全科医学中的心理健康病案研究(二十六)——抑郁与恶性肿瘤

Sasha Fehily，Grant Blashki，Fiona Judd，Leon Piterman，Hui Yang，Shane Thomas

在世界范围内，抑郁是首要的患病因素之一，6个人中就有1个人在生命过程中患过抑郁[1]。肿瘤是抑郁发生和发展的危险因素。肿瘤病人的抑郁发生率比一般人群高出3～5倍[2]。尽管有大量的科学文献报道了肿瘤病人的抑郁流行情况，但对其流行率的估计却相差很大。Couper等[3]的研究结果显示，肿瘤病人中的重性抑郁障碍(major depressive disorder)的流行率为10%～25%。国际上对肿瘤诊疗服务的研究一致认为，肿瘤病人的抑郁问题通常没有得到诊断，并很少得到治疗。

1 病史

李赞(化名)女士，两个孩子的母亲，58岁时被诊断为乳腺癌。诊断前2个月，她洗澡的时候在左侧乳房触摸到一个肿块。她到你的诊所来看病，你安排她做乳腺X线检查，然后再做超声检查，最后进行活组织检查。你把她的检查结果转到乳腺外科专家那里，请专家做进一步诊断。

今天她再次来到你的诊所看病，目的是讨论乳腺外科专家的诊断结果。李赞女士的诊断结果是浸润性导管癌(3度)，Nottingham总评分为8分；肿块直径2 cm，雌激素和孕激素受体呈阳性。她昨天去看了乳腺外科专家，专家建议做乳房切除术、淋巴结切除术，并接受为期5年的他莫昔芬(tamoxifen，三苯氧胺)治疗。此外，肿瘤学专家的会诊建议是辅助化疗和放疗。专家还告诉她，如果她想要做乳房再造手术，可以考虑在做乳房切除术的同时做再造术。

在与李赞女士讨论的过程中，你发现她的情绪和上次来看病时很不一样。你再进一步询问她怎样应对自己现在发现的病情，她开始眼中含泪，说自己这些日子心境一直很差。她说最近不愿意去见任何亲近的朋友。她的妈妈一直在努力地支持她，跟她进行过一次严肃的谈话，告诉她怎样克服当前的困难。不过李赞认为这种谈话更让她灰心丧气，所以她回避跟她妈妈谈论这个话题。她挣扎着与脑海中不断涌现的有关死亡的想法做斗争，不过她否认自己有自杀想法。她还说自己的食欲不振，自从第一次发现乳房肿块后，体质量一直下降，现在体质量减少了3 kg。

2 体检

对病人进行心理健康状态检查：她穿着干净整洁并且宽松的衣服。她留着长发，但看上去头发不太干净。她很少和你目光接触，偶尔自言自语，而且她说话的声音很轻。她的情绪是忧郁的。没有发现她有明显的思维障碍，她自己也否认自己有任何妄想和幻觉。她对时间、地点和人物有定向力。她对自己最近的心境变化表现出较好的洞察力。

对病人进行体检：这是一位正常和身材苗条的妇女。她的生命体征正常，没有甲状腺机能减退的征象。所有身体检查中惟一发现是左乳房下外四分之一处的一个无压痛的小硬结。没有触摸到淋巴结肿大。

3 提问

3.1 提问1：肿瘤病人每天要应对哪些困难？

3.2 提问2：应该考虑哪些重要的鉴别诊断？在阐明正确诊断的时候，会面临哪些困难？

3.3 提问3：抑郁和恶性肿瘤之间有因果联系吗？

3.4 提问4：为什么要认识到治疗肿瘤病人抑郁的重要性？

3.5 提问5：针对恶性肿瘤病人的抑郁，有哪些治疗选择？

4 解答

4.1 解答1：肿瘤病人每天要应对的困难 当一个人接受癌症诊断的时候，必须面对很多情感上的困难。肿瘤病人会有一些自然的情感反应，比如自己问自己一些不合理的和无助的问题，如“为什么是我得癌症？”、“是不是我做错了什么事情？”。病人还可能对疾病的不确定性感到迷茫，对不得不面对死亡感到束手无策。这些情感困难使病人处于焦虑状态，影响他们的健康，需要进行治疗。就李赞的病例而言，大约40%的乳腺癌病人有抑郁和焦虑症状[4]。病人常见的压力是与朋友和家人谈论自己的病情。大多数病人对别人的同情、支持和帮助感到不舒服，认为这是自己给别人平添了麻烦。

在患癌症这样的疾病过程中，需要应对很多现实中的问题。病人不可避免地要打乱自己原来的生活计划。在病人进入治疗过程时，不可能持续原来那样的家庭生活，也不可能继续实现原来的工作承诺。由于长期处于生病状态，并由于治疗的副作用使人感到虚弱无力，病人很可能无法行使社会和家庭责任，这需要改变家庭其他成员的责任分工。从更大的范围看，需要改变工作场所和社会的责任分工。

除了情感和现实中面临的问题外，病人还可能患其他的肿瘤相关疾病，并可能患因为治疗而造成的疾病。

4.2 解答2：应该考虑的重要的鉴别诊断以及在阐明正确诊断时面临的困难 当接受肿瘤诊断的时候，病人会出现悲伤或害怕等正常反应，因此你必须要考虑到的一个问题是确定病人所经历的情感变化是不是对压力的正常反应。为了能给病人提供正确的治疗措施，一定要把这些正常的情感反应与综合征性心境障碍(syndromal mood disorder，如重性抑郁)相鉴别。

对患躯体疾病的病人，比如癌症病人，明确地诊断出抑郁性障碍可能是比较困难的。首先，病人的抑郁症状可能被错误地归因于肿瘤，因为抑郁的躯体化症状与肿瘤直接导致的心理症状是难以鉴别开来的。这些症状通常包括：疲劳、体质量降低、缺乏食欲、睡眠紊乱、精力下降等。通常某些认知症状，如缺乏兴趣、集中力差、记忆紊乱、容易激惹、做决定困难等，对诊断和治疗检测来说更有价值[3]。

此外，化疗或放疗等治疗措施可能导致某些躯体化抑郁症状(如疲劳感)，或许不是抑郁的问题。反过来看，有很多抑郁症状可能被错误地认为是治疗措施的副作用导致的，从而导致识别不出来抑郁障碍。还有必要指出的是，有很多因素可以影响肿瘤病人的心境，比如疼痛、无法活动、虚弱无力、对死亡的恐惧等。

最后一点，特别是在治疗阶段的后期，很多肿瘤病人表达出“宁愿去死”的想法。非常重要的是，要明确病人的这个想法是抑郁性疾病的一部分，还是病人对肿瘤的心理反应。如果是抑郁性疾病的一种表现，我们可以改变治疗抑郁的策略，选择那些更可能有益于改善病人生活质量的治疗方法。需要提醒的是，对肿瘤的诊断是众所周知的自杀危险因素。

4.3 解答3：抑郁和恶性肿瘤之间的联系 各科研文献对肿瘤病人抑郁障碍的流行率报道并不一致，即便如此，流行率的估计范围已经高到足以让研究者努力地探讨两者的关系。首先，有个别类型的肿瘤可以直接对人的心境产生生物学效应，比如颅内肿瘤可以对大脑造成直接的占位效应，造成心境变化。还有越来越多的证据表明，某些肿瘤影响下丘脑-垂体-肾上腺轴，其作用机制是全身皮质醇激素分泌受到了影响[5]。人们认为某些肿瘤，如胰腺癌和小细胞肺癌，会通过尚不明确的激素效应造成病人抑郁。此外，很多肿瘤治疗药物(如皮质类固醇激素)和化疗药物(如长春碱、环磷酰胺、干扰素)[3]也能造成心境紊乱。其他药物以及某些外科措施(如卵巢切除术或抗雄激素治疗)可能造成激素失衡，继而影响病人心境。

对于患乳腺癌的女病人来说，使用他莫昔芬(一种雌激素受体拮抗剂)经常会导致更年期症状。在用他莫昔芬的女病人中，大约有2/3的人有血管舒缩症状(潮热和夜间出汗)。这些症状往往伴随焦虑、睡眠紊乱以及社交和工作能力变差，并可能加剧抑郁症状。

某些人口学特征与抑郁的高流行率有关，如诊断肿瘤时比较年轻、女性、肿瘤部位、肿瘤转移、以往手术情况等。另外的一些因素则可能影响抑郁的发展，如经济状况、人格特质、社会支持、种族和文化背景等。某些肿瘤与抑郁的相关性更大，特别是口咽癌、胰腺癌、乳腺癌、肺癌。

4.4 解答4：认识到治疗肿瘤病人的抑郁的重要性 研究结果表明，患抑郁的肿瘤病人住院时间长、治疗结果差、生活质量下降。此外，抑郁能使治疗的副作用(如疼痛强度和疲劳感)更加明显[4]。抑郁症状可以导致病人对治疗的依从性差，这可能是由于抑郁病人缺乏动机和集中力受损造成的。因此，虽然肿瘤病人都会正常地出现轻度或不稳定的抑郁症状，但肿瘤却不会必然地导致持续的心境低落、认知障碍或躯体化症状(如抑郁性障碍)。之所以很多肿瘤病人的抑郁得不到诊断和治疗，最常见的原因是医务人员认识不到这一点。

4.5 解答5：针对恶性肿瘤病人的抑郁治疗选择 有强有力的证据表明，采用心理疗法治疗肿瘤病人的抑郁可以让病人获得各种收益。心理教育(psychoeducation)、认知行为疗法(CBT)、人际治疗法(IPT)都能够改善病人的心境紊乱，提高他们的自信心。有证据表明，采用小组式的干预方法，能够起到特别的效果，这些方法包括认知行为疗法、支持-倾述疗法(supportive-expressive therapy，SET)、正念减压法(mindfulness-based stress reduction，MBSR)、非正式支持小组法(informal support groups)[4]。

如果病人出现中度或严重的抑郁，则提示应该采用药物治疗。选择性5-羟色胺再摄取抑制剂(SSRIs)是一线的药物干预。临床随机对照研究证据表明，氟西汀(fluoxetine，百忧解)、帕罗西汀(paroxetine)和安定(sertaline)都是有效的。有些病人使用SSRIs可能出现恶心症状；如果使用化疗药物也可能加重恶心症状。另外，还可以使用文拉法辛(一种5-羟色胺去甲肾上腺素受体抑制剂，SNRI)，不过它可能有一些额外的镇静作用。有证据表明三环类抗抑郁药(TCAs)对抑郁是有效的；不过要限制这类药物的使用，因为它有明显的副作用，并在过量服用时有中毒的危险。

重要的是要意识到某些抗抑郁药与化疗药物的相互作用。最常见的药物相互作用是通过CYP450同工酶系统产生的代谢作用。这是抗抑郁药的常见代谢途径，而抗肿瘤药物可以造成这些抗抑郁药在血清中的蓄积。需要注意的是，抗抑郁药(特别是SSRIs)与他莫昔芬有相互作用[6]。帕罗西汀以及其他SSRIs在较小的程度上拮抗CYP450同工酶2D6。因此，如果要使用SSRIs的话，要选择对2D6代谢作用最小的药物，比如西酞普兰(citalopram)[4]。另外一个例子是蒽环类化疗药物(anthracycline-based chemotherapies)，该药物经常用于乳腺癌化疗，它会与三环类抗抑郁药发生相互作用，导致心电图上的QT延迟，使病人容易发生尖端扭转型室性心动过速(心动过速的一种特殊类型)[4]。对于所有的临床病例来说，要根据具体病人的具体临床问题，选择恰当的治疗方法。同时，在治疗策略中要考虑到更广泛的心理学问题以及家庭和社会因素[7]，因为这些因素可能造成病人心境紊乱的反弹，也是心境紊乱的危险因素。

1 Depression[EB/OL].http://www.beyondblue.org.au/the-facts/depression.

2 Chan A,Ng TR,Yap KY.Clinically relevant anticancer antidepressant drug interactions[J].Expert Opin Drug Metab Toxicol,2012,8(2):173-199.

3 Couper JW,Pollard AC,Clifton DA.Depression in cancer[J].MJA Open,2012,1(Suppl 4):13-17.

4 Agarwala P,Riba MB.Tailoring depression treatment for women with breast cancer[J].Current psychiatry,2010,9(11):39-49.

5 Pasquini M,Biondi M.Depression in cancer patients:A critical review[J].Clin Pract Epid Ment Health,2007,3:21-30.

6 Desmaris JE,Loopers KJ.Managing menopausal symptoms and depression in tamoxifen users:Implications of drug and medicinal interactions[J].Maturitas,2010,67:296-308.

7 Blashki G,Judd FK,Piterman L.General practice psychiatry[M].North Ryde(NSW):McGraw-Hill Australia,2006.

·WorldGeneralPractice/FamilyMedicine·

【IntroductionoftheColumn】 The Journal presents the Column of Case Studies of Mental Health in General Practice;with academic support from Australian experts in general practice,psychology and psychiatry from Monash University and the University of Melbourne.The Column′s purpose is to respond to the increasing need for the development of mental health services in China.Through study and analysis of mental health cases,we hope to improve understanding of mental illnesses in Chinese primary health settings,and to build capacity amongst community health professionals in managing mental illnesses and psychological problems in general practice.A patient-centred whole-person approach in general practice is the best way to maintain and improve the physical and mental health of residents.Our hope is that these case studies will lead the new wave of general practice and mental health service development both in practice and research.A number of Australian experts from the disciplines of general practice,mental health and psychiatry will contribute to the Column.Professor Blashki,Professor Judd and Professor Piterman are authors of the text General Practice Psychiatry;the Chinese version of the book to be published in 2014.The Journal cases are helping to prepare for the translation and publication of a Chinese version of the book in China.We believe Chinese mental health in primary health care will reach new heights under this international cooperation.

Depression is one of the leading causes of morbidity worldwide with the lifetime rate of 1 in 6 people[1].Cancer is a risk factor for the development of depression,with the incidence being three to five times more than that of the general population[2].Despite the wealth of literature,the prevalence of depression in this subgroup widely varies in its estimation.According to Couper et al the prevalence of defined major depressive disorder in people who have cancer is estimated to be 10%-25%[3].International cancer services are united in recognising that depression often goes undiagnosed and undertreated depression in patient′s suffering from cancer.

1 History

Mrs Li Than,a single mother of two,was 58 when she was diagnosed with breast cancer.Two months previously,while Li was taking a shower,she felt a lump on her left breast.After presenting to your practice,she was sent for a mammogram,then an ultrasound and finally a biopsy.You referred her to a breast surgeon to discuss the diagnosis.

She has presented to your practice today to discuss the recommendations made to her by the surgeon.Li′s diagnosis was invasive ductal carcinoma grade 3 with a total Nottingham score of 8.The mass was two centimetres in diameter and was positive for oestrogen and progesterone receptors.She saw a breast surgeon yesterday who recommended a mastectomy,lymphadenectomy and five years of tamoxifen treatment,in addition to a consultation with an oncologist for likely adjuvant chemotherapy and radiotherapy.She was informed that if she wanted breast reconstruction surgery,it would be possible for it to be performed at the same time as the mastectomy.

On discussion with Li,you discover that her affect is markedly different from her last presentation.Upon further questioning about how she is coping,she becomes teary and describes a persistently low mood.She has noticed a recent reluctance to see any of her close friends.Her mother has been trying to support her emotionally and to have a serious discussion about what she is going through,but Li just finds this frustrating and avoids the discussion.Li is struggling with overwhelming thoughts about death,but denies suicidal ideation.She has noticed a reduction in her appetite and has consequently lost three kilograms since she first noticed the breast lump.

2 Examination

On mental status examination,she is neatly dressed in loose-fitting clothes.Her hair is long and not particularly tidy.She maintains poor eye contact,has minimal spontaneous speech and is softly spoken.Her affect is depressed.No formal thought disorder is evident and she denies any delusional thinking or hallucinations.She is oriented to time,place and person.She displays a good degree of insight into her recent change in mood.

Her physical examination reveals a normal,thin woman.Her vital signs are normal and she has no signs of hypothyroidism.All that is remarkable throughout the rest of the physical examination is a small firm non-tender breast mass in the lower outer quadrant of the left breast.There is no palpable lymphadenopathy.

3 Questions

3.1 Question1:What are the common day to day hardships that someone with cancer would have to deal with?

3.2 Question2:What are the key differential diagnoses to consider and what difficulties are faced when delineating the correct diagnosis?

3.3 Question3:Is there a causal link between depression and malignancy?

3.4 Question4:Why is it important to recognize and treat depression in patients with cancer?

3.5 Question5:What are the options available for treating depression in patients with malignancy?

4 Answers

4.1 Answer1:What are the common day to day hardships that someone with cancer would have to deal with? There are many emotional difficulties a person must face on receiving a diagnosis of cancer.It is natural to respond by asking oneself irrational and unhelpful questions such as "why me?" and "is this my fault?".Patients may also find difficulty in coming to terms with the uncertainty of the illness and having to face the possibility of death.This causes an anxiousness surrounding one′s health and required treatments.Of relevance to Li′s case,approximately 40% of patients with breast cancer suffer from depression and anxiety symptoms[4].A common area of stress is communicating the news to friends and family.Many feel uncomfortable with receiving sympathy,support and assistance,seeing it as a burden on other people.

Similarly many practical issues have to be dealt with during the course of an illness such as cancer.An interruption of life plans is inevitable.It is hard to continue coordinating family and work commitments around regular treatment.Patients are likely to face an inability to fulfill their social and familial responsibilities due to associated periods of being unwell or suffering from treatment side effects that cause debilitation.This can also require a change of other people′s roles in the family,at work and in society at large.

In addition to coping with these emotional and practical issues,cancer patients might also be suffering from physical ailments associated with their illness and its treatment.

4.2 Answer2:What are the key differential diagnoses to consider and what difficulties are faced when delineating the correct diagnosis? Feelings of sadness and fear are normal responses to receiving a cancer diagnosis,so an essential consideration is to determine whether the patient is experiencing what can be regarded as a normal response to stress.In order to provide appropriate medical treatment,it is crucial to differentiate these normal feelings from a syndromal mood disorder (major depression).

It can be difficult to be clear about the diagnosis of a depressive disorder in patients with physical illnesses such as cancer.First,symptoms of depression can be misattributed to cancer due to the difficultly in differentiating between somatic symptoms of depression and the direct physiological symptoms associated with cancer.Some of these commonly include;fatigue,loss of weight and appetite,sleep disturbance and decreased energy.Cognitive symptoms such as loss of interest,poor concentration,memory disturbance,irritability,difficulty making decisions are generally more useful in making a diagnosis and monitoring treatment[3].

Additionally,somatic depressive symptoms such as fatigue can be caused by treatments such as chemotherapy and radiotherapy,rather than being due to untreated depression.Conversely,a number of depressive symptoms can be mislabeled as treatment side effects leading to risk of under-recognition of a depressive disorder.It is also necessary to note the multiple factors that are likely to be contributing to a patient′s mood in the setting of malignancy including pain,immobility,debilitation and fear of death.

Finally,particularly in the later stages of treatment,many patients with cancer express the thought that they would rather be dead.It is important to be clear whether such thinking is part of a depressive illness,and so may be changed by treatment with potentially significant benefits for the person′s quality of life,or whether this is a thought expressed in the absence of a depressive disorder.Of note,a diagnosis of cancer is a well-known risk factor for suicide.

4.3 Answer3:Is there a causal link between depression and malignancy? While the prevalence of depressive disorders in patients with cancer varies throughout the literature,the estimated ranges are high enough to warrant the search for a link between the two.Firstly,a small number of cancers may have direct biological effects on mood.For example,intracranial lesions can have a direct mass effect in the brain,causing mood alteration.There is also increasing evidence to suggest that some cancers influence the Hypothalamic-Pituitary-Adrenal axis.The mechanism of mood alteration here is postulated to be due to a change in systemic cortisol secretion[5].Some cancers,such as pancreatic cancer and small cell lung cancer are thought to cause depression by a yet to be clarified hormonal effect.Additionally,many of the oncological therapeutic agents,such as corticosteroids and chemotherapies including vinblastine,cyclophosphamide and interferon[3]are known to cause mood disturbance.Other agents and some surgical interventions,such as oophorectomy or androgen ablation,can result in hormone imbalance,which in turn may affect mood.

For women with breast cancer,the use of tamoxifen,an oestrogen receptor antagonist,often induces menopausal symptoms.Vasomotor symptoms (hot flushes and night sweats) occur in around two thirds of women treated with tamoxifen.These symptoms are often associated with anxiety,sleep disturbance and poorer social and occupational functioning,and may exacerbate depressive symptoms.

Some demographic variables have been associated with a higher prevalence of depression,including younger age of diagnosis,being female,location of the cancer,metastases and prior surgery.Other variables are also likely to influence the development of depression,such as economic status,personality traits,social support and ethnic and cultural background.Similarly,depression is more commonly associated with certain cancers,particularly oropharyngeal,pancreatic,breast and lung cancer.

4.4 Question4:Why is it important to recognize and treat depression in patients with cancer? Research has demonstrated that depression in individuals with cancer is linked to prolonged hospital stays,worse clinical outcomes and a reduction in quality of life.Additionally,depression can lead to worsened side effects,such as pain intensity and fatigue[4].Depressive symptoms can contribute to non-compliance with treatment;this may be secondary to a lack of motivation or impaired concentration.Thus,it is important to be clear that whilst mild and fluctuating depressive symptoms can be normal in patients with cancer,sustained low mood accompanied by cognitive and somatic symptoms (i.e.a depressive disorder) is not.Failure to recognize this is one of the most common causes of patients being undiagnosed and untreated.

4.5 Answer5:What are the options available for treating depression in patients with malignancy? Strong evidence surrounds the benefits of psychotherapy in treating depression in patients with cancer.Psychoeducation,Cognitive Behavioural Therapy (CBT) and Interpersonal Therapy (IPT) have all been shown to improve mood disturbance and self-esteem.Several group interventions particularly shown to be effective include;CBT,supportive-expressive therapy (SET),mindfulness-based stress reduction (MBSR),as well as informal support groups[4].

Pharmacological therapy is indicated for individuals with moderate or severe depression.Selective Seratonin Receptor Inhibitors (SSRIs) are used as first-line pharmacological intervention.Fluoxetine,paroxetine and sertaline all have supporting evidence in RCTs.In some patients the SSRI′s may cause nausea,or exacerbate nausea due to chemotherapeutic agents.Venlafaxine,a Seratonin Noradrenaline Receptor Inhibitor (SNRI) is also used,and may have some additional analgesic benefit.Tricyclic antidepressants (TCAs) have demonstrated effectiveness;however,use is limited due to side effects and the danger of toxicity in overdose.

It is important to be aware of some interactions between antidepressant medication and chemotherapeutic agents.The most frequent interaction is due to the metabolism via the CYP450 isoenzyme system.This common metabolic pathway for antidepressants and anti-cancer drugs can cause a disturbance in the plasma concentration of these medications.Of note,Antidepressants,particularly some SSRIs interact with Tamoxifen[6].Paroxetine and to a lesser extent some other SSRIs inhibit the CYP450 isoenzyme,2D6.So if using an SSRI,choose an agent with minimal effect on the 2D6 metabolism such as citalopram[4].Another example is anthracycline-based chemotherapies,which are frequently used in breast cancer patients,can interact with TCAs and lead to QT prolongation on ECG,predisposing the patient to the development of torsades de pointes,a particular type of tachycardia[4].As in all clinical encounters,it is important to choose the appropriate treatments based on the specific clinical issues in the patient and to ensure that treatment includes consideration of broader psychological issues,family and social factors which may act as both resilience and risk factors for the patient′s mood disturbance[7].

1 Depression[EB/OL].http://www.beyondblue.org.au/the-facts/depression.

2 Chan A,Ng TR,Yap KY.Clinically relevant anticancer antidepressant drug interactions[J].Expert Opin Drug Metab Toxicol,2012,8(2):173-199.

3 Couper JW,Pollard AC,Clifton DA.Depression in cancer[J].MJA Open,2012,1(Suppl 4):13-17.

4 Agarwala P,Riba MB.Tailoring depression treatment for women with breast cancer[J].Current psychiatry,2010,9(11):39-49.

5 Pasquini M,Biondi M.Depression in cancer patients:A critical review[J].Clin Pract Epid Ment Health,2007,3:21-30.

6 Desmaris JE,Loopers KJ.Managing menopausal symptoms and depression in tamoxifen users:Implications of drug and medicinal interactions[J].Maturitas,2010,67:296-308.

7 Blashki G,Judd FK,Piterman L.General practice psychiatry[M].North Ryde(NSW):McGraw-Hill Australia,2006.