus, these results suggest that this trial was a failed trial and not a negative trial. \n\n Most modern studies of maintenance therapy use enriched design, meaning that those that responded in acute phase to the medication being tested are randomized to continuation of the same drug or replacement with placebo. This practice to a large extent mirrors clinical practice as clinicians are likely to continue the medication that worked in the acute phase for maintenance treatment. Interestingly, in the divalproex RCT, some but not all patients that were randomized into the double-blind phase were divalproex responders. In a post-hoc analysis of this study, in this enriched subgroup of patients that responded to divalproex during the acute phase and randomized to continuation of divalproex vs switch to placebo, divalproex was more effective in preventing relapse of mood episodes compared with placebo. \n\n Further, divalproex was superior to placebo on a number of other secondary efficacy measures such as lower rates of discontinuation for any mood episode or a depressive episode. Surprisingly, there was also a trend for superiority of divalproex relative to lithium in time to any mood episode. Other RCTs have shown that divalproex is as effective as lithium (221) in preventing relapse of mood episodes. \n\n As well, two meta-analysis have concluded that divalproex is effective in preventing relapse of mood episodes (370, 372), and a population based cohort study in the UK showed that there were no differences in efficacy between divalproex, quetiapine and olanzapine in the maintenance treatment of bipolar disorder (359). \n\nTaken together, we believe these efficacy data support our rationale for a Level 1 rating. This along with clinical experience, real world cohort data, and safety, justify our recommendation of divalproex as a first-line maintenance treatment. \nFigure Caption: Divalproex as a first-line maintenance therapy for bipolar I disorder: Summary of evidence RCT, randomized controlled trial [Colour figure can be viewed at http://wileyonlinelibrary.com]\n\nAbbreviations: RCT: Randomized controlled trial\n\n",
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        "text": "6. BIPOLAR II DISORDER > 6.2. Pharmacological treatment of bipolar II disorder > 6.2.3. Acute management of bipolar II depression > Second-line > Figure 5. > paragraph id: 5\n\n >  # Figure 5. Why is lithium recommended as a second-line agent for bipolar II depression? Reconciling conflicting data \n\n In a 16-week double blind RCT, lithium was as effective as sertraline and lithium + sertraline combination (427) which qualifies lithium for Level 2 evidence. Additional supporting data come from a single-blinded trial which showed that lithium was as effective as lamotrigine in treating BDII depression over 6 weeks (445). However, neither of these studies had a placebo arm. Positive placebo-controlled data come from 4 small placebo-controlled crossover studies conducted in the 1960s and 1970s, in which lithium was effective in a mixed sample of BDI and BDII depressed patients (446-449). Results were reported separately for BDII in 2 of the studies and were identical to BDI (pooled response rate = 65% for both) (446). \n\n In contrast, in the only modern a placebo-controlled parallel group study, lithium was not superior to placebo in BDII depression (254). Further, lithium was less effective than venlafaxine in a 12-week RCT (450). \n\n A potential explanation might have to do with trough serum lithium levels. Lithium levels ranged from 0.8-1.3 mEq/L, and were o˜en at the high end of that range in the older placebo-controlled RCTs while in the negative placebo-controlled RCT, the mean serum lithium level was lower (<0.61 mEq/L in the combined BDI + BDII sample, not reported separately for BDII). Thus, the optimal serum level for treating bipolar II depression is unclear. However, based on the placebo-controlled BDII trials, as well as placebo-controlled studies in BDI (247), a serum level of 0.8-1.2 mEq/L appears most likely to be beneficial. \n\n In addition to the evidence for efficacy in acute depression, lithium also has efficacy in preventing mood episodes in BDII (400, 452-454). Therefore, in balance, we believe the evidence, though mixed, justifies recommending lithium as a second-line agent for BDII depression. \nFigure Caption: Lithium as a second-line agent for bipolar II depression: Summary of evidence. BDI, bipolar disorder type I; BDII, bipolar disorder type II; BDNOS, bipolar disorder not otherwise specified; RCT, randomized controlled trial [Colour figure can be viewed at http://wileyonlinelibrary.com]\n\nAbbreviations: RCT: Randomized controlled trial\n\n",
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        "text": "6. BIPOLAR II DISORDER > 6.2. Pharmacological treatment of bipolar II disorder > 6.2.3. Acute management of bipolar II depression > Second-line > Figure 6. > paragraph id: 6\n\n > Figure # Figure 6. Should antidepressants be used in bipolar II depression? Addressing the controversy \n\n The question of whether, and if so when and how, to use antidepressants in BDII remains controversial due to concerns regarding both safety (particularly the possibility of hypomanic switch, mixed symptoms, and increased cycling) and efficacy. \n\n With respect to safety, a meta-analysis that compared rates of antidepressant-associated mood elevations in BDII, BDI, and MDD reported that they were significantly less frequent in BDII than BDI, and occurred almost exclusively into hypomania rather than mania (454). Switch rates were low even during antidepressant monotherapy and with antidepressants associated with high switch rates in BDI (tricyclics, venlafaxine). An ISBD task force report on antidepressants also concluded that their risk-benefit ratio was more favorable in BDII (261, 449). \n\nThe issue of efficacy is less clear due to limited evidence. RCTs have shown that sertraline monotherapy was as effective as lithium and lithium+ sertraline combination, and that venlafaxine monotherapy was more effective than lithium, sufficient for level 2 evidence for these agents. In a RCT of BDI and BDII patients, bupropion was shown to be as effective as sertraline and venlafaxine (277). Open-label data also suggest efficacy for fluoxetine, and there are maintenance data for venlafaxine and fluoxetine in preventing relapses. These positive findings should be balanced against the fact that paroxetine and bupropion were not be“er than placebo for acute depression in patients taking concomitant mood stabilizing medications. Moreover, it is important to bear in mind that 1) there are no placebo-controlled acute-phase trials of antidepressant monotherapy in BDII, 2) many antidepressants have not been studied at all (and we do not believe it is warranted to extend positive findings from sertraline/venlafaxine -or for that ma“er negative findings from paroxetine/bupropion -to “antidepressants” generally), 3) the existing trials enrolled people with pure (non-mixed) depression, and their efficacy/safety in the broader spectrum of BDII patients is unclear, and 4) many of the existing trials have significant weaknesses, including one or more of: low dosing of the antidepressant; sub-therapeutic dosing of comparator medications; and lack of replication. \n\n All of this makes it particularly difficult to make evidence based recommendations regarding antidepressants in BDII. We have restricted our recommendations to the specific agents that have been studied, and we recommend bupropion, sertraline,and venlafaxine monotherapy as second-line treatments; and fluoxetine as third-line. We further recommend that any antidepressant, especially in monotherapy, be reserved for patients with pure depression and avoided in those with mixed symptoms or a history of antidepressantinduced hypomania (261). Whether antidepressants should also be avoided in patients with rapid cycling is unclear, since some studies report poorer outcomes in rapid-cycling patients (455) while others do not (450, 456-458). Patients prescribed antidepressants must be educated regarding early-warning signs of hypomania and carefully monitored for them. Finally, there is a pressing need for further studies of other antidepressants in BDII, in both monotherapy and combination therapy. \nFigure Caption: Antidepressants for bipolar II depression: What is their role? BDI, bipolar disorder type I; BDII, bipolar disorder type II; ISBD, International Society for Bipolar Disorders; MDD, major depressive disorder; RCT, randomized controlled trial [Colour figure can be viewed at http://wileyonlinelibrary.com]\n\nAbbreviations: MDD: Major depressive disorder; RCT: Randomized controlled trial\n\n",
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        "text": "6. BIPOLAR II DISORDER > 6.2. Pharmacological treatment of bipolar II disorder > 6.2.3. Acute management of bipolar II depression > Second-line > Figure 7. > paragraph id: 7\n\n >  # Figure 7. Why is lamotrigine a second-line recommenda on for bipolar II depression? Reconciling conflicting data \n\n Lamotrigine monotherapy was studied in two trials in BDII depression: one in which 221 BDII patients received 200 mg/day or placebo for 8 weeks, and a second in which 206 BDI or BDII patients (N = 84 with BDII) received 100–400 mg/day for 10 weeks (254). Both produced negative results. A meta-analysis confirmed that lamotrigine was not superior to placebo in BDII depression, although it did separate from placebo in BDI (248). Several methodological shortcomings likely resulted in the studies underestimating the drug’s effect, including 1) a slow titration which resulted in subjects being on the target dose for a short time, 2) a target dose lower than that often used in clinical practice and in successful maintenance studies (255, 324), and 3) higher placebo response rates. In contrast, a single-blind RCT with a relatively high dose (final peak dose=300mg) and a longer duration (16 weeks) found that lamotrigine monotherapy was as effective as adequately-dosed lithium (mean final serum level=1.1 mEq/L) in N=98 BDII patients (445). Two large RCTs in BDI+BDII and a 12-week open-label trial in patients with BDI+BDII+BDNOS also reported that adjunctive lamotrigine was effective, but did not report results separately for BDII (252, 253). Finally, lamotrigine has robust efficacy in preventing depressive relapse in BDI and BDII (324, 459). Taking all of these factors into consideration we recommend lamotrigine as a second-line treatment, particularly for patients who can tolerate a slow titration and delayed effect. \nFigure Caption: Lamotrigine as a second-line agent for bipolar II depression: Summary of evidence BDI, bipolar disorder type I; BDII, bipolar disorder type II; RCT, randomized controlled trial [Colour figure can be viewed at http://wileyonlinelibrary.com]\n\nAbbreviations: RCT: Randomized controlled trial\n\n",
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        "text": "7. SPECIFIC POPULATIONS > 7.2. Management of bipolar disorder in children and adolescents > 7.2.2. Pharmacological management > Acute management of bipolar depression > Figure 8. > paragraph id: 8\n\n >  # Figure 8. Reconciling the paucity of RCT data with abundant clinical experience in determining level of recommendation for treatment of pediatric bipolar depression \n\n Aside from lurasidone, which has positive RCT data (597) alongside good tolerability, options include either treatments with substantial tolerability concerns (olanzapine-fluoxetine combination) or treatments with no RCT data (eg. lithium, lamotrigine) or without positive RCT data (eg.quetiapine). In this instance, clinical experience combined with tolerability considerations and adult data informed the ranking of recommendations. Lithium and lamotrigine have not been tested in RCTs in pediatric bipolar depression. However, there is abundant clinical experience with these agents in treating depression in the pediatric group alongside positive open trials. Further, these agents are recommended for treating acute bipolar in adult populations, and they have good tolerability. Thus, despite lack of RCT data, they are recommended as second-line agents for treating acute bipolar depression in pediatric population. \n\n In terms of quetiapine, of the two negative RCTs (601, 602), one had a dose range of 300-600 mg/day but was limited to 32 participants and had a 67% placebo response rate. The other study was dosed at only 150-300 mg/day and had a 55% placebo response rate. One can argue that the quetiapine studies have been failed, rather than truly negative, studies. Therefore, given its demonstrated efficacy in adult bipolar depression and methodological problems in studies of pediatric bipolar depression and based on clinical experience, it is recommended as a third-line option. \n Ultimately, treatment decisions in general, but particularly in the context of empirical uncertainty, should be informed by a thorough discussion of comparative risks and benefits of competing options. Risk-benefit ratios may differ across patients depending on factors such as BD subtype, comorbid anxiety, and sleep disturbance. \nFigure Caption: Treatments for pediatric bipolar depression: Summary of evidence [Colour figure can be viewed at http://wileyonlinelibrary.com]\n",
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        "text": "7. SPECIFIC POPULATIONS > 7.4. Management of comorbid conditions in bipolar disorder > 7.4.1. Comorbid psychiatric disorders > Anxiety disorders > Figure 9. > paragraph id: 9\n\n >  # Figure 9. Primary treatments for anxiety disorders: Should they be used to treat co-morbid anxiety in bipolar disorder? \n\n There are no large RCTs that examined the efficacy of SSRIs, SNRIs, pregabalin or lorazepam in treating anxiety symptoms in BD patients with co-morbid GAD. However, several RCTs assessed the efficacy of these agents in patients with primary GAD and have been found to be effective (723). So,should clinicians employ these treatments in treating co-morbid anxiety symptoms in GAD? As with any clinical decision, CANMAT recommends assessing risk-benefit ratio. \n\n Pregabalin is effective and is not associated with risk of mood destabilization and is well tolerated. Hence, pregabalin would be considered an appropriate option although this has not been tested in BD population with co-morbid anxiety. Lorazepam also does not cause mood instability but given the potential dependence with longer-term use, only short-term use of lorazepam may be appropriate. In the case of antidepressants, especially with SNRIs, the risk of manic/hypomanic switch is likely higher. Therefore, if antidepressants are being considered for treating anxiety symptoms, it is recommended to primarily use SSRIs. Further, if SSRIs are used, it is important to ensure adequate mood stabilization with one or more prophylactic antimanic agents (eg. lithium or divalproex or an atypical antipsychotic). \n\n Lorazepam and clonazepam do not provoke mood instability, they are rapidly effective for the acute management of anxiety and they may address early warning signs of mania by inducing sleep. While inappropriate prescribing may result in misuse and dependence and caution must be exercised when prescribing benzodiazepines to elderly patients in particular, the use of benzodiazepines may be appropriate for treating anxiety associated with bipolar disorder. Short-term use is desirable but some patients are unable to tolerate other anxiety treatments and experience significant symptomatic relief and functional improvement due to the judicious use of benzodiazepines.\nFigure Caption: What is the role of primary treatments for anxiety disorders in treating co-morbid anxiety in bipolar disorder? RCT, randomized controlled trial [Colour figure can be viewed at http://wileyonlinelibrary.com]\n\nAbbreviations: RCT: Randomized controlled trial\n\n",
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        "text": "1. INTRODUCTION > Table 1. > paragraph id: 10\n\n[**Table**\n{Row 1 - Level: 1, Evidence: Meta-analysis with narrow confidence interval or replicated double-blind (DB), randomized controlled trial (RCT) that includes a placebo or active control comparison (n ≥ 30 in each active treatment arm)}\n{Row 2 - Level: 2, Evidence: Meta-analysis with wide confidence interval or one DB RCT with placebo or active control comparison condition (n ≥ 30 in each active treatment arm)}\n{Row 3 - Level: 3, Evidence: At least one DB RCT with placebo or active control comparison condition (n = 10-29 in each active treatment arm) or health system administrative data}\n{Row 4 - Level: 4, Evidence: Uncontrolled trial, anecdotal reports, or expert opinion}]\nAbbreviations: RCT: Randomized controlled trial\n\n",
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        "text": "1. INTRODUCTION > Table 2. > paragraph id: 11\n\n[**Table**\n{Row 1 - Line: First, Evidence level: Level 1 or level 2 evidence for efficacy plus clinical support for safety/tolerability and no risk of treatment-emergent switch (The text will specifically note when lack of clinical support for safety/tolerability or risk of treatment-emergent switch has impacted recommendations.)}\n{Row 2 - Line: Second, Evidence level: Level 3 or higher evidence for efficacy plus clinical support for safety/tolerability and low risk of treatment-emergent switch (The text will specifically note when lack of clinical support for safety/tolerability or risk of treatment-emergent switch has impacted recommendations.)}\n{Row 3 - Line: Third, Evidence level: Level 4 evidence or higher for efficacy plus clinical support for safety/tolerability}\n{Row 4 - Line: Not recommended, Evidence level: Level 1 evidence for lack of efficacy, or level 2 evidence for lack of efficacy plus expert opinion}]",
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        "text": "1. INTRODUCTION > Table 3. > paragraph id: 12\n\n[**Table**\n{Row 1 - Section 1: Introduction: Section 2: Foundations of management}\n{Row 2 - Section 1: Introduction: Section 3: Acute management of bipolar mania}\n{Row 3 - Section 1: Introduction: Section 4: Acute management of bipolar I depression}\n{Row 4 - Section 1: Introduction: Section 5: Maintenance therapy for bipolar I disorder}\n{Row 5 - Section 1: Introduction: Section 6: Bipolar II disorder}\n{Row 6 - Section 1: Introduction: Section 7: Specific populations}\n{Row 7 - Section 1: Introduction: Section 8: Safety and monitoring}]",
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        "text": "1. INTRODUCTION > Table 4. > paragraph id: 13\n\n[**Table**\n{Row 1 - Term: Mood stabilizer, Use: Use in the literature is inconsistent, and so this term will not be used in these guidelines}\n{Row 2 - Term: Divalproex, Use: Encompasses valproate, valpromide, valproic acid and divalproex sodium}\n{Row 3 - Term: Conventional antipsychotics, Use: Include first-generation antipsychotics with high affinity for dopamine D2 receptors. Note these are referred to as dopamine receptor antagonists (D2) in the new neuroscience-based nomenclature}\n{Row 4 - Term: Atypical antipsychotics, Use: Comprise second-generation antipsychotics with affinity for dopamine D2 and serotonin 5-HT2 receptors as well as those that have partial agonist effects at D2/D3 receptors. Note these are referred to as dopamine and serotonin receptor antagonists (D2 and 5-HT2A), dopamine 2 partial agonists and serotonin receptor antagonists, and dopamine 2/3 partial agonists in the new neuroscience-based nomenclature}\n{Row 5 - Term: Recurrence, Use: Re-emerging episode(s) of mania or depression whether it be within the previous episode or a new episode. Note that, while the literature may use \"relapse\" and \"recurrence\", respectively, inconsistencies in how they are applied and their irrelevance to treatment decisions mean we will use \"recurrence\" to refer to both}\n{Row 6 - Term: Maintenance, Use: Prophylactic therapy after stabilization of acute manic or depressive episodes}]",
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        "text": "2. FOUNDATIONS OF MANAGEMENT > 2.2. Diagnostic assessment > 2.2.2. DSM-5 specifiers for bipolar and related disorders > Table 5. > paragraph id: 14\n\n[**Table**\n{Row 1 - Specifier: Anxious distress, Manic episode: X, Depressive episode: X}\n{Row 2 - Specifier: Mixed features, Manic episode: X, Depressive episode: X}\n{Row 3 - Specifier: Rapid cycling, Illness course: X}\n{Row 4 - Specifier: Melancholic features, Depressive episode: X}\n{Row 5 - Specifier: Atypical features, Depressive episode: X}\n{Row 6 - Specifier: Psychotic features, Manic episode: X, Depressive episode: X}\n{Row 7 - Specifier: Catatonia, Manic episode: X, Depressive episode: X}\n{Row 8 - Specifier: Peripartum onset, Manic episode: X, Depressive episode: X}\n{Row 9 - Specifier: Seasonal pattern, Illness course: X}\n{Row 10 - Specifier: Remission, Manic episode: X, Depressive episode: X}\n{Row 11 - Specifier: Current episode severity, Manic episode: X, Depressive episode: X}]",
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        "text": "2. FOUNDATIONS OF MANAGEMENT > 2.2. Diagnostic assessment > 2.2.4. Screening and diagnosis of bipolar disorder > Table 6. > paragraph id: 15\n\n[**Table**\n{Row 1 - Feature: Symptomatology and mental state signs, Suggestive of bipolarity: Hypersomnia and/or increased daytime napping\nHyperphagia and/or increased weight\nOther \"atypical\" depressive symptoms such as leaden paralysis\nPsychomotor retardation\nPsychotic features and/or pathological guilt\nLability of mood; irritability; psychomotor agitation; racing thoughts, Suggestive of unipolarity: Initial insomnia/reduced sleep\nAppetite and/or weight loss\nNormal or increased activity levels\nSomatic complaints}\n{Row 2 - Feature: Course of illness, Suggestive of bipolarity: Early onset of first depression (<25 years)\nMultiple prior episodes (≥5 episodes), Suggestive of unipolarity: Late onset of first depression (>25 years)\nLong duration of current episode (>6 months)}\n{Row 3 - Feature: Family history, Suggestive of bipolarity: Positive family history of bipolar disorder, Suggestive of unipolarity: Negative family history of bipolar disorder}]",
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        "text": "2. FOUNDATIONS OF MANAGEMENT > 2.2. Diagnostic assessment > 2.2.5. Comorbidities and mimics > Table 7. > paragraph id: 16\n\n[**Table**\n{Row 1 - Diagnosis: Major depressive disorder or persistent depressive disorder, Distinguishing features: Manic or hypomanic episodes probed for and not present}\n{Row 2 - Diagnosis: Bipolar or related disorder due to another medical condition, Distinguishing features: Episodes are judged to be a consequence of a medical condition such as traumatic brain injury, brain tumours such as frontal lobe meningiomas, multiple sclerosis, stroke, Cushing's disease or hyperthyroidism. Onset or exacerbation of mood coincides with that of the medical condition}\n{Row 3 - Diagnosis: Substance- or medication-induced mood disorder, Distinguishing features: Episodes are judged to be a consequence of a substance such as an illicit drug, or a medication (stimulants, steroids,\nl\n-dopa or antidepressants) or toxin exposure. Episodes may be related to intoxication or withdrawal}\n{Row 4 - Diagnosis: Cyclothymic disorder, Distinguishing features: Hypomanic symptoms do not meet the full criteria for a hypomanic episode, and depressive symptoms do not meet the criteria for a major depressive episode}\n{Row 5 - Diagnosis: Psychotic disorders (schizoaffective disorder, schizophrenia and delusional disorder), Distinguishing features: Periods of psychotic symptoms in the absence of prominent mood symptoms. Consider onset, accompanying symptoms, pervious course and family history}\n{Row 6 - Diagnosis: Borderline personality disorder (Can occur comorbidly with bipolar disorder.), Distinguishing features: Instability of interpersonal relationships, self-image and mood, with marked impulsivity and a central theme of intense abandonment fears. Early onset and long-standing course. True euphoria and prolonged well-functioning intervals are extremely rare}\n{Row 7 - Diagnosis: Narcissistic personality disorder (Can occur comorbidly with bipolar disorder.), Distinguishing features: Grandiosity, need for admiration and lack of empathy of early onset. Grandiosity not associated with mood changes or functional impairments}\n{Row 8 - Diagnosis: Antisocial personality disorder (Can occur comorbidly with bipolar disorder.), Distinguishing features: Early onset of disregard for, and violation of, the rights of others, which does not occur only in the context of a manic episode}]",
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        "text": "2. FOUNDATIONS OF MANAGEMENT > 2.3. Suicide risk > Table 8. > paragraph id: 17\n\n[**Table**\n{Row 1 - Variable: Sex, Increased likelihood of suicide attempts: Female, Increased likelihood of suicide deaths: Male}\n{Row 2 - Variable: Age, Increased likelihood of suicide attempts: Younger\nOlder--higher lethality, Increased likelihood of suicide deaths: Older--higher ratio of deaths/attempts}\n{Row 3 - Variable: Race, Increased likelihood of suicide attempts: Minorities--youth only}\n{Row 4 - Variable: Marital status, Increased likelihood of suicide attempts: Single, divorced, single parents}\n{Row 5 - Variable: Age of onset, Increased likelihood of suicide attempts: Younger}\n{Row 6 - Variable: First episode polarity, Increased likelihood of suicide attempts: Depression\nMixed symptoms\nMania--more violent attempts}\n{Row 7 - Variable: Predominant polarity, Increased likelihood of suicide attempts: Depressive}\n{Row 8 - Variable: Current episode polarity, Increased likelihood of suicide attempts: Depressive\nMixed, Increased likelihood of suicide deaths: Depressive\nMixed\nManic with psychotic features}\n{Row 9 - Variable: Other episode characteristics, Increased likelihood of suicide attempts: Mixed features\nGreater number/severity of episodes\nRapid cycling\nAnxiety\nAtypical features\nSuicidal ideation, Increased likelihood of suicide deaths: Hopelessness\nPsychomotor agitation}\n{Row 10 - Variable: Psychiatric comorbidity, Increased likelihood of suicide attempts: Substance use disorder\nCigarette smoking\nCoffee intake\nAnxiety disorder\nEating disorder, Increased likelihood of suicide deaths: Anxiety disorder}\n{Row 11 - Variable: Personality disorders, Increased likelihood of suicide attempts: Present--particularly borderline or cluster B}\n{Row 12 - Variable: Physical comorbidity, Increased likelihood of suicide attempts: Obesity or high BMI}\n{Row 13 - Variable: First-degree family history, Increased likelihood of suicide attempts: Mood disorders\nBD\nSuicide, Increased likelihood of suicide deaths: Mood disorders\nBD\nSuicide}\n{Row 14 - Variable: Prior suicide attempts, Increased likelihood of suicide attempts: Present, Increased likelihood of suicide deaths: Present}\n{Row 15 - Variable: Early life trauma, Increased likelihood of suicide attempts: Childhood abuse\nEarly life stress}\n{Row 16 - Variable: Psychosocial precipitants, Increased likelihood of suicide attempts: Interpersonal problems\nOccupational problems\nBereavement\nSocial isolation, Increased likelihood of suicide deaths: Present within 1 week of death}\n{Row 17 - Variable: Sexual dysfunction, Increased likelihood of suicide attempts: Present}]",
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        "text": "2. FOUNDATIONS OF MANAGEMENT > 2.4. Chronic disease management > Table 9. > paragraph id: 18\n\n[**Table**\n{Row 1 - Self-management support: Self-management support, Empower and prepare patients to manage their health and health care: Use effective self-management support strategies that include assessment, goal setting, action planning, problem solving, and follow-up}\n{Row 2 - Self-management support: Decision support, Empower and prepare patients to manage their health and health care: Promote clinical care that is consistent with scientific evidence and patient preferences}\n{Row 3 - Self-management support: Decision support, Empower and prepare patients to manage their health and health care: Embed evidence-based guidelines into daily clinical practice and share this and other information with patients to encourage their participation}\n{Row 4 - Self-management support: Decision support, Empower and prepare patients to manage their health and health care: Use proven provider education materials}\n{Row 5 - Self-management support: Community, Empower and prepare patients to manage their health and health care: Encourage patients to participate in effective community programs}\n{Row 6 - Self-management support: Community, Empower and prepare patients to manage their health and health care: Form partnerships with community organizations}\n{Row 7 - Self-management support: Delivery system design, Empower and prepare patients to manage their health and health care: Provide clinical care and self-management support that patients understand and that fits with their cultural background}\n{Row 8 - Self-management support: Delivery system design, Empower and prepare patients to manage their health and health care: Ensure regular follow-up by the care team, with defined tasks for different team members}\n{Row 9 - Self-management support: Delivery system design, Empower and prepare patients to manage their health and health care: Provide clinical case management services for complex patients}\n{Row 10 - Self-management support: Clinical information systems, Empower and prepare patients to manage their health and health care: Provide timely reminders for providers and patients}\n{Row 11 - Self-management support: Clinical information systems, Empower and prepare patients to manage their health and health care: Facilitate individual patient care planning}\n{Row 12 - Self-management support: Clinical information systems, Empower and prepare patients to manage their health and health care: Share information with patients and providers to coordinate care}\n{Row 13 - Self-management support: Health system, Empower and prepare patients to manage their health and health care: Measure outcomes and use information to promote effective improvement strategies aimed at comprehensive system change}\n{Row 14 - Self-management support: Health system, Empower and prepare patients to manage their health and health care: Develop agreements that facilitate care coordination within and across organizations}]",
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        "text": "2. FOUNDATIONS OF MANAGEMENT > 2.6. Psychosocial interventions > Table 10. > paragraph id: 19\n\n[**Table**\n{Row 1 - : Psychoeducation (PE), Maintenance: Recommendation (Level of Evidence): First-line (Level 2), Depression: Recommendation (Level of Evidence): Insufficient evidence}\n{Row 2 - : Cognitive behavioural therapy (CBT), Maintenance: Recommendation (Level of Evidence): Second-line (Level 2), Depression: Recommendation (Level of Evidence): Second-line (Level 2)}\n{Row 3 - : Family-focused therapy (FFT), Maintenance: Recommendation (Level of Evidence): Second-line (Level 2), Depression: Recommendation (Level of Evidence): Second-line (Level 2)}\n{Row 4 - : Interpersonal and social rhythm therapy (IPSRT), Maintenance: Recommendation (Level of Evidence): Third-line (Level 2), Depression: Recommendation (Level of Evidence): Third-line (Level 2)}\n{Row 5 - : Peer support, Maintenance: Recommendation (Level of Evidence): Third-line (Level 2), Depression: Recommendation (Level of Evidence): Insufficient evidence}\n{Row 6 - : Cognitive and functional remediation, Maintenance: Recommendation (Level of Evidence): Insufficient evidence, Depression: Recommendation (Level of Evidence): Insufficient evidence}\n{Row 7 - : Dialectical behavioural therapy (DBT), Maintenance: Recommendation (Level of Evidence): Insufficient evidence, Depression: Recommendation (Level of Evidence): Insufficient evidence}\n{Row 8 - : Family/caregiver interventions, Maintenance: Recommendation (Level of Evidence): Insufficient evidence, Depression: Recommendation (Level of Evidence): Insufficient evidence}\n{Row 9 - : Mindfulness-based cognitive therapy (MBCT), Maintenance: Recommendation (Level of Evidence): Insufficient evidence, Depression: Recommendation (Level of Evidence): Insufficient evidence}\n{Row 10 - : Online interventions, Maintenance: Recommendation (Level of Evidence): Insufficient evidence, Depression: Recommendation (Level of Evidence): Insufficient evidence}]\nAbbreviations: CBT: Cognitive-behavioural therapy; MBCT: Mindfulness-based cognitive therapy\n\n",
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        "text": "3. ACUTE MANAGEMENT OF BIPOLAR MANIA > 3.2. Management of agitation > Table 11. > paragraph id: 20\n\n[**Table**\n{Row 1 - Dose range of studies (Doses are reported as per studies.): Dose range of studies (Doses are reported as per studies.), Level of recommendation: Level of recommendation, Agent: Agent, Formulation: Formulation, Level of evidence: Level of evidence}\n{Row 2 - Dose range of studies (Doses are reported as per studies.): Dose range of studies (Doses are reported as per studies.), Level of recommendation: First-line, Agent: Aripiprazole, Formulation: IM, Level of evidence: 2}\n{Row 3 - Dose range of studies (Doses are reported as per studies.): 2 mg IM, Level of recommendation: First-line, Agent: Lorazepam, Formulation: IM, Level of evidence: 2}\n{Row 4 - Dose range of studies (Doses are reported as per studies.): 2 mg IM, Level of recommendation: First-line, Agent: Loxapine, Formulation: Inhaled, Level of evidence: 1}\n{Row 5 - Dose range of studies (Doses are reported as per studies.): 2 mg IM, Level of recommendation: First-line, Agent: Olanzapine, Formulation: IM, Level of evidence: 2}\n{Row 6 - Dose range of studies (Doses are reported as per studies.): 10 mg, Level of recommendation: Second-line, Agent: Asenapine, Formulation: Sublingual, Level of evidence: 3}\n{Row 7 - Dose range of studies (Doses are reported as per studies.): 10 mg, Level of recommendation: Second-line, Agent: Haloperidol, Formulation: IM, Level of evidence: 3}\n{Row 8 - Dose range of studies (Doses are reported as per studies.): 10 mg, Level of recommendation: Second-line, Agent: Haloperidol + midazolam, Formulation: IM, Level of evidence: 3}\n{Row 9 - Dose range of studies (Doses are reported as per studies.): 10 mg, Level of recommendation: Second-line, Agent: Haloperidol + promethazine, Formulation: IM (Doses are not specifically for bipolar disorder but included schizophrenia or other diagnoses.), Level of evidence: 3}\n{Row 10 - Dose range of studies (Doses are reported as per studies.): 10 mg, Level of recommendation: Second-line, Agent: Risperidone, Formulation: ODT (Doses are not specifically for bipolar disorder but included schizophrenia or other diagnoses.), Level of evidence: 3}\n{Row 11 - Dose range of studies (Doses are reported as per studies.): 10 mg, Level of recommendation: Second-line, Agent: Ziprasidone, Formulation: IM (Doses are not specifically for bipolar disorder but included schizophrenia or other diagnoses.), Level of evidence: 3}\n{Row 12 - Dose range of studies (Doses are reported as per studies.): 10 mg, Level of recommendation: Third-line, Agent: Haloperidol, Formulation: PO (Assessed 2 h after the dose.), Level of evidence: 4}\n{Row 13 - Dose range of studies (Doses are reported as per studies.): N/A, Level of recommendation: Third-line, Agent: Loxapine, Formulation: IM, Level of evidence: 4}\n{Row 14 - Dose range of studies (Doses are reported as per studies.): Mean (SD) = 486.7 (317.2) mg/day, Level of recommendation: Third-line, Agent: Quetiapine, Formulation: PO (Assessed 2 h after the dose.), Level of evidence: 4}\n{Row 15 - Dose range of studies (Doses are reported as per studies.): 2 mg, Level of recommendation: Third-line, Agent: Risperidone, Formulation: PO (Doses are not specifically for bipolar disorder but included schizophrenia or other diagnoses.), Level of evidence: 4}]",
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        "text": "3. ACUTE MANAGEMENT OF BIPOLAR MANIA > 3.3. Pharmacological treatment of manic episodes > No heading > paragraph id: 21\n\n > Table: Image link: https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba0a/5947163/4d5287be01a4/BDI-20-97-g010.jpg-----\nTable Caption: Hierarchical rankings of first and second-line treatments recommended for management of acute mania \n#### Table 12. Hierarchical rankings of first and second‐line treatments recommended for management of acute mania\n\n\n##### First-line treatments: Monotherapies\n\n\n###### Lithium\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Acute depression: level 2 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Quetiapine\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Acute depression: level 1 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of mania during maintenance: level 3 evidence. Prevention of depression during maintenance: level 2 evidence. Acute depression: level 2 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Asenapine\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Prevention of depression during maintenance: level 2 evidence. Acute depression: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Aripiprazole\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; although monotherapies are listed above combination therapies in the hierarchy, combination therapies may be indicated as the preferred choice in patients with previous history of partial response to monotherapy and in those with psychotic mania or in situations where rapid response is desirable. Acute depression: level 1 negative evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Paliperidone(>6mg)\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; although monotherapies are listed above combination therapies in the hierarchy, combination therapies may be indicated as the preferred choice in patients with previous history of partial response to monotherapy and in those with psychotic mania or in situations where rapid response is desirable. Acute depression: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: minor impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Risperidone\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 3 evidence. Prevention of mania during maintenance: level 3 evidence. Prevention of depression during maintenance: no data. Acute depression: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: minor impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Cariprazine\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: no data. Prevention of mania during maintenance: no data. Prevention of depression during maintenance: no data. Acute depression: level 1 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: limited impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n##### First-line treatments: Combination therapies\n\n\n###### Quetiapine and Lithium/divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Acute depression: level 4 evidence; no controlled trials; however, clinical experience suggests that it is a useful strategy.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Aripiprazole and Lithium/divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 2 evidence. Prevention of any mood episode during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; did not separate from placebo in those with index mania; no studies available in index depression. Acute depression: level 4 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Risperidone and Lithium/divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 4 evidence. Prevention of mania during maintenance: level 4 evidence. Prevention of depression during maintenance: no data. Acute depression: level 4 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Asenapine and Lithium/divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 2 evidence. Prevention of any mood episode during maintenance: level 4 evidence. Prevention of mania during maintenance: level 4 evidence. Prevention of depression during maintenance: no data. Acute depression: level 4 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n##### Second-line treatments: Combination therapies\n\n\n###### Olanzapine\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Acute depression: level 1 evidence; did not separate from placebo on core symptoms of depression.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Carbamazepine\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Prevention of depression during maintenance: level 2 evidence. Acute depression: level 3 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: moderate impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Olanzapine and Lithium/divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 4 evidence. Prevention of mania during maintenance: level 4 evidence. Prevention of depression during maintenance: level 4 evidence. Acute depression: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Lithium and divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 2 evidence. Prevention of any mood episode during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Prevention of depression during maintenance: no data. Acute depression: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Ziprasidone\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: level 3 evidence. Prevention of mania during maintenance: level 3 evidence. Prevention of depression during maintenance: no data. Acute depression: level 1 negative evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: moderate impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.\n\n###### Haloperidol\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 1 evidence. Prevention of any mood episode during maintenance: no data. Prevention of mania during maintenance: level 4 evidence. Prevention of depression during maintenance: level 4 negative evidence. Acute depression: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: moderate impact on treatment selection.\n\n###### ECT\n\n\n####### Level of evidence by phase of treatment\n\nAcute mania: level 3 evidence. Prevention of any mood episode during maintenance: level 4 evidence. Prevention of mania during maintenance: level 4 evidence. Prevention of depression during maintenance: level 4 evidence. Acute depression: level 4 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: minor impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of depressive switch: limited impact on treatment selection.",
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        "text": "3. ACUTE MANAGEMENT OF BIPOLAR MANIA > 3.3. Pharmacological treatment of manic episodes > 3.3.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Table 13. > paragraph id: 22\n\n[**Table**\n{Row 1 - : Third-line, Agent: Carbamazepine/oxcarbazepine + Li/DVP, Level of evidence: Level 3}\n{Row 2 - : Third-line, Agent: Chlorpromazine, Level of evidence: Level 2}\n{Row 3 - : Third-line, Agent: Clonazepam, Level of evidence: Level 2}\n{Row 4 - : Third-line, Agent: Clozapine, Level of evidence: Level 4}\n{Row 5 - : Third-line, Agent: Haloperidol + Li/DVP, Level of evidence: Level 2}\n{Row 6 - : Third-line, Agent: rTMS, Level of evidence: Level 3}\n{Row 7 - : Third-line, Agent: Tamoxifen, Level of evidence: Level 2}\n{Row 8 - : Third-line, Agent: Tamoxifen + Li/DVP, Level of evidence: Level 2}\n{Row 9 - : Not recommended, Agent: Allopurinol, Level of evidence: Level 1 negative}\n{Row 10 - : Not recommended, Agent: Eslicarbazepine/licarbazepine, Level of evidence: Level 2 negative}\n{Row 11 - : Not recommended, Agent: Gabapentin, Level of evidence: Level 2 negative}\n{Row 12 - : Not recommended, Agent: Lamotrigine, Level of evidence: Level 1 negative}\n{Row 13 - : Not recommended, Agent: Omega-3 fatty acids, Level of evidence: Level 1 negative}\n{Row 14 - : Not recommended, Agent: Topiramate, Level of evidence: Level 1 negative}\n{Row 15 - : Not recommended, Agent: Valnoctamide, Level of evidence: Level 2 negative}\n{Row 16 - : Not recommended, Agent: Zonisamide, Level of evidence: Level 2 negative}]",
        "metadata": {
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            "headings": "3. ACUTE MANAGEMENT OF BIPOLAR MANIA > 3.3. Pharmacological treatment of manic episodes > 3.3.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Table 13.",
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    {
        "text": "4. ACUTE MANAGEMENT OF BIPOLAR DEPRESSION > 4.4. Pharmacological treatment for acute bipolar depression > No heading > paragraph id: 23\n\n > Table: Image link: https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba0a/5947163/222801ee447a/BDI-20-97-g011.jpg-----\nTable Caption: Hierarchical rankings of first and second-line treatments recommended for management of acute bipolar I depression \n#### Table 14. Hierarchical rankings of first and second‐line treatments recommended for management of acute bipolar I depression\n\n\n##### First-line treatments\n\n###### Quetiapine\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 1 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Acute mania: level 1 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### Lurasidone and Lithium/divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 1 evidence. Prevention of any mood episode during maintenance: level 3 evidence; trend for superiority on the primary efficacy measure, hence the lower rating. Prevention of depression during maintenance: level 3 evidence; effective in those with an index episode of depression. Prevention of mania during maintenance: level 4 evidence; negative data from the trial are probably due to methodological issues; rating based on expert opinion. Acute mania: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate / limited impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### Lithium\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 2 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Acute mania: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### Lamotrigine\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 2 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 2 evidence. Acute mania: level 1 negative evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: moderate impact on treatment selection. Acute phase tolerability concerns: limited impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: limited impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### Lurasidone\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 2 evidence. Prevention of any mood episode during maintenance: level 4 evidence. Prevention of depression during maintenance: level 4 evidence. Prevention of mania during maintenance: level 4 evidence. Acute mania: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### Lamotrigine(adj)\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 2 evidence. Prevention of any mood episode during maintenance: level 4 evidence. Prevention of depression during maintenance: level 4 evidence. Prevention of mania during maintenance: level 4 evidence. Acute mania: level 4 negative evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: moderate impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n##### Second-line treatments\n\n###### Divalproex\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 2 evidence. Prevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 2 evidence. Prevention of mania during maintenance: level 3 evidence. Acute mania: level 1 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### SSRIs/bupropion(adj)\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 1 evidence. Prevention of any mood episode during maintenance: no data. Prevention of depression during maintenance: level 4 evidence. Prevention of mania during maintenance: no data. Acute mania: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of manic / hypomanic switch: minor impact on treatment selection.\n\n###### ECT\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 4 evidence. Prevention of any mood episode during maintenance: level 4 evidence. Prevention of depression during maintenance: level 4 evidence. Prevention of mania during maintenance: level 4 evidence. Acute mania: level 3 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: minor impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### Cariprazine\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 1 evidence. Prevention of any mood episode during maintenance: no data. Prevention of depression during maintenance: no data. Prevention of mania during maintenance: no data. Acute mania: level 1 evidence.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: limited impact on treatment selection. Risk of manic / hypomanic switch: limited impact on treatment selection.\n\n###### Olanzapine-fluoxetine\n\n\n####### Level of evidence by phase of treatment\n\nAcute depression: level 2 evidence. Prevention of any mood episode during maintenance: no data. Prevention of depression during maintenance: no data. Prevention of mania during maintenance: no data. Acute mania: no data.\n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection. Risk of manic / hypomanic switch: minor impact on treatment selection.",
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            "headings": "4. ACUTE MANAGEMENT OF BIPOLAR DEPRESSION > 4.4. Pharmacological treatment for acute bipolar depression > No heading",
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        "text": "4. ACUTE MANAGEMENT OF BIPOLAR DEPRESSION > 4.4. Pharmacological treatment for acute bipolar depression > 4.4.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Table 15. > paragraph id: 24\n\n[**Table**\n{Row 1 - : Third-line, Agent: Aripiprazole (adj), Level of evidence: Level 4}\n{Row 2 - : Third-line, Agent: Armodafinil (adj), Level of evidence: Level 4}\n{Row 3 - : Third-line, Agent: Asenapine (adj), Level of evidence: Level 4}\n{Row 4 - : Third-line, Agent: Carbamazepine, Level of evidence: Level 2}\n{Row 5 - : Third-line, Agent: Eicosapentaenoic acid (EPA) (adj), Level of evidence: Level 2}\n{Row 6 - : Third-line, Agent: Ketamine (IV) (adj), Level of evidence: Level 3}\n{Row 7 - : Third-line, Agent: Light therapy +/− total sleep deprivation (adj), Level of evidence: Level 3}\n{Row 8 - : Third-line, Agent: Levothyroxine (adj), Level of evidence: Level 3}\n{Row 9 - : Third-line, Agent: Modafinil (adj), Level of evidence: Level 2}\n{Row 10 - : Third-line, Agent: N\n-acetylcysteine (adj), Level of evidence: Level 3}\n{Row 11 - : Third-line, Agent: Olanzapine, Level of evidence: Level 1}\n{Row 12 - : Third-line, Agent: Pramipexole (adj), Level of evidence: Level 3}\n{Row 13 - : Third-line, Agent: Repetitive transmagnetic stimulation (rTMS) (adj), Level of evidence: Level 2}\n{Row 14 - : Third-line, Agent: SNRI/MAOI (adj), Level of evidence: Level 2}\n{Row 15 - : Not recommended, Agent: Antidepressant monotherapy, Level of evidence: Level 2 negative}\n{Row 16 - : Not recommended, Agent: Aripiprazole, Level of evidence: Level 1 negative}\n{Row 17 - : Not recommended, Agent: Lamotrigine + folic acid, Level of evidence: Level 2 negative}\n{Row 18 - : Not recommended, Agent: Mifepristone (adj), Level of evidence: Level 2 negative}]\nAbbreviations: MAOI: Monoamine oxidase inhibitor; SNRI: Serotonin-norepinephrine reuptake inhibitor\n\n",
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            "headings": "4. ACUTE MANAGEMENT OF BIPOLAR DEPRESSION > 4.4. Pharmacological treatment for acute bipolar depression > 4.4.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Table 15.",
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        "text": "5. MAINTENANCE THERAPY FOR BIPOLAR DISORDER > 5.2. Treatment adherence > Table 16. > paragraph id: 25\n\n[**Table**\n{Row 1 - Sociodemographics: Psychological, Male, younger age, low level of education, single: Poor insight, lack of awareness of disease, negative attitude to treatment, fear of side effects, negative attitude to medication, low overall life satisfaction, low cognitive functioning}\n{Row 2 - Sociodemographics: Comorbidity, Male, younger age, low level of education, single: Alcohol or cannabis use, obsessive compulsive disorder}\n{Row 3 - Sociodemographics: Social, Male, younger age, low level of education, single: No social activities, work impairment}\n{Row 4 - Sociodemographics: Chronology, Male, younger age, low level of education, single: Younger age of onset, current inpatient status, hospitalization or suicide attempt in past 12 months}\n{Row 5 - Sociodemographics: Disease characteristics, Male, younger age, low level of education, single: Mixed episode, rapid cycling, delusions and hallucinations, greater severity of illness, BDI diagnosis, higher number of episodes}\n{Row 6 - Sociodemographics: Treatment-related factors, Male, younger age, low level of education, single: Side effects of medications, inadequate efficacy of medication, use of antidepressants, low treatment doses}]",
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            "headings": "5. MAINTENANCE THERAPY FOR BIPOLAR DISORDER > 5.2. Treatment adherence > Table 16.",
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    {
        "text": "5. MAINTENANCE THERAPY FOR BIPOLAR DISORDER > 5.5. Pharmacological treatments for maintenance therapy > No heading > paragraph id: 26\n\n > Table: Image link: https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba0a/5947163/d41c278959a0/BDI-20-97-g012.jpg-----\nTable Caption: Hierarchical rankings of first- and second-line treatments recommended for maintenance treatment in bipolar disorder \n#### Table 17. Hierarchical rankings of first‐ and second‐line treatments recommended for maintenance treatment in bipolar disorder\n\n\n##### First-line treatment\n\n\n###### Lithium \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Acute Depression: level 2 evidence. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Quetiapine \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Acute Depression: level 1 evidence. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Lamotrigine \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 2 evidence. Acute Depression: level 1 evidence. Acute Mania: level 1 negative evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: moderate impact on treatment selection. Acute phase tolerability concerns: limited impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: limited impact on treatment selection.\n\n###### Asenapine \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Acute Depression: no data. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection.\n\n###### Quetiapine + Lithium/divalproex \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Acute Depression: level 4 evidence. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Aripiprazole + Lithium/divalproex \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; did not separate from placebo in those with index mania; no studies available in index depression. Prevention of mania during maintenance: level 2 evidence. Acute Depression: level 4 evidence. Acute Mania: level 2 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Aripiprazole \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; did not separate from placebo in those with index mania; no studies available in index depression. Prevention of mania during maintenance: level 2 evidence. Acute Depression: level 1 negative evidence. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection.\n\n###### Aripiprazole OM \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; did not separate from placebo in those with index mania; no studies available in index depression. Prevention of mania during maintenance: level 2 evidence. Acute Depression: no data. Acute Mania: no data. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: limited impact on treatment selection. Maintenance phase tolerability concerns: minor impact on treatment selection.\n\n##### Second-line treatments\n\n\n###### Olanzapine \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: level 1 evidence. Prevention of mania during maintenance: level 1 evidence. Acute Depression: level 1 evidence; did not separate from placebo on core symptoms of depression. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Risperidone LAI \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 1 evidence. Prevention of depression during maintenance: no data; did not separate from placebo in those with index mania; no studies available in index depression. Prevention of mania during maintenance: level 1 evidence. Acute Depression: no data. Acute Mania: no data. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: minor impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Risperidone LAI (adj) \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: level 4 evidence. Prevention of mania during maintenance: level 2 evidence. Acute Depression: no data. Acute Mania: no data. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: significant impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Carbamazepine \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: level 2 evidence. Prevention of mania during maintenance: level 2 evidence. Acute Depression: level 3 evidence. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: moderate impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: minor impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Paliperidone (>6 mg) \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; did not separate from placebo in those with index mania; no studies available in index depression. Prevention of mania during maintenance: level 2 evidence. Acute Depression: no data. Acute Mania: level 1 evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: limited impact on treatment selection. Acute phase tolerability concerns: minor impact on treatment selection. Maintenance phase safety concerns: minor impact on treatment selection. Maintenance phase tolerability concerns: moderate impact on treatment selection.\n\n###### Lurasidone + Lithium/divalproex \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 3 evidence; trend for superiority on the primary efficacy measure, hence the lower rating. Prevention of depression during maintenance: level 3 evidence; effective in those with an index episode of depression. Prevention of mania during maintenance: level 4 evidence. Acute Depression: level 2 evidence. Acute Mania: no data. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: minor impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: moderate / limited impact on treatment selection.\n\n###### Ziprasidone + Lithium/divalproex \n\n\n####### Level of evidence by phase of treatment\n\nPrevention of any mood episode during maintenance: level 2 evidence. Prevention of depression during maintenance: no data; did not separate from placebo in those with index mania; no studies available in index depression. Prevention of mania during maintenance: level 2 evidence. Acute Depression: level 3 negative evidence. Acute Mania: level 2 negative evidence. \n\n####### Considerations for treatment selection\n\nAcute phase safety concerns: moderate impact on treatment selection. Acute phase tolerability concerns: moderate impact on treatment selection. Maintenance phase safety concerns: moderate impact on treatment selection; divalproex and carbamazepine should be used with caution in women of childbearing age. Maintenance phase tolerability concerns: minor impact on treatment selection.",
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        "text": "5. MAINTENANCE THERAPY FOR BIPOLAR DISORDER > 5.5. Pharmacological treatments for maintenance therapy > 5.5.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Table 18. > paragraph id: 27\n\n[**Table**\n{Row 1 - : Third-line, Agent: Aripiprazole + lamotrigine, Level of evidence: Level 2}\n{Row 2 - : Third-line, Agent: Clozapine (adj), Level of evidence: Level 4}\n{Row 3 - : Third-line, Agent: Gabapentin (adj), Level of evidence: Level 4}\n{Row 4 - : Third-line, Agent: Olanzapine + fluoxetine, Level of evidence: Level 2}\n{Row 5 - : Not recommended, Agent: Perphenazine, Level of evidence: Level 2 negative}\n{Row 6 - : Not recommended, Agent: Tricyclic antidepressants, Level of evidence: Level 2 negative}]",
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            "headings": "5. MAINTENANCE THERAPY FOR BIPOLAR DISORDER > 5.5. Pharmacological treatments for maintenance therapy > 5.5.5. Step 5: add on or switch therapy (third-line agents) > Third-line > Table 18.",
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        "text": "6. BIPOLAR II DISORDER > 6.2. Pharmacological treatment of bipolar II disorder > 6.2.3. Acute management of bipolar II depression > Table 19. > paragraph id: 28\n\n[**Table**\n{Row 1 - Recommendation: First-line, Agent: Quetiapine, Level of evidence: Level 1}\n{Row 2 - Recommendation: Second-line, Agent: Lithium, Level of evidence: Level 2}\n{Row 3 - Recommendation: Second-line, Agent: Lamotrigine, Level of evidence: Level 2}\n{Row 4 - Recommendation: Second-line, Agent: Bupropion (adj), Level of evidence: Level 2}\n{Row 5 - Recommendation: Second-line, Agent: ECT, Level of evidence: (Level 3)}\n{Row 6 - Recommendation: Second-line, Agent: Sertraline (For patients with pure depression (non-mixed).), Level of evidence: Level 2}\n{Row 7 - Recommendation: Second-line, Agent: Venlafaxine (For patients with pure depression (non-mixed).), Level of evidence: Level 2}\n{Row 8 - Recommendation: Third-line, Agent: Agomelatine (adj), Level of evidence: Level 4}\n{Row 9 - Recommendation: Third-line, Agent: Bupropion (adj), Level of evidence: Level 4}\n{Row 10 - Recommendation: Third-line, Agent: Divalproex, Level of evidence: Level 4}\n{Row 11 - Recommendation: Third-line, Agent: EPA (adj), Level of evidence: Level 4}\n{Row 12 - Recommendation: Third-line, Agent: Fluoxetine (For patients with pure depression (non-mixed).), Level of evidence: Level 3}\n{Row 13 - Recommendation: Third-line, Agent: Ketamine (IV or sublingual) (adj), Level of evidence: Level 3}\n{Row 14 - Recommendation: Third-line, Agent: N-acetylcysteine (adj), Level of evidence: Level 4}\n{Row 15 - Recommendation: Third-line, Agent: Pramipexole (adj), Level of evidence: Level 3}\n{Row 16 - Recommendation: Third-line, Agent: T3/T4 thyroid hormones (adj), Level of evidence: Level 4}\n{Row 17 - Recommendation: Third-line, Agent: Tranylcypromine, Level of evidence: Level 3}\n{Row 18 - Recommendation: Third-line, Agent: Ziprasidone (For patients with depression and mixed hypomania.), Level of evidence: Level 3}\n{Row 19 - Recommendation: Not recommended, Agent: Paroxetine, Level of evidence: 2 negative}]\nAbbreviations: ECT: Electroconvulsive therapy\n\n",
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            "headings": "6. BIPOLAR II DISORDER > 6.2. Pharmacological treatment of bipolar II disorder > 6.2.3. Acute management of bipolar II depression > Table 19.",
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        "text": "6. BIPOLAR II DISORDER > 6.2. Pharmacological treatment of bipolar II disorder > 6.2.4. Maintenance treatment > Table 20. > paragraph id: 29\n\n[**Table**\n{Row 1 - Recommendation: First-line, Agent: Quetiapine, Evidence level: Level 1}\n{Row 2 - Recommendation: First-line, Agent: Lithium, Evidence level: Level 2}\n{Row 3 - Recommendation: First-line, Agent: Lamotrigine, Evidence level: Level 2}\n{Row 4 - Recommendation: Second-line, Agent: Venlafaxine, Evidence level: Level 2}\n{Row 5 - Recommendation: Third-line, Agent: Carbamazepine, Evidence level: Level 3}\n{Row 6 - Recommendation: Third-line, Agent: Divalproex, Evidence level: Level 3}\n{Row 7 - Recommendation: Third-line, Agent: Escitalopram, Evidence level: Level 3}\n{Row 8 - Recommendation: Third-line, Agent: Fluoxetine, Evidence level: Level 3}\n{Row 9 - Recommendation: Third-line, Agent: Other antidepressants, Evidence level: Level 3}\n{Row 10 - Recommendation: Third-line, Agent: Risperidone (Primarily for prevention of hypomania.), Evidence level: Level 4}]",
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            "headings": "6. BIPOLAR II DISORDER > 6.2. Pharmacological treatment of bipolar II disorder > 6.2.4. Maintenance treatment > Table 20.",
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        "text": "7. SPECIFIC POPULATIONS > 7.1. Management of bipolar disorder in women at various stages of the reproductive cycle > 7.1.3. Pharmacological management of bipolar disorder during pregnancy > Table 21. > paragraph id: 30\n\n[**Table**\n{Row 1 - : Lithium, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): D, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): L4}\n{Row 2 - : Anticonvulsants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Carbamazepine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): D\nm}\n{Row 3 - : Anticonvulsants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Divalproex, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): D\nm}\n{Row 4 - : Anticonvulsants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Lamotrigine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 5 - : Atypical antipsychotics, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Aripiprazole, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 6 - : Atypical antipsychotics, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Clozapine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): B\nm}\n{Row 7 - : Atypical antipsychotics, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Olanzapine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 8 - : Atypical antipsychotics, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Quetiapine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 9 - : Atypical antipsychotics, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Risperidone, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 10 - : Atypical antipsychotics, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Ziprasidone, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 11 - : SSRI antidepressants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Citalopram, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 12 - : SSRI antidepressants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Escitalopram, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 13 - : SSRI antidepressants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Fluoxetine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 14 - : SSRI antidepressants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Fluvoxamine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 15 - : SSRI antidepressants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Paroxetine, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): D\nm}\n{Row 16 - : SSRI antidepressants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Sertraline, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): C\nm}\n{Row 17 - : Other antidepressants, Pregnancy risk category (Adapted from ACOG Committee on Practice Bulletins-Obstetrics: US Food and Drug Administration Rating. A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out (human data lacking, animal studies positive or not done); D = positive evidence of risk (benefit may outweigh risk). The \"m\" subscript is for data taken from the manufacturer's package insert.): Bupropion, Lactation risk category (Hale TW and Rowe HE.Lactation risk categories are listed as follows: L1, safest; L2, safer; L3, moderately safe; L4, possibly hazardous; L5, contraindicated.): B\nm}]\nAbbreviations: SSRI: Selective serotonin reuptake inhibitor\n\n",
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            "headings": "7. SPECIFIC POPULATIONS > 7.1. Management of bipolar disorder in women at various stages of the reproductive cycle > 7.1.3. Pharmacological management of bipolar disorder during pregnancy > Table 21.",
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        "text": "7. SPECIFIC POPULATIONS > 7.2. Management of bipolar disorder in children and adolescents > 7.2.1. Presentation and diagnosis > Table 22. > paragraph id: 31\n\n[**Table**\n{Row 1 - Symptom: Elation, Bipolar mania hypomania: Episodic, prolonged, pathological (inappropriate to context or uncharacteristic), associated with change in functioning, \"travels\" with ≥3 other manic symptoms, Attention deficit hyperactivity disorder: If present, not clearly episodic or pathological, Oppositional defiant disorder: If present, not clearly episodic or pathological}\n{Row 2 - Symptom: Irritability, Bipolar mania hypomania: Episodic, prolonged, pathological, associated with change in functioning, \"travels\" with ≥4 other manic symptoms, Attention deficit hyperactivity disorder: Can be an associated feature, related to stimulant rebound, or due to a comorbid illness (eg, ODD), Oppositional defiant disorder: Diagnostic criterion, lacks distinct prolonged episodes, does not \"travel\" with other manic symptoms}\n{Row 3 - Symptom: Sleep, Bipolar mania hypomania: Reduced need for sleep (ie, significantly less sleep than usual without increased daytime fatigue or somnolence); change must be mood-related, Attention deficit hyperactivity disorder: Insomnia (ie, difficulty falling asleep); can be an associated feature or associated with stimulants, but need for sleep is unchanged, Oppositional defiant disorder: Not a symptom or common characteristic; may defy bedtime rules or routine}\n{Row 4 - Symptom: Grandiosity, Bipolar mania hypomania: Distinct uncharacteristic increase in confidence or self-importance; change must be mood-related, Attention deficit hyperactivity disorder: Not a symptom or common characteristic, Oppositional defiant disorder: Defiance toward authority figures is common but not necessarily mood-related}\n{Row 5 - Symptom: Hyperactivity and distractibility, Bipolar mania hypomania: Episodic; if comorbid ADHD is diagnosed, then distinctly \"worse than usual\" change must be mood-related, Attention deficit hyperactivity disorder: Diagnostic criteria, nonepisodic, Oppositional defiant disorder: Not prominent or episodic}]\nAbbreviations: ADHD: Attention-deficit hyperactivity disorder\n\n",
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        "text": "8. SAFETY AND MONITORING > 8.1. Medical evaluation and laboratory investigations > Table 23. > paragraph id: 32\n\n[**Table**\n{Row 1 - CBC: Fasting glucose}\n{Row 2 - CBC: Fasting lipid profile (TC, vLDL, LDL, HDL, TG)}\n{Row 3 - CBC: Platelets}\n{Row 4 - CBC: Electrolytes and calcium}\n{Row 5 - CBC: Liver enzymes}\n{Row 6 - CBC: Serum bilirubin}\n{Row 7 - CBC: Prothrombin time and partial thromboplastin time}\n{Row 8 - CBC: Urinalysis}\n{Row 9 - CBC: Urine toxicology for substance use}\n{Row 10 - CBC: Serum creatinine}\n{Row 11 - CBC: eGFR}\n{Row 12 - CBC: 24h creatinine clearance (if history of renal disease)}\n{Row 13 - CBC: Thyroid-stimulating hormone}\n{Row 14 - CBC: Electrocardiogram (>40 years or if indicated)}\n{Row 15 - CBC: Pregnancy test (if relevant)}\n{Row 16 - CBC: Prolactin}]",
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            "headings": "8. SAFETY AND MONITORING > 8.1. Medical evaluation and laboratory investigations > Table 23.",
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        "text": "8. SAFETY AND MONITORING > 8.3. Safety and tolerability of pharmacotherapy > Table 24. > paragraph id: 33\n\n[**Table**\n{Row 1 - Risk of treatment emergent switch: Risk of treatment emergent switch}\n{Row 2 - Risk of treatment emergent switch: Risk of treatment emergent switch, : Lithium}\n{Row 3 - Risk of treatment emergent switch: Anticonvulsants, : Carbamazepine}\n{Row 4 - Risk of treatment emergent switch: Anticonvulsants, : Divalproex}\n{Row 5 - Risk of treatment emergent switch: Anticonvulsants, : Gabapentin}\n{Row 6 - Risk of treatment emergent switch: Anticonvulsants, : Oxcarbazepine}\n{Row 7 - Risk of treatment emergent switch: Anticonvulsants, : Lamotrigine}\n{Row 8 - Risk of treatment emergent switch: Atypical antipsychotics, : Aripiprazole}\n{Row 9 - Risk of treatment emergent switch: Atypical antipsychotics, : Asenapine}\n{Row 10 - Risk of treatment emergent switch: Atypical antipsychotics, : Cariprazine}\n{Row 11 - Risk of treatment emergent switch: Atypical antipsychotics, : Clozapine}\n{Row 12 - Risk of treatment emergent switch: Atypical antipsychotics, : Lurasidone}\n{Row 13 - Risk of treatment emergent switch: Atypical antipsychotics, : Olanzapine}\n{Row 14 - Risk of treatment emergent switch: Atypical antipsychotics, : Paliperidone}\n{Row 15 - Risk of treatment emergent switch: Atypical antipsychotics, : Quetiapine}\n{Row 16 - Risk of treatment emergent switch: Atypical antipsychotics, : Risperidone}\n{Row 17 - Risk of treatment emergent switch: Atypical antipsychotics, : Ziprasidone}\n{Row 18 - Risk of treatment emergent switch: Conventional antipsychotics, : Haloperidol}\n{Row 19 - Risk of treatment emergent switch: Conventional antipsychotics, : Loxapine}\n{Row 20 - Risk of treatment emergent switch: Antidepressants (adjunctive (Antidepressant monotherapy is not recommended in bipolar I disorder; for more information on bipolar II disorder, see Section 6.), : Agomelatine}\n{Row 21 - Risk of treatment emergent switch: Antidepressants (adjunctive (Antidepressant monotherapy is not recommended in bipolar I disorder; for more information on bipolar II disorder, see Section 6.), : Bupropion}\n{Row 22 - Risk of treatment emergent switch: Antidepressants (adjunctive (Antidepressant monotherapy is not recommended in bipolar I disorder; for more information on bipolar II disorder, see Section 6.), : Ketamine IV}\n{Row 23 - Risk of treatment emergent switch: Antidepressants (adjunctive (Antidepressant monotherapy is not recommended in bipolar I disorder; for more information on bipolar II disorder, see Section 6.), : MAOIs}\n{Row 24 - Risk of treatment emergent switch: Antidepressants (adjunctive (Antidepressant monotherapy is not recommended in bipolar I disorder; for more information on bipolar II disorder, see Section 6.), : SNRIs}\n{Row 25 - Risk of treatment emergent switch: Antidepressants (adjunctive (Antidepressant monotherapy is not recommended in bipolar I disorder; for more information on bipolar II disorder, see Section 6.), : SSRIs}\n{Row 26 - Risk of treatment emergent switch: Antidepressants (adjunctive (Antidepressant monotherapy is not recommended in bipolar I disorder; for more information on bipolar II disorder, see Section 6.), : TCAs}\n{Row 27 - Risk of treatment emergent switch: Stimulants, : Amphetamines}\n{Row 28 - Risk of treatment emergent switch: Stimulants, : Modafinil}\n{Row 29 - Risk of treatment emergent switch: Dopamine agonists, : Pramipexole}]",
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