Huberman Warns Bipolar Patients of Fatal Risks from Purely Holistic Therapies

Huberman警告双相患者：仅依赖整体疗法存在致命风险 尽管高剂量鱼油和谈话疗法能提供关键的辅助支持，但双相情感障碍是一种严重的神经化学紊乱，必须使用处方药物进行治疗，以预防致命的自杀风险和不可逆的脑萎缩。 本期节目探讨了双相情感障碍的神经生物学机制与临床现实，区分了双相 I 型较长的躁狂期与双相 II 型交替出现的轻躁狂及深层抑郁周期。Andrew Huberman 追溯了 John Cade 医生发现锂盐的历史，并详细阐述了锂盐的神经保护与抗炎特性如何保护脆弱的内感受神经回路免受兴奋性毒性的损害。讨论强调，尽管调整生活方式以及补充高剂量 omega-3 等营养保健品能提供有价值的系统性缓冲，但控制这一高危疾病仍需要由医生严格监督、结合处方药与针对性谈话疗法的综合治疗方案。 双相情感障碍影响全球约1%的人口，发病年龄通常在20至25岁之间，其剧烈且难以适应的情绪与能量波动导致患者的自杀风险比普通人群高出20至30倍。 (0:00) 双相I型以持续7天以上的躁狂发作为诊断特征，常伴有迫切语流、夸大妄想和极度缺乏睡眠却不感疲劳；双相II型则表现为持续4天以内的轻躁狂，并伴随长达2周以上的重度抑郁发作。 (1:09) 自1949年被发现以来，锂盐一直是双相障碍的关键药物，它能抑制神经组织炎症，保护负责内感受的神经回路免受过度兴奋引起的兴奋性毒性损伤；但因治疗安全窗口极窄，患者需严格进行血药浓度监测。 (14:30) 单纯的谈话疗法对双相障碍几乎无法奏效，治疗必须以正规精神科药物为主导，并结合认知行为疗法（CBT）、人际与社会节奏疗法（IPSRT）、生活规律以及高剂量Omega-3脂肪酸等协同支持。 (17:31)

Andrew Huberman frames bipolar disorder as a severe neurobiological condition driven by neural circuit hyperactivity and impaired interoception, arguing that effective stabilization demands strict pharmacological intervention over standalone talk therapy. Diagnostic Distinctions Between Bipolar I and II (1:09) Bipolar disorder affects approximately 1% of the population, typically emerging between ages 20 and 25, and carries a suicide risk 20 to 30 times greater than that of the general population. Huberman distinguishes Bipolar I by the occurrence of a full manic episode lasting at least seven days. Diagnosis requires at least three hallmark symptoms, such as pressured speech, extreme distractibility, physical agitation, grandiosity, or going a week without sleep while remaining untroubled. Huberman notes that contrary to common belief, individuals with Bipolar I do not necessarily experience depressive episodes. In contrast, Bipolar II involves shorter, less severe hypomanic episodes lasting four days or fewer, paired with debilitating depressive episodes that persist for two weeks or more. Huberman emphasizes that neither condition adheres to a predictable cyclical rhythm. Mood patterns can alternate erratically or present as rapid cycling across several days, which complicates clinical diagnoses during initial psychiatric consultations. Excitotoxicity, Interoceptive Atrophy, and Lithium (14:30) Huberman links the biological progression of bipolar disorder to a deteriorating balance between exteroception (perception of external stimuli) and interoception (awareness of internal bodily states). Beginning in a patient's late teens or early twenties, sustained hyperactivity within specific neural circuits induces excitotoxicity—a destructive process caused by toxic intracellular accumulations of calcium and glutamate. Over decades, this hyperactivity leads to the atrophy of neural circuits responsible for interoception, explaining why manic individuals often fail to register that they have gone days without eating or sleeping. Lithium counters this degeneration through cellular anti-inflammatory effects and neuroprotection. Originating from Dr. John Cade's 1940s experiments on guinea pigs and his 1949 clinical publication, lithium prevents excitotoxic cell death and shields vulnerable interoceptive circuits. However, Huberman cautions that lithium carries a narrow therapeutic window, necessitating rigorous blood-level monitoring, particularly during the first three months of treatment. Therapeutic Hierarchy: Medication, ECT, and Adjuncts (17:31) Because bipolar disorder stems from core chemical and circuit disruptions, Huberman asserts that talk therapy on its own is rarely, if ever, effective. Cognitive Behavioral Therapy (CBT) and Interpersonal and Social Rhythm Therapy (IPSRT) provide substantial benefit only when combined with prescription pharmacotherapy. For severe, treatment-resistant depression, electroconvulsive therapy (ECT) serves as an effective last resort, though it requires anesthesia, carries memory loss risks, involves high financial costs, and does not treat manic phases. Lifestyle measures and nutraceuticals function strictly as supportive adjuncts rather than primary cures. A double-blind, four-month study involving 30 subjects aged 18 to 64 demonstrated that high-dose omega-3 supplementation (9.6 grams of fish oil daily) substantially mitigated bipolar depression compared to an olive oil control. Huberman stresses that such supplements, alongside consistent sleep, exercise, and light exposure protocols, must merely supplement psychiatrist-led medical care. The Correlative Link to Creative Expression (26:40) Examining historical connections between mood disorders and creative achievement, Huberman references an occupational analysis of over 1,000 eminent 20th-century Western individuals. The data revealed stark disparities: professional athletes, military personnel, and natural scientists had the lowest rates of mood disorders, with athletes demonstrating virtually zero percent incidence of mania. Conversely, creative fields displayed high susceptibility. In the referenced data, up to 90% of exceptional poets suffered from major depression or mania, while approximately 30% of theater actors experienced manic episodes. Huberman emphasizes that these findings reflect correlation rather than causation, noting that while manic and depressive states can historically fuel artistic and literary expression, the condition remains an intensely dangerous clinical impairment. Huberman concludes that while bipolar states historically correlate with creative output, the illness represents a progressive, life-threatening disruption of neural circuitry that requires immediate clinical evaluation and medically supervised drug treatment rather than reliance on alternative therapies.

Andrew Huberman 在本期节目中阐述了双相情感障碍的神经生物学机制、临床分型及干预手段，强调该病是涉及神经回路渐进性损伤与极高自杀风险的严重生理疾患，必须依赖处方药物作为核心治疗基石。 临床特征、诊断分型与自杀风险 (0:00) 双相情感障碍（历史上常称双相抑郁）在人群中的患病率约为 1%，发病年龄通常在 20 至 25 岁之间，也可更早出现。该疾病表现为能量、感知与情绪的剧烈病理性波动，患者的自杀风险达到普通人群的 20 至 30 倍。双相 I 型的核心诊断标准为持续 7 天或更长时间的狂躁发作，精神科医生通常评估注意力涣散、冲动行为、夸大妄想、思维奔逸、躯体躁动、连续多天无需睡眠且无疲惫感，以及语速极快的压迫性言语等症状，患者需至少持续表现出其中三项。Huberman 指出，双相 I 型患者不一定会必然坠入严重抑郁，部分个体仅表现为持续性狂躁。相比之下，双相 II 型则由持续 4 天或更短、强度相对较低的轻狂躁，以及持续 2 周以上的重度致残性抑郁共同构成。由于情绪波动极少呈现规律的正弦波，且可能出现数天内快速交替的快速循环模式，临床医生通过单次就诊往往极难确诊。 内感受回路萎缩与锂剂的神经保护机制 (14:30) 人类感知主要分为面向外部环境的外感受与面向身体内部状态（如心率、呼吸等）的内感受。Huberman 指出，双相情感障碍的核心神经生物学特征是内感受神经回路的进行性萎缩，这直接解释了为何狂躁期患者完全无法自我察觉数天不睡、绝食或语速过快等内部状态异常。在 20 岁出头或青少年期早期，特定回路的持续过度活跃会诱发兴奋性毒性，即细胞内钙离子与谷氨酸的病理性过量积聚，最终导致活跃神经元死亡与回路损伤。作为该领域的经典药物，锂盐主要通过两大途径起效：显著抑制脑部神经组织的炎性反应，以及提供强效的神经保护功能，阻止兴奋性毒性造成的内感受神经回路结构性萎缩。 约翰·凯德的发现历程与锂盐监测要求 (7:30) 锂剂治疗的发现源于澳大利亚精神病学家 John Cade。他在二战期间作为战俘被关押于新加坡（1942年至1945年），期间观察到战友们极端的情绪和能量波动，进而提出狂躁可能源自脑内某种有机化学物质积聚的假说。1945 年战后重返临床后，Cade 收集狂躁症患者尿液并注射至豚鼠体内，发现其毒性显著高于常人。在排查尿素与尿酸的过程中，他因尿酸极难溶解而加入锂以制备可溶的尿酸锂溶液，并在严格的对照实验中发现仅注射纯锂溶液同样能使动物镇静。1949 年 9 月 3 日，Cade 在《澳大利亚医学杂志》上发表了关于锂盐治疗精神性兴奋的里程碑论文。Huberman 强调，尽管锂盐疗效明确，但其治疗安全窗口极窄且具有明显毒性，患者存在显著个体剂量差异，因此在启动治疗的前 3 个月内必须进行高度密集的医学监护与严密的血药浓度检测。 阶梯式治疗体系与生活方式协同作用 (17:31) Huberman 明确警告，单纯依靠谈话疗法或纯自然疗法应对双相情感障碍是极其危险且基本无效的，必须由执业精神科医生主导针对神经化学与回路紊乱的处方药物治疗。谈话疗法必须与药物联合使用，其中证据最充分的是认知行为疗法（CBT），人际与社会节奏疗法（IPSRT）则着眼于患者在家庭及社会人际关系网络中的整合。对于常规药物无效的难治性抑郁，电休克疗法（ECT）虽具极高疗效，但因需要全身麻醉住院、费用高昂且伴随记忆缺失副作用，仅能作为针对严重抑郁阶段的终末手段，且该疗法对狂躁无治疗效果。在生活方式与辅助手段方面，高质量睡眠、规律运动、营养摄入、社交互动与严格的光照管理构成了神经递质稳定的基础支撑；临床双盲对照研究亦表明，在 4 个月内每日补充 9.6 克高剂量鱼油（EPA/DHA）能大幅减轻双相抑郁症状，但该营养干预绝不能脱离处方药而独立存在。 心境障碍与创造力的历史关联研究 (26:40) 尽管双相情感障碍带来严重功能受损和高自杀率，历史数据表明其与高创造力产出存在强相关性。Huberman 援引了一项针对 20 世纪 1,000 多名杰出西方成功人士传记的研究：专业运动员、军人及自然/社会科学家的心境障碍发病率最低，其中职业运动员几乎为 0% 狂躁发生率；与之相对，艺术家与作家群体的发病率显著偏高，在杰出诗人群体中，有高达约 90% 的人饱受重度抑郁或狂躁症折磨；话剧演员的抑郁发生率虽低于诗人，但其全狂躁发作比例高达约 30%。Huberman 澄清该数据仅代表相关性而非因果关系，并强调这些状态在现实中具有极高的自杀及盲目冲动风险，一旦怀疑罹患该病必须立即寻求专业医疗救助。 双相情感障碍是由兴奋性神经毒性驱动的严峻脑功能障碍，药物干预与医学监护是不可或缺的生存底线；尽管其病理特质与艺术创造力存在显著历史关联，早期专业化诊疗与神经保护依然是阻断脑回路持续恶化的首要前提。

[0:00] Andrew Huberman: tremendous damage [1:09] Andrew Huberman: untroubled by it [1:09] Andrew Huberman: pulled apart [1:09] Andrew Huberman: no room for conversation [5:00] Andrew Huberman: sine wave [7:30] Andrew Huberman: absolutely incredible history [11:03] John Cade: Maybe the lithium alone is having this calming effect on these guinea pigs. [13:20] Andrew Huberman: absolutely profound and positive effect [14:30] Andrew Huberman: excitotoxicity [15:50] Andrew Huberman: atrophy of neural circuits for interoception [17:31] Andrew Huberman: talk therapy on its own is rarely if ever effective for bipolar depression and bipolar disorder [21:37] Andrew Huberman: needs to be dealt with head-on through the appropriate chemistry and prescription drug approaches [21:37] Andrew Huberman: braid together [26:40] Andrew Huberman: eminent individuals

[0:00] Welcome to Huberman Lab Essentials, [0:01] [music] where we revisit past episodes [0:04] for the most potent and actionable [0:06] science-based [music] tools for mental [0:08] health, physical health, and [0:09] performance. [0:11] I'm Andrew Huberman and I'm a professor [0:13] of neurobiology and ophthalmology at [0:15] Stanford School of Medicine. Today we [0:18] are going to be discussing bipolar [0:19] disorder, often called bipolar [0:21] depression. [0:22] Bipolar depression is a condition in [0:25] which people undergo massive shifts in [0:27] their energy, their perception, and [0:29] their mood. However, it is very [0:31] important to note that these shifts in [0:33] mood, energy, and perception are all [0:35] maladaptive. They can often cause [0:37] tremendous damage to the person [0:39] suffering from bipolar disorder and [0:41] tremendous damage to the people in their [0:43] lives. In fact, people suffering from [0:45] bipolar disorder are at 20 to 30 times [0:48] greater risk of suicide. So, today is a [0:51] serious discussion and it's certainly [0:53] one in which people who are suffering [0:55] from manic bipolar disorder or who know [0:57] people that are suffering from manic [0:58] bipolar disorder can benefit from. So, [1:01] bipolar disorder impacts about 1% of [1:04] people. That might seem like a small [1:05] percentage, but if you think about a [1:07] room of 100 people, [1:09] that means that at least one of them is [1:12] very likely to have bipolar disorder. [1:14] The typical age of onset is anywhere [1:17] from 20 to 25 years old, although it can [1:19] be much earlier. There are basically two [1:22] kinds of bipolar disorder, referred to [1:25] as bipolar 1 and bipolar 2. Bipolar 1 is [1:28] characterized by a fairly extended [1:31] period of mania. What is mania? Mania is [1:34] a period of very elevated mood, energy, [1:38] distractibility, impulsivity, and some [1:40] other symptomatology that we'll talk [1:41] about going forward. But, this manic [1:44] episode is extreme. One of the key [1:48] clinical criteria or diagnostic criteria [1:51] for bipolar 1 is that a person suffer [1:54] from these manic episodes or display [1:56] these manic episodes for 7 days or more. [1:59] Typically, a person will be brought into [2:02] a clinic or a person would bring [2:04] themselves to a clinic or meet with a [2:06] psychiatrist. And the psychiatrist is [2:08] going to start to evaluate for a couple [2:11] of different things. But first of all, [2:13] what they're going to try and figure out [2:14] is whether or not the person has at [2:16] least three of the following symptoms. [2:18] The first symptom is distractibility. [2:20] People who are in a manic episode will [2:22] be talking about a pen and then they'll [2:23] be talking about, you know, something [2:24] they saw the other day and then [2:25] something they want to purchase and then [2:26] a place they're going to travel to, etc. [2:28] But they are also very prone to any [2:31] stimulus within the room. So, highly [2:32] distractible, highly impulsive. [2:35] Impulsivity relates to actions. So, the [2:38] person might be fidgeting with something [2:39] and then they might try and leave the [2:41] room. The other is grandiosity. People [2:43] who have manic bipolar disorder who are [2:46] in a manic episode will often display [2:49] words of or actions of grandiosity. [2:51] These are actual beliefs that the person [2:53] comes to have about their grandiose [2:56] position in the world or grandiose [2:58] opportunities or potential in the world. [3:00] Flight of ideas are also typical of [3:02] manic episodes. So, this is a little bit [3:04] like distractibility, but this would be [3:06] people talking extensively about one [3:08] thing and then switching and talking [3:10] extensively about something else. The [3:11] other aspect of manic bipolar disorder [3:14] that often presents itself in the manic [3:16] episodes are agitation. People feeling [3:18] extremely physically agitated, so a lot [3:19] of shaking and moving about. Um this can [3:22] venture into the realm of paranoia, but [3:24] a lot of agitation, a difficulty sitting [3:27] down and being still, a difficulty [3:30] in just looking, feeling, and acting [3:33] calm. [3:34] And then another condition is no sleep. [3:37] And when I say no sleep, I mean no sleep [3:40] or very minimal sleep. As incredible as [3:43] it sounds, people who are in a manic [3:46] episode can often go 7 days or more with [3:49] zero sleep. And a key feature of this [3:51] zero sleep is that they're not troubled [3:53] by it. Can only imagine how pulled apart [3:56] most of us would feel under those [3:57] conditions, and yet they are just going [4:00] and going and going with no sleep, up [4:02] all hours, shopping, talking, [4:06] running, doing all sorts of different [4:08] things in the categories of other [4:09] symptoms that we talked about before, [4:11] and it doesn't bother them that they're [4:13] not sleeping. And then, the last sort of [4:17] category of symptoms that the [4:18] psychiatrist is evaluating for and [4:20] seeing if they present is rapid [4:22] pressured speech. It's coming at you, [4:24] coming at you, coming at you, and [4:25] there's really no room for conversation. [4:27] So, we've got distractibility, [4:28] impulsivity, grandiosity, flight of [4:30] ideas, agitation, no sleep, and rapid [4:34] pressured speech. For someone to be [4:36] diagnosed as in a manic episode, they do [4:38] not have to be engaging in or displaying [4:42] all of those symptoms. [4:44] They do, however, need to present at [4:47] least three of those symptoms, and then, [4:49] in order to meet the condition of [4:50] bipolar one, [4:52] they have to be presenting those three [4:54] symptoms for at least 7 days. It could [4:57] be longer, but at least 7 days. Now, [5:00] bipolar one disorder [5:02] means they're having these extended [5:03] manic episodes, 7 days or more, but it [5:06] does not necessarily mean that they are [5:08] dropping into a depressive episode as [5:11] well. This is a common misconception [5:13] about bipolar disorder, because, as it's [5:15] often called, bipolar disorder is [5:18] referred to as bipolar depression, and [5:20] yet, many people with bipolar disorder [5:22] don't necessarily experience the deep [5:24] depressive episodes. The second category [5:27] of bipolar disorder is bipolar two. So, [5:29] BP2, or bipolar disorder two, is [5:32] somewhat different than bipolar disorder [5:33] one. First of all, it's characterized [5:36] most often by the presence of both manic [5:38] episodes, mania, and depressive [5:41] episodes, or what's referred to as [5:42] hypomania. Bipolar two is often [5:45] diagnosed on the basis of the presence [5:47] of manic episodes that are lasting 4 [5:50] days or even less. So, someone with BP2 [5:53] might have 4 days of this increased [5:55] energy, goal-directed activity, they're [5:57] irritable, they're euphoric, they're not [5:59] sleeping, etc., but it's only lasting [6:01] for about 4 days. Or, they could be [6:03] having longer extended periods of mania, [6:06] but they are hypomanic episodes. They're [6:09] not quite as intense. So, the pressured [6:11] speech isn't quite as pressured. The [6:13] impulsivity isn't quite as severe, etc., [6:15] etc. The other aspect of bipolar 2 is [6:17] one that I mentioned briefly a moment [6:19] ago, which is that it's often associated [6:22] with the drops into the depressive [6:24] episodes. One person might go from very [6:26] high highs that last 7 days or more to [6:28] very low lows. Bouts of depression, [6:31] major depression that can last 2 weeks [6:32] or more. [6:33] Other people are rapid cycling by way [6:36] of, you know, 3 days manic, 3 days [6:37] normal, 3 days manic, and then dropping [6:39] into 3 days depression. So, you want to [6:41] erase that picture in your mind that [6:43] manic bipolar disorder is this sine [6:45] wave, this cycling up and down between [6:48] mania and depression. It can take a lot [6:50] of different forms. [6:51] And again, [6:53] this is a serious challenge for the [6:55] psychiatrist to diagnose people because [6:57] of that [6:58] fact that they're only getting a [6:59] snapshot of the person unless they've [7:01] known them for some time and are working [7:03] with them for some time. But, this is [7:05] also especially important for those of [7:07] you that [7:08] either have bipolar depression or [7:10] suspect that you might, or that know [7:13] someone with bipolar depression or [7:16] suspect somebody might have bipolar [7:18] depression, aka bipolar disorder. [7:20] Because if you're noticing that somebody [7:22] is very manic and then normal, well, [7:25] that's a very different picture than [7:27] somebody who's going from very manic to [7:28] very deep bouts of depression. The very [7:31] manic to deep bouts of depression is [7:33] easier to recognize because of the [7:35] extremes of those highs and lows. Now, [7:37] this might seem somewhat obvious to all [7:39] of you as I describe it, and yet it's a [7:41] very important as a frankly a citizen of [7:44] the planet who knows other human beings [7:47] to keep an eye out for these manic [7:48] episodes because again, whether or not [7:50] it's 4 days or less or whether or not [7:52] it's 7 days or more, [7:54] these manic episodes really are the the [7:56] defining criteria of bipolar disorder [7:59] aka bipolar depression. Now, I'd like to [8:01] talk about some of the treatments for [8:03] bipolar disorder. [8:04] And in the discussion of those [8:06] treatments, there's an absolutely [8:08] incredible history of discovery of one [8:11] particular treatment that still shows [8:13] great success in many patients, although [8:16] some people can't take it for reasons [8:18] that we'll talk about. The key player in [8:20] this story is a physician by the last [8:23] name Cade. Cade was an Australian [8:25] psychiatrist [8:26] who also was a soldier. And [8:29] during World War II, after the fall of [8:31] Singapore to Japan, he became a prisoner [8:33] of war. [8:35] And he was a prisoner of war from 1942 [8:37] until 1945. [8:39] So, he had some time for observation. [8:41] And during his imprisonment, he observed [8:44] some of his fellow inmates as going [8:46] through pretty wild vacillations in mood [8:48] and energy. Essentially going from manic [8:51] episodes to depressed episodes or from [8:53] manic to normal episodes. [8:55] And for one reason or another, [8:58] we don't know why because I couldn't [9:00] find any report as to why he [9:01] hypothesized this, but he hypothesized [9:04] that there was some build-up of some [9:05] chemical in these [9:07] people's brains that then they would [9:10] urinate out. And that urinating out of [9:14] whatever chemical was in there would [9:17] allow them to be more relaxed and not [9:19] manic. Eventually, he got out of this [9:21] prison as we as we mentioned in 1945, [9:23] and he started doing experiments in [9:25] addition to seeing patients in his [9:28] clinic. And what he did is he started to [9:30] take urine from people who exhibited [9:32] mania and urine from people who were not [9:34] manic. And he took that urine and he [9:37] would inject it into guinea pigs as an [9:39] experimental model. [9:41] And [9:42] his general observation was that there [9:44] was something in the urine that was [9:46] indeed making [9:48] the guinea pigs more manic if they were [9:50] injected with urine from a manic [9:53] patient, right? The exact measures that [9:55] he was taking in these guinea pigs [9:57] wasn't exactly clear. This is um at a [9:59] time or an era in science when you could [10:01] uh just sort of report things a little [10:03] bit more subjectively. Although there [10:04] were still numbers and statistics, what [10:06] Cade figured out was that the urine from [10:08] manic patients seemed to be more toxic [10:10] for these guinea pigs. [10:12] And he also knew that there are two [10:14] toxic substances in urine, urea and uric [10:18] acid. So he was able to separate the [10:21] urea and uric acid from people with [10:23] mania and patients that did not have [10:26] mania. And [10:28] he figured out that the urea was the [10:29] same in both these mentally ill manic [10:32] patients and the non-manic patients. So [10:35] instead he focused on the uric acid. Now [10:38] in order to put the uric acid into [10:40] solution so that he could inject it into [10:42] these guinea pigs, he had to try a [10:44] number of different compounds in order [10:46] to dilute it. It just so happens that [10:48] and you chemists will be familiar with [10:50] this, but there's certain things that [10:51] just don't go into solution easily. You [10:53] put the powder in a a vial, you add some [10:55] water or a saline or another solution, [10:57] you mix it up and the powder stays [10:58] suspended in there. It just doesn't it [11:00] doesn't actually [11:02] uh ever [11:03] become a clear liquid that you can [11:05] inject. So in order to try injecting [11:08] different strengths of uric acid, he [11:10] ended up using lithium to assist in the [11:13] dilution. And lithium worked. So what he [11:16] basically was doing, again for you [11:17] chemists, is he was taking uric acid, he [11:20] was adding lithium, and making a [11:22] solution of lithium urate. Okay? This is [11:25] a lot of details, but this is important [11:27] because what he eventually found is that [11:30] when he [11:31] diluted the uric acid with lithium and [11:33] created lithium urate, lithium urate [11:36] could actually calm down these guinea [11:39] pigs that were injected with the toxic [11:41] urea. [11:42] He also found that lithium urate had a [11:45] generally calming effect on these guinea [11:48] pigs. So, now we're really off in crazy [11:50] territory, if you right? We're talking [11:52] about urine from patients that's [11:54] separating out urea and uric acid. We're [11:57] adding lithium to the uric acid. We're [11:59] injecting this into the guinea pigs. [12:00] This is getting pretty wild and pretty [12:02] weird. But, this is medicine and from [12:04] time to time this is medicine and [12:06] science. [12:08] Cade was a good scientist in addition to [12:10] being a good physician. And by good [12:12] scientist, I mean that he did control [12:14] experiments. Here he was injecting [12:17] lithium urate into animals and seeing an [12:21] effect, but he knew that that solution [12:23] of lithium urate contained not just the [12:26] uric acid, but it also contained [12:28] lithium. And so, he quite appropriately [12:31] asked, "Maybe the lithium alone is [12:34] having this calming effect on these [12:36] guinea pigs." And indeed, that was the [12:38] case. When he did the proper control [12:40] experiment and injected only lithium [12:43] solution into these guinea pigs, [12:46] they calmed down. From there, [12:49] he in sort of 1940s style medicine, and [12:52] this you would not happen now, he very [12:54] quickly moved from that animal model [12:56] into human patients and started [12:58] injecting human patients with lithium or [13:00] providing lithium orally to those [13:02] patients. And lo and behold, found an [13:06] absolutely profound and positive effect [13:09] of lithium in reducing symptoms of [13:12] mania. And as all good physician [13:15] scientists do, he wrote up his results. [13:17] And he wrote it up in a paper [13:20] entitled lithium salts in the treatment [13:22] of psychotic excitement. Okay, back then [13:25] they didn't call it mania, they called [13:26] it psychotic excitement. This is a paper [13:28] that was published September 3rd, 1949 [13:30] in the Medical Journal of Australia, a [13:32] classic study in the field of [13:34] psychiatry. Lithium, I should mention, [13:36] has a number of important features, but [13:38] it also a number of important side [13:40] effects that need to be considered. [13:41] First of all, it does have [13:44] a certain toxicity, and so levels of [13:46] lithium in the blood need to be [13:47] monitored extremely carefully. So, it's [13:50] not the sort of thing that people can [13:51] just take it a given dose, and every [13:53] patient responds the same. There's a lot [13:55] of oversight and a lot of blood tests [13:56] that have to be done, especially in the [13:58] first 3 months of lithium treatment. [14:00] Now, with that said, scientists and [14:02] clinicians have been quite rigorous in [14:04] trying to understand why and how lithium [14:07] works in order to understand the why and [14:09] how of bipolar disorder. Scientists and [14:12] physicians understand that just because [14:14] we have one treatment that works, [14:16] if it has any side effects at all, there [14:18] is the possibility for better [14:19] treatments. And only by understanding [14:21] how lithium works at the cellular level, [14:24] at the neural circuit level, etc., do we [14:26] really stand to find those new [14:27] discoveries. Lithium seems to be able to [14:30] suppress inflammation, and [14:32] importantly, it can suppress [14:34] inflammation in neural tissues and [14:36] within the brain in particular. The [14:38] other thing about lithium is that [14:40] lithium is neuroprotective. [14:42] Neuroprotection is an ability for [14:45] neurons to be better able to handle [14:47] stress of different kinds, in [14:49] particular, excitotoxicity. [14:51] There's a phenomenon in bipolar disorder [14:54] and a lot of other psychiatric [14:55] conditions in which hyperactivity of [14:57] certain brain areas actually starts to [15:00] kill off neurons. [15:01] Hyperactivity doesn't always do this, [15:03] but it turns out that if certain brain [15:05] circuits are too active for too long, [15:07] some of the chemicals associated with [15:09] neuronal activity, things like calcium [15:11] and neurotransmitters like glutamate, [15:12] can actually kill the very neurons that [15:14] are active. So, it seems that lithium [15:16] can prevent some of that neurotoxicity. [15:18] I've talked about this a little bit on [15:19] the Huberman Lab Podcast before, but [15:21] there are two modes of perception. [15:23] Exteroception is literally an attention [15:26] to things that are happening beyond the [15:27] confines of our skin. Then there's [15:29] interoception, which is perception of [15:31] things that are happening internally. [15:33] So, we are always existing in a balance [15:35] between exteroception and interoception. [15:38] But, as it turns out, people with [15:40] bipolar disorder, over time, and [15:42] especially into the second and third [15:44] decade of having bipolar disorder, seem [15:46] to have progressively diminished levels [15:49] of interoception. And that very likely [15:51] is important in their inability to [15:53] register, for instance, that wow, they [15:55] are talking at an excessive rate, or [15:57] they haven't slept in 5 days, or they [16:00] haven't eaten in a long period of time. [16:03] This [16:04] atrophy of neural circuits for [16:06] interoception [16:08] is starting to emerge as one of the [16:10] defining neural circuit characteristics [16:12] or underpinnings of bipolar. Now, I [16:15] bridge to this conversation about neural [16:16] circuits from the statement that lithium [16:20] can protect against some of the [16:22] neurotoxic effects of neural circuits [16:25] being very active. The reality is that [16:29] people with bipolar depression very [16:30] likely have a hyperactivity, that is an [16:33] increased level of activity in certain [16:35] circuits within the brain early in the [16:37] expression of their disease. And that [16:39] typically, as I mentioned earlier, sets [16:41] in around the early 20s, although [16:42] sometimes it that can be even earlier, [16:44] in the teens and so forth. But, that [16:47] hyperactivity, [16:48] we think, leads to a toxicity, an [16:52] excitotoxicity [16:53] of certain elements of the neural [16:55] circuits that are responsible for [16:56] interoception. And it appears that [16:58] lithium very likely protects us against [17:01] some of that atrophy of those circuits [17:02] for interoception. [17:04] Now, I would like to also talk about [17:06] some of the not so typical therapeutics [17:09] for bipolar disorder, and also point to [17:11] the things that have been tried and [17:13] failed for successful treatment of [17:16] bipolar disorder because some of those [17:18] things [17:19] are often talked about and suggested [17:21] especially in online communities and [17:24] while it's not clear that any of them [17:25] are particularly hazardous [17:28] on their own although some of them do [17:29] carry some hazards [17:31] I do think it's important because of the [17:33] critical time sensitive nature of [17:35] bipolar disorder and the urgency of [17:37] getting treatments early to try and [17:39] prevent some of the longer lasting [17:41] neural circuit changes that if people [17:43] can avoid some of the less effective or [17:45] demonstrated to be ineffective [17:47] treatments that they stand to combat [17:49] bipolar disorder much more successfully. [17:52] First of all a key point about drug [17:53] therapies versus [17:55] non-drug therapies or talk therapies. [17:58] Without question [18:00] drug therapies are going to be most [18:02] effective when done also with talk [18:05] therapies and we'll talk about which [18:07] talk therapies have been demonstrated to [18:08] be most effective. [18:10] There is some argument about what I'm [18:12] about to say next but in general [18:14] most psychiatrists will tell you or [18:16] certainly the ones I've spoken to have [18:18] told me that talk therapy on its own [18:21] is rarely if ever effective for [18:25] bipolar depression and bipolar disorder [18:27] whether or not it's BP1 or BP2. That's [18:30] just the reality of it. There are both [18:32] established and more novel forms of talk [18:35] therapy [18:36] being used again in concert with drug [18:38] treatments for bipolar disorder. [18:40] Cognitive behavioral therapy is the one [18:42] that seems to be best at least by way of [18:44] the statistics and papers that exist. [18:46] It's also the one that's been explored [18:48] the most. So one of the reasons why it's [18:49] often considered the most popular or [18:51] effective is because it's also been [18:52] around longer and it's been explored the [18:54] most. Cognitive behavioral therapy [18:56] in general is a progressive exposure of [18:59] the patient in a very controlled way in [19:01] a clinical setting to some of the [19:03] triggers or the conditions that would [19:06] exacerbate bipolar disorder. And then [19:08] there's a category of therapy [19:10] called interpersonal and social rhythm [19:12] therapy. This is deserving of its own [19:15] entire [19:16] uh episode really. Interpersonal and [19:18] social rhythm therapy is sort of an [19:20] expansion on family focused therapy, [19:22] although it's distinct in certain ways [19:24] as well, [19:25] and really focuses on how people are [19:27] relating to others in their life and in [19:30] the workplace and in the school [19:32] environment and also within the family, [19:33] etc. And I should say that [19:36] a overall theme that's emerging in [19:38] psychiatry and psychology is to start, [19:40] wherever possible, to incorporate more [19:43] of the social aspects and the [19:45] interpersonal aspects. In other words, [19:47] not just talking to an examining a [19:48] patient as one biological system, one [19:51] nervous system, one set of chemicals, [19:53] and one life, but rather a set of [19:55] chemicals, neural circuits, and a life [19:57] that's embedded in the chemicals and [19:58] neural circuits and lives of other [19:59] people. One very exciting and emerging [20:01] treatment that does show great promise [20:04] and in some cases great outcomes for [20:07] bipolar disorder is, believe it or not, [20:09] electric shock therapy. Generally used [20:12] for treatment-resistant depression, so [20:14] these are people that have no positive [20:16] response or ongoing positive response to [20:18] drug therapies or other therapies. The [20:20] problem with ECT is that it's really [20:22] only useful for treatment-resistant [20:25] depression. It doesn't actually target [20:26] the manic aspects of bipolar uh [20:29] depression and bipolar disorder, but [20:31] nonetheless is used when drug treatments [20:33] don't work. Some of the negatives of [20:35] electric [20:36] shock therapy um or electroconvulsive [20:39] therapy ECT is the is the proper acronym [20:42] and and way it's described is that it's [20:43] quite invasive, right? This is something [20:45] that um you need to go to the hospital [20:47] for and often times there's some um [20:48] inpatient care required after the [20:50] electric shock uh convulsive therapy. [20:52] It's a fairly high cost, especially for [20:54] those that don't have insurance. And of [20:56] course it requires anesthesia. For most [20:58] people that's not going to be a problem, [20:59] but uh for many people that could be a [21:02] problem. And there's often some [21:04] associated memory loss. [21:06] And so the memory loss, the invasive [21:10] nature of ECT, and the cost often times [21:13] rule out ECT for most patients, and [21:16] that's why it's sort of a late stage or [21:17] kind of last resort type thing for [21:19] treatment-resistant depression. There [21:21] are two naturopathic, or I should say [21:24] nutrition supplement-based approaches to [21:27] bipolar disorder that get talked about a [21:28] lot, and one of them shows some [21:31] interesting promise or effectiveness [21:33] even in a limited context. [21:37] Before marching into this description of [21:39] these two compounds, in fact, before [21:41] even mentioning these two compounds, I [21:43] do want to emphasize what's been said [21:46] and written about over and over again, [21:48] and what was relayed to me from expert [21:51] psychiatrists. [21:52] It is not wise to rely purely on talk [21:54] therapy or on [21:56] natural approaches to the treatment of [21:58] bipolar disorder given [22:00] the intensity of the disorder and the [22:03] high propensity for suicide risk in [22:05] people with bipolar disorder. It is a [22:07] chemical and neural circuit disruption, [22:10] and it needs to be dealt with head-on [22:11] through the appropriate chemistry and [22:14] prescription drug approaches from a [22:16] board-certified psychiatrist. I don't [22:18] say this to protect me, I say this truly [22:20] to protect those who either suffer from [22:23] or think they may suffer from bipolar [22:24] disorder. If you know someone who you [22:26] think might suffer from bipolar [22:27] disorder, [22:29] now, all that is not to say that there [22:31] aren't useful lifestyle interventions [22:33] that can support people with bipolar [22:34] disorder. So, I just briefly want to [22:36] mention those. And again, I'm lifting [22:37] the statements I'm about to make [22:39] from [22:40] some excellent online lectures from [22:42] psychiatrists at Stanford and elsewhere, [22:44] which essentially say that [22:47] of course, of course, of course, [22:50] getting better sleep, getting adequate [22:52] exercise, getting proper nutrition, [22:54] having quality healthy social [22:57] interactions, [22:58] even getting regular sunlight in the day [23:00] and avoiding bright light at night. All [23:02] of those things are going to braid [23:04] together to support the nervous system [23:07] and the psyche of somebody with bipolar [23:09] disorder, [23:10] but they braid together to [23:12] support the psyche and the [23:13] neurochemistry and the neural circuits [23:14] of anybody and everybody. With that [23:16] said, there are two substances generally [23:19] found as supplements, although there are [23:21] other sources of them as well, including [23:23] within nutritional sources, that have [23:25] been shown, at least in some studies, to [23:27] be pretty effective in [23:29] adjusting the symptoms of bipolar [23:31] disorder. And those two things are [23:33] inositol [23:34] and omega-3 fatty acids. Now, inositol [23:38] is a compound [23:40] that is taken for a variety of reasons. [23:42] It's something we've talked about on the [23:43] podcast before. I personally take [23:44] inositol not because I have bipolar [23:46] disorder. In fact, I am quite lucky that [23:48] I don't have bipolar disorder, but I [23:50] take inositol at 900 mg of myo-inositol [23:53] every third night or so in order to [23:55] improve my sleep. It also seems to have [23:57] a fairly potent anti-anxiety effect [24:00] during the day. So, the ability for fish [24:03] oil, and in particular the omega-3 fatty [24:06] acids, which come in varieties like EPA [24:08] and DHA, have been explored at [24:10] relatively high dosages for their [24:12] ability to offset some of the effects of [24:16] mania and to offset the effects of [24:18] depressive episodes in bipolar disorder. [24:21] There are several studies that have [24:22] shown that supplementing with [24:24] fish oil or omega-3 fatty acids at [24:27] levels of, for instance, 9.6 g of fish [24:30] oil per day for 4 months greatly reduced [24:33] symptoms of bipolar depression [24:36] compared to the control [24:38] group, which received olive oil. Olive [24:40] oil is a different form of fat, [24:42] monounsaturated fat, but doesn't contain [24:44] as much of the omega-3 fatty acids and [24:46] so forth. So, 9. 9.6 g of fish oil per [24:51] day over 4 months is a lot of fish oil [24:54] to be ingesting on a given day. This was [24:56] a double-blind [24:57] uh study. This was only carried out, I [24:59] should mention, in 30 subjects, but it [25:01] was males and females, and the age range [25:03] was pretty broad, anywhere from 18 all [25:05] the way up to 64 years of age, which is [25:07] important given [25:08] the sort of longitudinal or changes over [25:10] time that one sees in bipolar disorder. [25:13] Here's the major takeaway. [25:15] Supplementing with high-dose omega-3s [25:17] does seem to be beneficial for a good [25:19] number of people with bipolar disorder. [25:21] However, again, I want to highlight, [25:23] however, it should not be viewed as the [25:26] only treatment approach for bipolar [25:28] disorder. But I don't think I can [25:29] overemphasize enough that, especially [25:32] for bipolar disorder and the great risk [25:33] of suicide and suffering and, you know, [25:36] inappropriate spending, or I should say [25:38] maladaptive spending and impulsivity [25:40] that's associated with bipolar disorder, [25:41] that it's hard to imagine a scenario in [25:44] which just talk therapy and fish oil and [25:46] lifestyle interventions are going to [25:47] completely uh suppress or treat bipolar [25:50] disorder. People with bipolar disorder [25:51] really need to consider the full picture [25:54] of treatments, the drug treatments, the [25:57] talk therapy treatments, and lifestyle [25:59] treatments, and [26:01] nutraceutical, or we can say [26:03] supplement-based treatments such as [26:05] omega-3 supplementation, as a [26:08] full and necessary picture for dealing [26:10] with their illness. Before we begin to [26:13] conclude our discussion about bipolar [26:14] disorder, [26:15] I want to talk a little bit about this [26:16] word disorder. [26:18] And this is a theme that doesn't just [26:20] relate to bipolar disorder, but other [26:22] psychiatric disorders as well. [26:24] And when we think of a disorder, we [26:26] think of something that is really [26:28] detrimental to us, something that really [26:30] impairs our ability to function in work, [26:32] in school, in relationships, and really [26:35] starts to pull down our health status in [26:37] a variety of ways. And certainly bipolar [26:39] disorder meets those criteria. [26:42] However, [26:44] there is this idea that things like [26:46] bipolar disorder, even things like [26:48] schizophrenia in some cases, [26:50] are responsible for some of the creative [26:52] aspects or the creative works that have [26:54] been observed and carried out by human [26:56] beings for many centuries. And believe [26:59] it or not, there are good data to [27:00] support the fact that certain aspects of [27:02] mania are associated with creativity. [27:06] It's been explored at a research level. [27:08] Really, there are data pointing to the [27:10] fact that certain individuals of certain [27:13] occupations tend to be more creative and [27:16] that creativity is associated with, [27:18] again, associated. This isn't causal. [27:20] It's associated or correlated with [27:22] higher levels or incidents of bipolar [27:24] depression and maybe even other forms of [27:26] depression. So, this is a study looking [27:29] at mood disorders in eminent [27:31] individuals. So, these are people that [27:33] are not just good at what they do, but [27:35] are exceptional at what they do and [27:37] explored the percentage of people in [27:41] given professions with either depression [27:43] or mania. [27:45] And this was actually a data set gleaned [27:47] from more than a thousand 20th century [27:50] Westerners [27:51] based on their biographies that were [27:54] reviewed by other people. So, it's a bit [27:56] of an indirect measurement. This isn't, [27:57] you know, psychiatrist data. This is [27:59] data or I should say these are data that [28:03] were compiled from self-reports or from [28:06] reads of self-reports. [28:08] And they explored a number of different [28:09] professions. So, for instance, they [28:11] looked at people in the military or [28:13] people who were professional athletes or [28:15] natural scientists or social scientists, [28:17] people who occupied positions in public [28:19] office or were musical performers, [28:22] artists, non-fiction writers, poetry, [28:24] etc. Turns out that if you were to look [28:26] at the profession, those in the military [28:29] and those who are professional athletes [28:31] or had jobs in the social or natural [28:33] sciences had the of those, there was a [28:37] lower percentage of those that had [28:39] depression or mania. In some cases, like [28:42] those who were professional athletes, [28:43] didn't seem to have There was no [28:44] incidents of mania, at least in this [28:46] data set. Whereas, at the opposite [28:48] extreme of the graph, those [28:51] that were poets, so these are eminent [28:53] individuals, people that were [28:54] exceptional poets, exceptional fiction [28:56] writers, exceptional artists, or [28:58] non-fiction writers, [29:00] well, there, especially for the poets, [29:03] you find that as many as 90% [29:07] of these very successful poets [29:09] had either depression or mania. Again, [29:13] associative correlative, [29:15] no causal relationship here. [29:18] But, it is really striking to see how [29:20] the creative occupations, poetry, [29:23] fiction, art, non-fiction writing, even [29:26] though non-fiction writing is about [29:27] non-fiction, it's still creative, music [29:29] composition, theater, much higher [29:31] incidence of things like mania. In fact, [29:33] for the people in theater, the actors, [29:36] even though the overall [29:39] occurrence of depression and mania is [29:40] lower than that in poets, the fraction [29:44] of those individuals that have mania is [29:47] exceedingly high. It's about 30% of [29:50] those that they looked at [29:52] who are actors [29:54] have manic episodes or have full-blown [29:57] mania. So, I'm referring to these data [29:58] because, first of all, I find them [30:00] incredibly interesting, right? Up until [30:02] now, we've been talking about bipolar [30:03] disorder and other mood disorders [30:05] for their maladaptive effects, and [30:07] again, they're extremely maladaptive, [30:08] much, much higher incidence of of [30:10] suicide, et cetera. But, we'd be wrong [30:12] to say that certain aspects of manic [30:14] episodes don't lend themselves well to [30:15] creativity, or that certain aspects of [30:18] major depression don't lend themselves [30:19] well [30:20] to creativity, or to the performing [30:23] arts, or to poetry. So, today, we've [30:24] really done a deep dive into bipolar [30:27] disorder, and to both the manic and the [30:29] depressive components that are [30:32] present or can be present in bipolar [30:34] disorder, and the different forms of [30:36] bipolar disorder, and some of the major [30:38] treatments for bipolar disorder, in [30:40] particular, lithium and its underlying [30:41] mechanisms. I do hope you found it [30:43] beneficial [30:44] both for yourself and for others. I just [30:47] want to remind people that bipolar [30:48] disorder is an extremely serious [30:49] condition. If you suspect that you have [30:52] bipolar disorder or you know somebody [30:53] who does, [30:55] please make sure that you or they talk [30:57] to a qualified health professional. So [30:59] once again, thank you for joining me [31:00] today for our discussion about the [31:01] biology and treatment of bipolar [31:03] disorder. And last but certainly not [31:05] least, thank you for your interest in [31:07] science. [31:10] >> [music]