兽研简要总结
焦虑、恐惧、重复行为、攻击性以及与年龄相关的认知衰退等行为问题，会显著影响犬和猫的福利及其与照护者的关系。药物越来越多地被用于管理这些问题，但治疗决策往往基于人类精神病学，而人类精神病学并不能总是直接应用于动物。本综述总结并比较了目前关于用于治疗犬和猫行为障碍药物的知识，重点关注主要脑内化学系统如何影响行为、各种治疗受到科学证据支持的程度，以及犬和猫对药物的处理方式可能有何不同。现有证据在犬中通常比在猫中更强，而且物种之间的重要差异可能影响药物安全性和治疗反应。人类精神病学研究可以提供有用的指导，但动物的行为状况应基于可观察的行为进行评估，而不是直接套用人类精神科诊断。通过整合现有证据、生物学机制和物种特异性差异，本综述为在犬和猫中更安全、更知情地使用行为药物提供了实用框架，并强调了需要进一步研究的领域。
1. 引言
伴侣动物的行为障碍是当代兽医实践中重要的临床和福利问题[1,2]。城市化加剧、人与动物关系的变化、长期室内饲养以及寿命延长，促使人们更加认识到焦虑相关疾病[2,3]、强迫行为、情境性恐惧反应和某些攻击性表现[4,5]，以及犬和猫与年龄相关的认知功能障碍[6]。因此，药物干预已成为多模式行为管理的常规组成部分[7]。
尽管使用日益增多，兽医精神药理学仍以处方实践异质性和证据在不同物种及疾病间的分布不均為特征[8]。在许多情况下，治疗决策明确或隐含地受到从人类精神病学文献外推的影响[9]。尽管哺乳动物神经回路之间的进化保守性总体一致，但从人类精神病学直接转化到兽医行为医学并不简单[10,11]。人类医学的诊断框架依赖于主观症状报告和标准化分类标准，而这些不能直接应用于非语言物种[10,12]。因此，需要一种结构化的比较方法，以区分机制重叠和不恰当的诊断转移[13]。
在本综述中，我们旨在通过结构化的比较框架，整合目前关于犬和猫行为障碍中靶向神经递质药物治疗的知识。具体而言，我们旨在(i)考察主要神经递质系统作为与犬和猫临床观察到的行为表型相关的潜在药理靶点，(ii)界定从人类精神病学进行机制转化与直接兽医临床证据之间的界限，以及(iii)总结与给药、治疗持续时间、药物相互作用、洗脱期考量和安全性监测相关的现有药物特异性和物种特异性药代动力学数据。
图1展示了犬和猫的关键药代动力学考量，包括吸收、分布、代谢和排泄。这些过程可能因药物、物种和个体患者特征而异，强调了药物特异性和患者特异性剂量选择、剂量滴定和临床监测的重要性。
2. 方法
2.1. 文献检索策略
采用结构化叙述性综述方法，以增强透明度，同时保持比较性综合所需的适当灵活性[14]。本次文献检索旨在支持结构化叙述性综述，并非旨在穷尽或满足系统综述的要求。检索了PubMed、Scopus和Web of Science中关于用于治疗犬和猫行为障碍的精神药物的药理管理和药代动力学的相关文献。最终文献检索于2026年10月2日进行。
检索词被组合为四个主要概念组：物种、行为表型、药理学或神经递质相关术语以及药代动力学术语。药代动力学术语包括“药代动力学”“生物利用度”“吸收”“代谢”“清除”“消除”“半衰期”“活性代谢物”和“药物相互作用”。每个概念组内的术语使用布尔运算符“OR”组合，相关概念组之间使用“AND”组合。物种相关术语包括“犬”“犬类”“猫”和“猫类”。行为表型术语包括“焦虑”“恐惧”“恐怖症”“分离焦虑”“强迫症”“重复行为”“攻击行为”“认知功能障碍”和“噪音恐惧症”。药理学和神经递质相关术语包括“SSRI”“选择性5-羟色胺再摄取抑制剂”“三环类抗抑郁药”“氟西汀”“氯米帕明”“曲唑酮”“加巴喷丁”“苯二氮䓬类”“α2受体激动剂”“右美托咪定”“司来吉兰”“单胺氧化酶抑制剂”“NMDA”和“谷氨酸”。
纳入1990年1月至最终检索日期之间发表的研究。仅在早期出版物提供了与本综述所讨论药物的药理学机制、安全性或临床使用直接相关的基础信息，且相关信息在1990年后的文献中未得到充分体现时，才纳入这些早期出版物。仅纳入英文出版物；非英文出版物予以排除。
2.2. 纳入与排除标准
符合条件的研究包括随机对照试验（RCT）、非随机前瞻性研究、观察性队列研究、病例对照研究、回顾性研究和病例系列，这些研究评估了犬或猫临床人群中的药理学干预措施。评估相关药物在犬或猫体内的生物利用度、代谢、半衰期、清除、消除或活性代谢物的药代动力学研究也被纳入。相关的荟萃分析和共识指南在适用时予以纳入。仅限于实验室啮齿动物模型且与兽医临床无直接相关性的研究予以排除。缺乏支持数据的观点性文章予以排除，除非其代表正式共识或临床指南。
将从三个数据库检索到的记录合并，并在筛选前去除重复记录。对标题和摘要进行相关性筛选，随后对可能符合条件的文章进行全文评估。还筛选了相关综述和纳入研究的参考文献列表，以识别数据库检索未捕获的符合条件的出版物。
研究选择和数据提取由两位作者共同完成。关于研究资格或解释的分歧通过讨论和共识解决。
2.3. 基于研究设计的证据分类
为便于比较现有兽医文献，研究按研究设计进行分类。A类包括随机对照试验和荟萃分析；B类包括前瞻性非随机研究和设计良好的观察性研究；C类包括回顾性研究和病例系列；D类包括缺乏直接临床验证的专家意见或机制推断。重要的是，这些类别描述的是现有证据的设计，而非治疗效应的总体确定性或强度。它们并不独立考虑样本量、偏倚风险、精确性、一致性、随访持续时间或独立重复。因此，这些类别仅用于描述性目的，并需结合适应证、物种、研究特征和支持文献的局限性进行解读。
3. 神经递质系统与行为表型
主要神经递质系统参与情绪加工、觉醒、抑制控制、动机和认知功能，并可能导致不同但相互重叠的行为表型。图2提供了主要神经生物学功能、代表性药理学靶点以及可能与这些系统相关的行为表型的综合概述。尽管为概念清晰起见将这些系统分别呈现，但存在大量功能重叠，许多精神药理学药物通过多种神经递质通路发挥治疗作用。这些关联代表合理的神经生物学和药理学关系，不应被解释为单一神经递质系统功能障碍导致特定行为障碍的证据。该框架为解读以下关于各神经递质系统的章节提供了基础，同时将合理的药理学靶点与已证实的因果机制区分开来。表1总结了人类精神病学与犬、猫行为表型之间主要神经递质系统的比较映射。
兽医行为医学涉及的主要神经递质系统，根据其主要神经生物学功能、代表性药理靶点及相关临床行为表型进行总结。5-羟色胺能通路通过与边缘系统和皮层环路的相互作用，参与焦虑相关反应、强迫性和重复性行为、分离相关痛苦及冲动控制的调节。起源于蓝斑的去甲肾上腺素能信号介导觉醒、注意力、应激反应性和急性恐惧反应。γ-氨基丁酸（GABA）能神经传递在中枢神经系统中提供抑制性控制，并通过GABAA正性变构调节剂参与抗焦虑、镇静和辅助性癫痫管理。加巴喷丁是一种α2δ配体，可调节电压门控钙通道，代表一种机制上不同的抗焦虑策略，因此与直接GABA能调节分开考虑。多巴胺能通路，特别是中脑边缘系统，调节动机、奖赏处理、强化和认知功能，而谷氨酸能神经传递在学习、记忆、恐惧消退和突触可塑性中发挥重要作用。每种神经递质系统均展示了代表性药物及其主要分子靶点；然而，许多精神药理药物影响多种神经递质通路和行为域。临床证据水平在犬中最高，而猫中的证据仍然有限，突显了物种特异性治疗解读和进一步临床研究的必要性。
3.1. 5-羟色胺能系统
5-羟色胺能系统在焦虑调节、冲动控制和重复行为调节中发挥核心作用[15,16,17,18]。5-羟色胺主要起源于背侧中缝核并广泛投射至边缘和皮层区域，影响哺乳动物物种的情绪调节。
根据选定人群的对照临床试验，选择性5-羟色胺再摄取抑制剂（SSRIs）和三环类抗抑郁药（TCAs）构成犬行为医学中分离焦虑和强迫症的一线药物治疗[19,20]。曲唑酮也作为辅助性5-羟色胺能药物用于犬和猫情境性焦虑及应激相关行为的治疗，尽管证据因物种和适应症而异[21,22]。猫患者的证据仍然稀少，尽管对照试验支持其用于选定的情境性适应症，如就诊前和运输相关焦虑。然而，考察慢性行为障碍的随机对照试验（RCTs）仍然稀疏，且现有证据大多来自小型前瞻性研究或病例系列[23]。尽管如此，RCTs已证明氟西汀和氯米帕明在减少猫喷尿方面的疗效[24,25]。5-羟色胺能药物可能需要数周才能达到最大临床效果。初始药理效应后的适应性神经可塑性变化被认为是这种延迟治疗反应的一种解释；然而，该机制尚未在所有物种中完全确立[26]。因此，在起始阶段常给予短效辅助药物。
潜在不良反应包括胃肠道紊乱、食欲改变、镇静或矛盾性兴奋，以及与其他5-羟色胺能药物联用时罕见的5-羟色胺毒性[23,27]。在单胺氧化酶抑制剂（MAOIs）和选择性5-羟色胺再摄取抑制剂之间转换时，需要仔细的洗脱期[28]。
在美国，口服盐酸氯米帕明片剂和盐酸氟西汀咀嚼片获FDA批准用于犬分离焦虑的治疗，氟西汀的批准用途包括与行为矫正计划联合给药。然而，兽医行为医学中使用的许多其他5-羟色胺能药物为超说明书用药[20,29]。
3.2. 去甲肾上腺素能系统
去甲肾上腺素能系统主要起源于蓝斑，在觉醒、警觉、应激反应性和急性恐惧反应调节中发挥核心作用。去甲肾上腺素能活性增加与人类精神疾病如惊恐障碍和创伤后应激障碍中的过度觉醒密切相关[30,31]。在伴侣动物中，去甲肾上腺素能信号可能促成情境性恐惧反应，包括兽医就诊期间的噪音相关恐惧/焦虑，以及对急性环境应激源的反应。
α2肾上腺素能激动剂，特别是右美托咪定，经口黏膜途径给药，在对照试验条件下已证明可有效减少犬的急性噪音相关恐惧反应[32]。这些药物减少突触前去甲肾上腺素释放并减弱交感神经激活，提供快速抗焦虑效果。尽管可乐定已在选定病例中超说明书使用，但缺乏已发表的对照兽医临床试验。因此，去甲肾上腺素能调节最恰当地被概念化为事件靶向或辅助治疗，而非广泛性焦虑综合征的主要长期管理方案。
心血管效应，包括心动过缓和低血压，是具有临床相关性的考量因素，尤其在老年和心脏功能受损的患者中[33]。需要根据物种特异性调整剂量并进行仔细监测，以尽量减少血流动力学风险。虽然从人类高唤醒模型进行机制层面的转化是合理的，但由于情境触发因素和行为表达方式的差异，直接进行精神病学诊断层面的迁移仍然不恰当。
在美国，右美托咪定口黏膜凝胶（Sileo）获FDA批准用于治疗犬的噪音厌恶[32]。2026年，美国FDA批准他西匹米定口服溶液（Tessie）用于治疗犬的噪音厌恶和分离焦虑[34]。支持这些获批适应证的证据包括为产品批准而提交的监管临床现场研究。同行评审证据也可获得，包括一项评估与主人离开相关的急性焦虑的小型随机、双盲、安慰剂对照交叉试点研究；然而，同行评审的临床文献范围仍然有限。
3.3. GABA能药物与α2δ钙通道配体
GABA作为哺乳动物中枢神经系统中主要的抑制性神经递质发挥作用，通过增强边缘回路内的抑制性张力来调节急性焦虑反应。苯二氮䓬类药物作为GABA-A受体的正性变构调节剂，增强抑制性神经传递并提供快速的抗焦虑和肌肉松弛效应[35]。在惊恐障碍和急性惊恐样状态的短期治疗中，苯二氮䓬类药物显示出比安慰剂更大的临床疗效，支持其在急性痛苦或可预测的应激情境中的相关性[36,37,38]。
在兽医患者中，苯二氮䓬类药物如阿普唑仑已被用于治疗短期情境性焦虑，特别是在急性噪音相关恐惧/焦虑和其他恐惧/应激相关情境中[39,40]。然而，对耐受性、依赖性和矛盾性脱抑制的担忧，尤其是在冲动或具有攻击倾向的个体中，限制了其长期应用[41,42,43]。在猫中，口服地西泮与罕见的特异性急性肝坏死相关，但其他苯二氮䓬类药物不具有相同的风险特征[44]。因此，建议在猫科患者中仔细选择药物并进行监测。
伊美匹酮是GABA-A受体苯二氮䓬结合位点的低亲和力部分激动剂，是一种具有临床相关性的非苯二氮䓬类GABA能药物[45]。在欧盟，伊美匹酮（Pexion®）被授权用于减轻犬噪音恐惧症相关的焦虑和恐惧。对照临床证据支持伊美匹酮在减轻犬噪音相关恐惧和焦虑方面的疗效[46]，如表2所总结。
虽然加巴喷丁不是经典的GABA受体激动剂，但它调节电压门控钙通道并间接影响兴奋性神经传递[47]。它通常用于减轻犬和猫的情境性应激，特别是在兽医诊所环境中。证据强度因适应证和物种而异。在猫科患者中，随机安慰剂对照试验支持其用于减轻就诊前和运输相关应激[48]。此外，一项在恐惧型收容所猫中进行的随机、双盲、安慰剂对照试验报告，每日给予加巴喷丁并配合行为矫正，可减少应激相关指标并改善行为康复进展[49]。相比之下，在犬和猫慢性行为障碍中更广泛的应用主要依赖于较小的前瞻性或回顾性研究，支持情境性使用之外的中等总体证据水平[50]。普瑞巴林是另一种α2δ亚基配体，其用于猫的情境性使用具有直接的临床和监管证据。普瑞巴林口服溶液（Bonqat®）在欧盟获得授权，并在美国获FDA批准用于缓解猫与运输和就诊相关的急性焦虑和恐惧[51]。其疗效在前瞻性、安慰剂对照临床现场研究中得到证实[51]。这些数据为α2δ钙通道配体在猫情境性焦虑和恐惧中提供了直接的临床支持；然而，这些证据不应外推至慢性或广泛性焦虑相关状况。GABA能药物和α2δ钙通道配体可为选定的急性或情境性行为适应证提供有用的支持；然而，它们应被整合到更广泛的行为和环境管理框架中，而非作为唯一的长期干预措施使用。
Table 2. Comparative Clinical Evidence by Species, Study Design, and Indication.
| Drug/Class | Primary Target | Dogs: Clinical Evidence | Cats: Clinical Evidence |
|---|---|---|---|
| Fluoxetine (SSRI) | SERT inhibition | 2 RCTs: separation anxiety [ 29 ] and compulsive disorder ( n = 63) [ 19 ] (Category A) | 1 RCT: urine spraying ( n = 17) [ 24 ] (Category A) |
| Clomipramine (TCA) | 5-HT and NE reuptake inhibition | 1 multicenter RCT: separation anxiety ( n = 95) [ 20 ] (Category A) | 1 multicenter RCT: urine spraying ( n = 67) [ 25 ] (Category A) |
| Trazodone | 5-HT2 antagonism and SERT inhibition | 1 randomized, double-blind, placebo-controlled crossover trial: veterinary-visit stress ( n = 20) [ 21 ] (Category A) | 1 randomized, double-blind, placebo-controlled crossover trial: pre-visit/transport anxiety ( n = 10) [ 22 ] (Category A) |
| Imepitoin | GABA-A receptor modulation | 1 randomized, double-blind, placebo-controlled clinical trial: noise-related fear/anxiety ( n = 238) [ 46 ] (Category A); authorized indication in the EU | No established direct clinical evidence for behavioral indications |
| Dexmedetomidine | α2-adrenoceptor agonism | 1 randomized, double-blind, placebo-controlled clinical trial: noise-related fear/anxiety ( n = 182) [ 32 ] (Category A) | No comparable controlled clinical trial identified for behavioral indications; evidence remains limited/indirect (Category C–D) |
| Tasipimidine | α2-adrenoceptor agonism | 2 pivotal randomized, double-blind, vehicle-controlled regulatory field studies: noise aversion ( n = 160) and separation anxiety ( n = 224) [ 34 ], plus 1 published randomized, double-blind, placebo-controlled crossover pilot study of owner-departure anxiety (Category A) | No established clinical evidence |
| Gabapentin | α2δ subunit of voltage-gated calcium channels | 1 double-blind, placebo-controlled clinical trial: veterinary-visit stress (Category A); 1 retrospective clinical study: broader behavioral disorders (Category C) | 1 randomized, blinded, placebo-controlled crossover trial: pre-visit/transport stress ( n = 20) [ 48 ] (Category A) |
| Pregabalin | α 2 δ subunit of voltage-gated calcium channels | No established direct clinical evidence for behavioral indications | Placebo-controlled clinical field evidence: acute anxiety and fear associated with transportation and veterinary visits ( n = 209) [ 51 ]; FDA-approved and authorized in the EU for this indication (Category A) |
| Selegiline | MAO-B inhibition | 1 large prospective open-label clinical study: canine cognitive dysfunction ( n = 641) [ 52 ], with additional experimental/behavioral studies (Category B) | No established direct clinical evidence for behavioral indications (Category D) |
| Benzodiazepines (e.g., alprazolam, diazepam) | GABA-A receptor positive allosteric modulation | Category B–C (situational fear/anxiety; evidence varies by agent and indication) | Category C–D; oral diazepam carries a risk of idiosyncratic acute hepatic necrosis |
3.4. 多巴胺能系统
多巴胺能通路，特别是从腹侧被盖区投射至伏隔核和前额叶皮层的中脑边缘回路，影响动机、奖赏处理和重复行为。在人类精神病学中，多巴胺能通路与冲动控制障碍和某些重复行为表型相关。在兽医学中，多巴胺能调节主要是在犬认知功能障碍综合征（CCD）的背景下进行研究的。
在美国，盐酸司来吉兰口服片（Anipryl®）获FDA批准用于控制与犬认知功能障碍综合征（CDS）相关的临床体征。已有报道患病犬出现临床改善，但现有证据应结合基础研究的局限性加以解读[52]。已有认知和行为参数改善的报道；然而，研究设计的局限性和所报告结局的变异性表明总体证据强度仅为中等[53]。多巴胺能对强迫行为和某些冲动攻击表型的贡献在机制上仍属可能，但常与5-羟色胺能通路交织。因此，将强迫行为完全归因于多巴胺能失衡会过度简化相关回路相互作用的复杂性。纳入5-羟色胺能–多巴胺能相互作用的回路层面模型可能更好地反映当前神经生物学认识[54]。
3.5. 谷氨酸能通路与新兴靶点
谷氨酸能神经传递在突触可塑性、学习和条件性恐惧反应的消退中起关键作用。在人类精神病学中，N-甲基-D-天冬氨酸（NMDA）受体及相关谷氨酸能通路的调节已在焦虑障碍和创伤相关疾病中进行探索[55]。在兽医行为医学中，针对谷氨酸能系统的直接临床试验罕见。
尽管如此，来自转化神经科学的机制性见解表明，谷氨酸能调节通过促进恐惧消退过程来增强暴露类行为干预的疗效[56]。目前，谷氨酸能策略，包括NMDA受体调节、mGluR调节和利鲁唑，在兽医行为医学中应被视为临床前或探索性概念，而非犬猫的既定临床治疗选择。此处纳入这些内容旨在突出转化研究的潜在方向，不应被解读为支持其常规临床使用。上文讨论的主要药物的比较临床证据按物种和研究设计类别汇总于表2。
3.6. 内源性大麻素系统与大麻二酚
内源性大麻素系统作为应激和焦虑相关行为的潜在调节因子，在兽医医学中正日益受到研究。大麻二酚（CBD）具有复杂的药理作用，超出经典大麻素受体的范围，可能影响5-羟色胺能信号传导、内源性大麻素张力以及应激相关的神经生物学通路。在犬中，对照研究已在噪声诱导恐惧、分离相关应激和乘车旅行模型中考察了CBD，尽管研究结果仍不一致[57,58,59]。一项使用烟花模型的安慰剂对照研究未证明CBD具有明确的抗焦虑作用[57]，而随后的一项盲法研究报告称，在分离和乘车旅行期间单次给予4 mg/kg剂量后，选定的行为和生理应激指标有所减轻[58]。更近期的交叉数据还提示，效应可能因剂量、制剂和同时存在的成分而异[60]。因此，目前CBD应被视为治疗犬行为障碍的新兴而非既定药理选择。关于最佳剂量、长期行为疗效以及跨行为表型的临床有效性的证据仍然有限。一项近期涉及100只Owner导向攻击猫的随机单盲临床试验报告称，大麻二酚（CBD）治疗后攻击评分降低，各活性治疗组之间（包括氟西汀）无统计学显著差异[61]。然而，这些初步发现并未确立治疗等效性，也不支持CBD用于猫行为障碍的常规临床使用。
4. 比较精神药理学的转化边界
比较兽医精神药理学的核心目标是界定机制可转化性与诊断过度延伸之间的边界。因此，转化解读应区分分子靶点和广泛神经功能的保守性与实验模型证据、犬猫的直接临床证据、可观察行为表型的相似性以及诊断等效性。尽管哺乳动物神经递质系统表现出显著的进化保守性，但用于定义精神疾病的解释框架在人类与非语言物种之间存在根本差异。这一区别在合理药理决策中具有理论和实践意义。人类精神病学与兽医行为医学之间的主要转化边界汇总于表3。
在机制层面，跨物种同源性支持转化推断。主要神经递质系统在哺乳动物中枢神经系统中具有进化保守性，并具有大致可比的受体家族和回路架构[62,63,64]。这些保守要素为假设驱动的治疗外推提供了依据，尤其是在靶向受体水平药效动力学或神经递质再摄取机制时。这种生物学连续性构成了转化精神药理学的基础。
然而，诊断等效性并不因机制相似性而成立。人类精神科诊断高度依赖主观内在体验，通常通过结构化临床访谈和自我报告量表进行评估[65]。在兽医医学中，行为综合征基于可观察的行为模式和照护者报告的变化来定义，而非主观内在体验[66]。可观察行为可能反映多种潜在状态，包括恐惧、挫败、疼痛、认知衰退、环境冲突或习得性反应。内省报告的缺失引入了固有的诊断模糊性，并限制了对基于《精神障碍诊断与统计手册》（DSM）的构念进行直接分类映射[67]。
这一区分尤为重要，因为许多人类精神疾病分类包含主观现象，如侵入性思维、妄想、持续性担忧或思维内容改变，而这些在无法言语的兽医患者中无法直接评估。在犬和猫中，临床评估必须主要依赖可观察的表型，包括运动模式、姿势、发声、排泄行为、回避和自主神经唤醒，并结合情境和照护者报告的信息。因此，不应假定创伤后应激障碍或广泛性焦虑障碍等人类诊断标签在伴侣动物中代表诊断等价的病症。基于表型的可观察行为和情境描述为临床评估和药理决策提供了更可靠的依据。
因此，将人类精神疾病标签严格移植到兽医行为医学中存在概念过度简化的风险。“焦虑谱系”模型在概念上或许可以转化，但离散的DSM诊断类别无法在犬和猫中等同实施[10]。例如，犬的分离焦虑诊断并不意味着与人类分离焦虑障碍在现象学上等价；相反，它反映的是在照护者缺席时观察到的一种情境特异性痛苦行为模式。在解读治疗反应预期和向照护者传达预后时，这一区分至关重要。
回路层面的框架提供了比分类诊断对齐更可靠的可转化模型[68]。兽医患者的行為表型可结合多种推定的神经生物学贡献因素和合理的药理靶点来解读，包括5-羟色胺能、去甲肾上腺素能、多巴胺能和抑制性神经递质系统。这些关联不应被解读为单一神经递质系统功能障碍构成某一行为表型潜在病因的证据。这种基于回路的方法降低了过度概括的风险，并使治疗选择与机制合理性而非诊断类比相一致。
此外，转化边界并非静态不变。随着客观行为表型分析工具、可穿戴传感设备和标准化评分系统的发展，兽医行为诊断可能变得更加精细并以生物学为基础[69,70]。然而，在此类工具在跨物种和跨情境中得到验证之前，临床转化必须保持谨慎，并明确承认机制保守性并不意味着诊断等价性的领域。
总之，最可靠的可转化策略优先考虑保守的受体和回路机制，应用表型导向的解读，并明确避免直接复制人类精神疾病分类学。这一经过校准的框架增强了科学严谨性，同时支持合理的、考虑物种差异的治疗调整。
5. 物种特异性药代动力学及临床意义
药代动力学变异性是兽医精神药理学中重要的转化考量因素。即使在受体层面的药效动力学是保守的，药代动力学差异仍可能影响药物暴露、给药间隔、蓄积、洗脱期以及不良反应或药物相互作用的风险。重要的是，这些差异具有药物和通路特异性，不应推广至所有精神药物。表4总结了犬和猫中可用的药物特异性药代动力学特征及其临床意义。一项关于复方口服曲唑酮单独给药或与加巴喷丁联合给药的猫药代动力学研究进一步说明了在解读镇静效应和潜在药物相互作用时，制剂特异性和联合用药特异性证据的重要性[71]。
犬和猫在肝脏生物转化途径上可能存在差异，包括葡萄糖醛酸结合和细胞色素P450介导的代谢；然而，这些差异的临床相关性具有药物和通路特异性[90,91,92]。因此，猫葡萄糖醛酸结合能力降低不应被解读为意味着所有精神药物均清除减慢或普遍需要降低剂量。在猫特异性药代动力学数据不足的情况下，给药和监测决策应基于单个药物的药代动力学特征和治疗窗，而非基于物种范围的通用规则。
个体间差异进一步增加了处方难度。即使在同一种物种内，吸收动力学、蛋白结合率和代谢率也可能存在显著差异。与年龄相关的生理变化，包括肝灌注减少、肾清除率降低、体成分改变以及多药合用暴露，在老年患者中尤为重要，而老年患者在行为医学病例中占相当大的比例[93,94,95]。然而，关于年龄相关药代动力学变化的许多证据来源于人类医学，老年犬和猫的直接药代动力学数据仍然匮乏；因此，这些考量应被视为间接证据，而非已确立的物种特异性证据。认知功能障碍综合征、慢性焦虑和强迫症常发生于老龄动物，凸显了药代动力学警惕性的重要性。
在精神药物之间转换时，洗脱期规划是一项重要考量，尤其是涉及单胺氧化酶抑制剂或5-羟色胺能药物时[28]。应将禁忌组合与需要谨慎或加强监测的药物组合区分开来。适当的洗脱期因药物而异，取决于所涉药物、活性代谢物、药效学效应和消除特征等因素；因此，不应将所有药物转换统一适用同一个洗脱间隔。例如，从氟西汀转换为MAOI司来吉兰时，由于氟西汀及其活性代谢物去甲氟西汀的消除时间延长，需要延长洗脱期。停用氟西汀与开始司来吉兰之间应至少间隔5周[96]。
多药合用会放大药代动力学的复杂性。行为障碍患者常同时接受皮肤科、内分泌科、神经科或骨科疾病的合并用药。应仔细考虑细胞色素介导的相互作用、蛋白结合置换和叠加的镇静效应[97]。近期犬类研究直接评估了tasipimidine与氯米帕明和氟西汀的合并给药，提供了药物组合特异性证据，这比仅基于药理学机制的预测与兽医实践更为直接相关[72,88]。在相互作用数据匮乏的猫科患者中，尽量减少不必要的药物叠加尤为重要。
监管状态也与药代动力学解读相互交织。获批适应证通常反映物种特异性剂量验证和安全性评估，而超说明书处方往往依赖外推数据和临床经验。鉴于物种特异性批准有限，超说明书用药在兽医行为医学中很常见。因此，透明的风险-获益评估、仔细的记录和持续监测是负责任处方的必要组成部分。
最终，药代动力学意识将精神药理学处方从受体靶向操作转变为经物种校准的临床过程。合理决策需要将机制理解与代谢变异性、合并症背景、年龄相关生理学以及实际监测限制相结合。剂量起始、滴定和监测应基于每种药物的药代动力学特征、治疗窗、适应证和可获得的物种特异性证据进行个体化调整。
6. 表型导向的临床整合
表5呈现了一个表型导向的临床决策框架，整合了鉴别诊断、药物治疗的预期作用和持续时间、物种特异性证据、不良反应、监测要求以及同步的行为和环境管理。
本综述中的临床表型由可观察的行为模式、其情境、持续性和功能影响来定义，而非直接等同于人类精神科诊断。分离相关焦虑/痛苦指与主人不在或分离相关的痛苦表现，可能包括发声、踱步、破坏性行为、不当排泄或无法安静。噪声相关恐惧/焦虑在本综述中用作描述特定声学刺激（如雷暴或烟花）所引发的恐惧或焦虑相关行为反应的一般性术语。“噪声恐惧症”和“噪声厌恶”等术语仅在反映原始研究使用的术语或获批监管适应症时保留，不应被解释为可互换的诊断类别。情境性恐惧或应激指与可识别事件（包括运输或就诊）相关的依赖性情境反应。强迫性或重复性行为指在已考虑相关医学和环境原因后，过度或干扰正常功能的重复性、相对不变的行为。更广泛性焦虑相关表现以描述性方式用于跨多种情境的持续性或复发性焦虑，而非直接等同于人类广泛性焦虑障碍。在所有情况下，应将医学状况、疼痛、环境因素和其他行为诊断视为潜在的鉴别诊断或促发因素。
6.1. 区分抗焦虑作用与镇静及行为表达减少
在情境性应激研究中，行为表达减少不应必然被解释为等同于抗焦虑作用。镇静、运动障碍或唤醒度降低可能减少运动、发声、抵抗或其他可观察行为，而未显示动物恐惧或焦虑相关状态的相应减轻。这一区分对α2肾上腺素能激动剂、苯二氮䓬类药物、曲唑酮和加巴喷丁尤为重要。因此，行为学结局应与警觉性或镇静评估、观察者盲法、可获得的生理学指标以及每项研究使用的具体结局指标结合解读。例如，口颊黏膜右美托咪定治疗犬噪声相关恐惧的随机试验纳入了功能性警觉性评估，并在部分疗效分析中排除了与临床相关镇静有关的观察。在犬曲唑酮就诊试验中，行为学评估辅以生理学指标，尽管并非所有生理学结局在曲唑酮与安慰剂之间存在差异。在猫加巴喷丁就诊前研究中，报告了主人评估的应激减轻和兽医操作依从性改善，但镇静也是常见的治疗效应。因此，操作更容易或行为活动减少不应单独被解释为抗焦虑作用的证据。当药物治疗与结构化行为矫正或环境管理方案一起评估时，观察到的治疗结局应被解释为联合干预的证据，而非药物的单独效应。
6.2. 焦虑谱系障碍
慢性焦虑相关状况，包括分离焦虑和其他焦虑相关表型，可能涉及5-羟色胺能通路，这些通路是合理的药理学靶点。慢性分离焦虑的一线药物治疗通常涉及SSRIs或三环类抗抑郁药[20,29]。辅助药物可在治疗开始或预期应激暴露期间使用。行为矫正仍是实现持久改善的必要共同干预措施。
在猫中，证据应作更狭窄的解读。氟西汀和氯米帕明的对照研究主要评估了尿液喷洒，而曲唑酮和加巴喷丁的对照研究主要集中于急性运输或就诊相关应激。这些特定结局的改善不应被解释为确立了治疗猫广泛性慢性焦虑或强迫性障碍的疗效。
6.3. 强迫性障碍
强迫性行为如追尾、吸吮胁腹和过度理毛通常使用5-羟色胺能药物治疗，对照临床证据支持犬的特定强迫性障碍，而猫的证据仍然有限[19,98]。环境改造和行为重定向策略是关键的辅助措施。
6.4. 攻击行为
攻击行为最好被概念化为一种行为表现，而非单一的诊断实体。具有临床意义的表现可能包括恐惧相关攻击、疼痛相关攻击、资源相关攻击、挫折相关攻击以及与神经系统或认知疾病相关的攻击。这些表现在触发因素、情境、持续性和相关动机因素方面可能有所不同，因此在药物干预之前应评估相关的医学和行为鉴别诊断。特别是，疼痛、神经系统疾病、认知功能障碍和其他医学状况可能促成或改变攻击行为。医学评估应超越局部疼痛和肌肉骨骼疾病，考虑可能促成唤醒改变、易激惹或行为反应性改变的全身性炎症、感染性、神经系统和内分泌状况[99,100]。在将攻击行为完全归因于原发性行为障碍之前，应将这些状况作为潜在促成因素或混杂因素进行评估。攻击行为还应按其社会目标和情境背景进行特征描述，包括针对主人的、针对陌生人的、针对同种个体的以及与操作相关的攻击[101,102,103]。这些表型区分可为行为评估和个体化管理提供信息；然而，支持针对每种攻击亚型的特定药物方案的证据仍然有限。
药物治疗不应被视为对作为单一病症的“攻击行为”的治疗。相反，药物可用于处理促成过程，如恐惧或焦虑、过度唤醒、疼痛、冲动控制受损或认知功能障碍，前提是临床适用。因此，治疗应基于行为学和医学评估进行个体化，并与环境管理、行为矫正和适当的安全措施相结合。支持药物干预攻击相关表现的证据仍然有限且异质性较大。
6.5. 认知功能障碍综合征
老年犬的认知功能障碍对司来吉兰的多巴胺能调节显示出中等程度的反应[52]。对焦虑、睡眠障碍和环境丰富化的辅助管理进一步支持认知稳定。
7. 讨论
本综述提出了一个结构化的比较框架，用于兽医精神药理学，将机制可转化性与诊断过度转化相分离，并将物种特异性药代动力学限制纳入临床决策。在各神经递质系统中，机制保守性为治疗选择提供了合理基础；然而，这种转化的有用性取决于证据强度、表型有效性以及种间变异的安全性意义。从本比较综述中浮现出若干与当代兽医行为实践和未来研究设计特别相关的交叉主题。
当前证据基础的一个主要局限是犬与猫研究之间的显著不平衡。对照临床证据可用于选定的犬适应症，而猫的证据更为有限且具有适应症特异性，对照试验集中在较少的临床场景中。因此，跨物种外推应保持暂定性，不应被视为等效的疗效或安全性证据。
第二个关键主题是行为医学中多药治疗的现实。长期5-羟色胺能药物通常需要数周才能达到最大临床效果[104]。因此，在需要立即降低风险的急性行为危机期间，可能会引入辅助药物。情境性抗焦虑药、镇静药或针对共病的药物因此常被纳入多模式策略中。
尽管联合治疗在选定病例中可能是合理的，但它增加了不良事件发生时因果归因的复杂性，并放大了药物-药物相互作用的风险，特别是在5-羟色胺能药物和镇静药联合使用中[105,106]。多药治疗因并发医学状况和老年生理学而进一步复杂化[107]。
这些现实强调了明确框架的临床价值，该框架将表型与潜在相关的神经生物学回路联系起来，阐明每种药物的预期作用（基础性 versus 辅助性），并强调洗脱计划和监测策略。没有这样的结构，处方可能漂向增量添加而非连贯的方案设计，增加可避免的不良结局的可能性。
攻击行为凸显了表型特异性临床评估和标准化结局测量的必要性。按社会目标、情境背景和促成医学状况区分攻击行为可能改善治疗结局的解释。然而，支持特定攻击亚型药物治疗的临床证据仍然有限，现有研究通常涉及小样本和选定的攻击表型[108,109]。
本综述还强调了在未明确设定边界的情况下，将人类精神病学框架应用于兽医患者时存在转化性误读的风险。受体和转运体层面的机制相似性可能使人们相信跨物种适用性；然而，诊断类别和主观症状构念并不能直接转化[110,111]。在兽医行为医学中，临床综合征是通过可观察的行为模式和照护者报告推断的，而这些可能受到家庭动态、照护者期望和情境变异性的影响。因此，过度依赖人类诊断标签可能使临床推理产生偏倚，并导致治疗靶点不匹配或对治疗反应产生不切实际的期望。更稳健的转化立场应承认，可迁移性在机制和回路层面最强，而表型定义和结局评估仍具有物种和情境特异性。在考虑新兴靶点（如谷氨酸能调节[112]）时，这一区分尤为重要。尽管谷氨酸能调节治疗难治性抑郁的人类临床数据支持其机制合理性[113]，但兽医行为医学中的直接随机临床试验证据仍然匮乏。因此，治疗意义应被表述为产生假设，并置于未来研究方向之中，而非作为已确立的临床推荐。
最后，生物标志物开发和精准医学方法代表了减少精神药理学决策不确定性的有前景的途径，但需要在兽医环境中进行仔细校准。客观行为表型分析，包括源自可穿戴设备和活动指标的定量测量，已越来越多地用于描述精神疾病特征，并可能促进临床研究中更客观的结局评估[114]。生理或生化标志物，如应激相关内分泌指标或自主神经指数，可支持治疗监测或区分应答者与无应答者[115]。与此同时，药物基因组学或代谢者状态方法在概念上对解决个体间变异性和不良事件风险具有吸引力，尤其是在猫中，因为猫的药代动力学数据和证据深度有限[90,116]。然而，应避免在缺乏稳健验证的情况下转化精准医学方法，而应侧重于能够有意义地改善决策的实用性工具，而非增加复杂性却无已证明的益处。
总体而言，现有文献支持精神药理学对特定犬和猫行为适应证的临床相关性，但证据的强度和可推广性因物种、药物和表型而差异显著。在解读本综述中呈现的比较框架时，应考虑这些局限性，并强调需要更严格且具有临床信息价值的兽医试验。
8. 未来方向
兽医精神药理学的未来研究应在追求更具推测性的精准医学方法之前，优先解决若干基础性证据缺口。首先，需要标准化且具有临床意义的表型定义，以区分异质性行为表现并提高研究间的可比性。其次，应开发经过验证且物种适宜的行为结局测量方法，并在可行时更多地纳入盲法评估和客观测量。第三，尤其需要在猫中开展更多对照临床试验，因为猫中的证据仍然有限且具有适应证特异性。
多巴胺能和谷氨酸能通路也值得进一步研究，作为对既定药物治疗反应不完全的行为障碍的潜在靶点。谷氨酸能调节可能尤其适合作为行为干预的辅助手段，通过在暴露方案中促进恐惧消退学习[117]。多巴胺能机制在强迫/重复行为和冲动性攻击中也值得进一步研究，尽管支持多巴胺靶向治疗用于伴侣动物的直接证据仍然有限。然而，这些应用在伴侣动物中仍处于探索阶段，需要对照临床验证才能确立治疗推荐。
还应在两个物种中扩展药物特异性药代动力学研究，包括重复给药研究以及在临床相关群体（如老年动物和合并症患者）中的研究。需要更长期的研究来描述反应持久性、不良反应、治疗中止以及部分或无反应。应使用真实世界多药治疗的实用性研究来评估常用药物组合及潜在药代动力学和药效学相互作用。最后，需要在常用治疗之间开展直接比较或头对头试验，以提供相对疗效、耐受性和治疗选择的信息。
可穿戴设备、生物标志物、药物基因组学和精准医学方法最终可能补充这些优先事项，但其临床价值尚未确立。目前，这些方法应被视为需要验证的探索性研究方向，而非可直接用于常规临床实施的工具。
9. 结论
比较兽医精神药理学可从这一整合神经递质靶点、转化边界和物种特异性药代动力学的结构化框架中获益。机制保守性支持合理的跨物种推断；然而，诊断非等效性和药代动力学变异性要求谨慎、校准的应用。通过将药物选择与证据分级、回路层面理解和物种感知解读相结合，临床医生可以提高治疗精准度，同时将风险降至最低。
查看英文原文▾
Simple Summary
Behavioral problems such as anxiety, fear, repetitive behaviors, aggression, and age-related cognitive decline can substantially affect the welfare of dogs and cats and their relationships with caregivers. Medications are increasingly being used to manage these problems, but treatment decisions are often made based on human psychiatry, which cannot always be directly applied to animals. This review summarizes and compares the current knowledge on medications used to treat behavioral disorders in dogs and cats, with a focus on how major brain chemical systems affect behavior, how strongly various treatments are supported by scientific evidence, and how dogs and cats may process medications differently. The available evidence is generally stronger for dogs than for cats, and important differences between species can affect drug safety and treatment responses. Human psychiatric research can provide useful guidance, but behavioral conditions in animals should be assessed based on observable behaviors rather than direct application of human psychiatric diagnoses. By consolidating current evidence, biological mechanisms, and species-specific differences, this review provides a practical framework for safer, more informed use of behavioral medications in dogs and cats and highlights areas where further research is needed.
1. Introduction
Behavioral disorders in companion animals are a considerable clinical and welfare concern in contemporary veterinary practice [1,2]. Increasing urbanization, changes in human–animal relationships, prolonged indoor housing, and extended lifespans have contributed to the heightened recognition of anxiety-related conditions [2,3], compulsive behaviors, situational fear responses, and selected aggression presentations [4,5], as well as age-associated cognitive dysfunction in dogs and cats [6]. Consequently, pharmacological intervention has become a routine component of multimodal behavior management [7].
Despite its expanding use, veterinary psychopharmacology remains characterized by heterogeneous prescription practices and evidence distribution across species and conditions [8]. In many cases, therapeutic decisions are influenced, explicitly or implicitly, by extrapolation from human psychiatric literature [9]. Although evolutionary conservation among mammalian neural circuits is broadly consistent, direct translation from human psychiatry to veterinary behavioral medicine is not straightforward [10,11]. Diagnostic frameworks in human medicine rely on subjective symptom reporting and standardized categorical criteria that cannot be applied directly in nonverbal species [10,12]. Consequently, a structured comparative approach is required to differentiate between mechanistic overlap and inappropriate diagnostic transfer [13].
In this review, we aimed to consolidate the current knowledge on neurotransmitter-targeted pharmacotherapy in canine and feline behavioral disorders via a structured comparative framework. Specifically, we aimed to (i) examine major neurotransmitter systems as potential pharmacological targets relevant to clinically observed behavioral phenotypes in dogs and cats, (ii) delineate the boundaries between mechanistic translation from human psychiatry and direct veterinary clinical evidence, and (iii) summarize the available drug- and species-specific pharmacokinetic data that are relevant to dosing, treatment duration, drug interactions, washout considerations, and safety monitoring.
Figure 1 illustrates the key pharmacokinetic considerations in dogs and cats, including absorption, distribution, metabolism, and elimination. These processes may vary according to the drug, species, and individual patient characteristics, emphasizing the importance of drug- and patient-specific dose selection, titration, and clinical monitoring.
2. Methods
2.1. Literature Search Strategy
A structured narrative review approach was adopted to enhance transparency while maintaining the appropriate flexibility for comparative synthesis [14]. This literature search was conducted to support a structured narrative review and was not intended to be exhaustive or to meet the requirements of a systematic review. PubMed, Scopus, and Web of Science were searched for relevant literature addressing the pharmacological management and pharmacokinetics of psychotropic drugs used to treat behavioral disorders in dogs and cats. The final literature search was conducted on 2 October 2026.
The search terms were combined into four primary concept blocks: species, behavioral phenotype, pharmacological or neurotransmitter terms, and pharmacokinetic terms. Pharmacokinetic terms included “pharmacokinetics,” “bioavailability,” “absorption,” “metabolism,” “clearance,” “elimination,” “half-life,” “active metabolite,” and “drug interaction.” Terms within each concept block were combined using the Boolean operator “OR,” and relevant concept blocks were combined using “AND.” Species-related terms included “dog,” “canine,” “cat,” and “feline.” Behavioral phenotype terms included “anxiety,” “fear,” “phobia,” “separation anxiety,” “compulsive disorder,” “repetitive behavior,” “aggression,” “cognitive dysfunction,” and “noise phobia.” Pharmacological and neurotransmitter-related terms included “SSRI,” “selective serotonin reuptake inhibitor,” “tricyclic antidepressant,” “fluoxetine,” “clomipramine,” “trazodone,” “gabapentin,” “benzodiazepine,” “alpha-2 agonist,” “dexmedetomidine,” “selegiline,” “monoamine oxidase inhibitor,” “NMDA,” and “glutamate.”
Studies published between January 1990 and the final search date were considered. Earlier publications were included only when they provided foundational information directly relevant to the pharmacological mechanism, safety, or clinical use of a drug discussed in this review and when the relevant information was not adequately represented in the post-1990 literature. Only English-language publications were included; non-English publications were excluded.
2.2. Inclusion and Exclusion Criteria
Eligible studies included randomized controlled trials (RCTs), non-randomized prospective studies, observational cohort studies, case–control studies, retrospective studies, and case series evaluating pharmacological interventions in canine or feline clinical populations. Pharmacokinetic studies evaluating bioavailability, metabolism, half-life, clearance, elimination, or active metabolites of relevant drugs in dogs or cats were also included. Meta-analyses and consensus guidelines were included when relevant. Studies restricted to laboratory rodent models without direct veterinary clinical relevance were excluded. Opinion articles lacking supporting data were excluded unless they represented formal consensus or clinical guidelines.
Records retrieved from the three databases were combined, and duplicate records were removed before screening. Titles and abstracts were screened for relevance, followed by full-text assessment of potentially eligible articles. Reference lists of relevant reviews and included studies were also screened to identify eligible publications not captured by the database searches.
Study selection and data extraction were performed by both authors. Disagreements regarding study eligibility or interpretation were resolved through discussion and consensus.
2.3. Study-Design-Based Evidence Classification
To facilitate comparison of the available veterinary literature, studies were categorized based on study design. Category A included randomized controlled trials and meta-analyses; Category B included prospective non-randomized studies and well-designed observational studies; Category C included retrospective studies and case series; and Category D included expert opinion or mechanistic inference without direct clinical validation. Importantly, these categories describe the design of the available evidence rather than the overall certainty or strength of a treatment effect. They do not independently account for sample size, risk of bias, precision, consistency, duration of follow-up, or independent replication. Thus, the categories were used descriptively and interpreted along with the indication, species, study characteristics, and limitations of the supporting literature.
3. Neurotransmitter Systems and Behavioral Phenotypes
Major neurotransmitter systems are involved in emotional processing, arousal, inhibitory control, motivation, and cognitive function and may contribute to distinct but overlapping behavioral phenotypes. Figure 2 provides an integrated overview of the principal neurobiological functions, representative pharmacological targets, and behavioral phenotypes potentially associated with these systems. Although these systems are presented individually for conceptual clarity, substantial functional overlaps exist, and many psychopharmacological agents exert therapeutic effects through multiple neurotransmitter pathways. These associations represent plausible neurobiological and pharmacological relationships and should not be interpreted as evidence that dysfunction of a single neurotransmitter system causes a specific behavioral disorder. This framework provides a basis for interpreting the following sections on individual neurotransmitter systems while distinguishing plausible pharmacological targets from demonstrated causal mechanisms. A comparative mapping of the major neurotransmitter systems across human psychiatry and canine and feline behavioral phenotypes is summarized in Table 1.
The major neurotransmitter systems involved in veterinary behavioral medicine are summarized based on their principal neurobiological functions, representative pharmacological targets, and associated clinical behavioral phenotypes. Serotonergic pathways are involved in the modulation of anxiety-related responses, compulsive and repetitive behaviors, separation-related distress, and impulse control through interactions with limbic and cortical circuits. Noradrenergic signaling originating from the locus coeruleus mediates arousal, attention, stress responsiveness, and acute fear reactions. Gamma-aminobutyric acid (GABA)ergic neurotransmission provides inhibitory control within the central nervous system and contributes to anxiolysis, sedation, and adjunctive seizure management through GABAA positive allosteric modulators. Gabapentin, an α2δ ligand that modulates voltage-gated calcium channels, represents a mechanistically distinct anxiolytic strategy, and is therefore considered separately from direct GABAergic modulation. Dopaminergic pathways, particularly the mesolimbic system, regulate motivation, reward processing, reinforcement, and cognitive function, whereas glutamatergic neurotransmission plays essential roles in learning, memory, fear extinction, and synaptic plasticity. Representative pharmacological agents and their primary molecular targets are shown for each neurotransmitter system; however, many psychopharmacological agents affect multiple neurotransmitter pathways and behavioral domains. The level of clinical evidence is greatest in dogs, whereas evidence in cats remains limited, highlighting the need for species-specific therapeutic interpretation and further clinical investigation.
3.1. Serotonergic System
The serotonergic system plays a central role in anxiety regulation, impulse control, and the modulation of repetitive behaviors [15,16,17,18]. Originating primarily from the dorsal raphe nucleus and projecting widely to the limbic and cortical regions, serotonin affects emotion regulation across mammalian species.
According to controlled clinical trials in selected populations, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) constitute first-line pharmacotherapy for separation anxiety and compulsive disorders in canine behavioral medicine [19,20]. Trazodone is also used as an adjunctive serotonergic agent in the treatment of situational anxiety and stress-related behaviors in dogs and cats, although the evidence varies by species and indication [21,22]. Evidence in feline patients remains scarce, although controlled trials support its use for selected situational indications, such as pre-visit and transport-related anxiety. However, RCTs examining chronic behavioral disorders remain sparse, and much of the available evidence is derived from small prospective studies or case series [23]. Nevertheless, RCTs have demonstrated the efficacy of fluoxetine and clomipramine in reducing urine spraying in cats [24,25]. Serotonergic agents may require several weeks to achieve maximal clinical effect. Adaptive neuroplastic changes following initial pharmacological effects have been proposed as one explanation for this delayed therapeutic response; however, this mechanism has not been fully established across species [26]. Consequently, short-acting, adjunctive agents are often administered during the initiation phase.
Potential adverse effects include gastrointestinal disturbances, altered appetite, sedation, or paradoxical excitation, and, rarely, serotonin toxicity when combined with other serotonergic agents [23,27]. Careful washout periods are required when transitioning between monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors [28].
In the United States (U.S.), oral clomipramine hydrochloride tablets and fluoxetine hydrochloride chewable tablets are FDA-approved for the treatment of separation anxiety in dogs, with the approved use of fluoxetine including administration in conjunction with a behavior modification plan. However, many other serotonergic agents used in veterinary behavioral medicine are prescribed off-label [20,29].
3.2. Noradrenergic System
The noradrenergic system, primarily originating from the locus coeruleus, plays a central role in arousal, vigilance, stress responsiveness, and modulation of acute fear reactions. Increased noradrenergic activity is strongly associated with hyperarousal in human psychiatric conditions such as panic disorder and posttraumatic stress disorder [30,31]. In companion animals, noradrenergic signaling may contribute to situational fear responses, including noise-related fear/anxiety during veterinary visits, and responses to acute environmental stressors.
Alpha-2 adrenergic agonists, particularly dexmedetomidine, which are administered via oromucosal routes, have demonstrated efficacy in reducing acute noise-related fear responses in dogs under controlled trial conditions [32]. These agents reduce presynaptic norepinephrine release and attenuate sympathetic activation, providing rapid anxiolytic effects. Although clonidine has been used off-label in selected cases, published controlled veterinary clinical trials are lacking. Noradrenergic modulation is, therefore, most appropriately conceptualized as an event-targeted or adjunctive therapy rather than as a primary long-term management solution for generalized anxiety syndromes.
Cardiovascular effects, including bradycardia and hypotension, are clinically relevant considerations, particularly in geriatric and cardiac-compromised patients [33]. Species-specific dosing adjustments and careful monitoring are required to minimize hemodynamic risk. While mechanistic translation from human hyperarousal models is plausible, direct psychiatric diagnostic transfer remains inappropriate because of differences in contextual triggers and behavioral expressions.
In the U.S., dexmedetomidine oromucosal gel (Sileo) is FDA-approved for the treatment of noise aversion in dogs [32]. In 2026, the U.S. FDA approved tasipimidine oral solution (Tessie) for the treatment of noise aversion and separation anxiety in dogs [34]. The evidence supporting these approved indications includes regulatory clinical field studies submitted for product approval. Peer-reviewed evidence is also available, including a small randomized, double-blind, placebo-controlled crossover pilot study evaluating acute anxiety associated with owner departure; however, the extent of the peer-reviewed clinical literature remains limited.
3.3. GABAergic Agents and α2δ Calcium-Channel Ligands
GABA functions as the principal inhibitory neurotransmitter in the mammalian central nervous system and modulates acute anxiety responses by enhancing inhibitory tone within limbic circuits. Benzodiazepines act as positive allosteric modulators of the GABA-A receptor, enhancing inhibitory neurotransmission and providing rapid anxiolytic and muscle-relaxant effects [35]. Benzodiazepines have shown greater clinical efficacy than placebos in the short-term treatment of panic disorder and acute panic-like states, supporting their relevance in acute distress or predictable stress scenarios [36,37,38].
In veterinary patients, benzodiazepines, such as alprazolam, have been used to treat short-term situational anxiety, particularly in acute noise-related fear/anxiety and other fear/stress-related contexts [39,40]. However, concerns about tolerance, dependence, and paradoxical disinhibition, especially in impulsive or aggression-prone individuals, limit their long-term application [41,42,43]. In cats, oral diazepam is associated with rare idiosyncratic acute hepatic necrosis, but other benzodiazepines do not have the same risk profile [44]. Thus, careful drug selection and monitoring are advised in feline patients.
Imepitoin is a low-affinity partial agonist at the benzodiazepine binding site of the GABA-A receptor and is a clinically relevant non-benzodiazepine GABAergic agent [45]. In the European Union, imepitoin (Pexion®) is authorized for the reduction of anxiety and fear associated with noise phobia in dogs. Controlled clinical evidence supports the efficacy of imepitoin in reducing noise-related fear and anxiety in dogs [46], as summarized in Table 2.
Although not a classical GABA receptor agonist, gabapentin modulates voltage-gated calcium channels and indirectly affects excitatory neurotransmission [47]. It is commonly used to reduce situational stress in dogs and cats, particularly in veterinary clinic settings. The strength of evidence varies based on the indication and species. In feline patients, randomized placebo-controlled trials support its use in the reduction of pre-visit and transport-related stress [48]. In addition, a randomized, double-blind, placebo-controlled trial in fearful shelter cats reported that daily gabapentin, administered alongside behavioral modification, reduced stress-related measures and improved behavioral rehabilitation progress [49]. In contrast, broader applications for chronic behavioral disorders in dogs and cats rely primarily on smaller prospective or retrospective studies, supporting a moderate overall level of evidence beyond situational use [50]. Pregabalin, another α2δ subunit ligand, has direct clinical and regulatory evidence for its situational use in cats. Pregabalin oral solution (Bonqat®) is authorized in the European Union and is FDA-approved in the U.S. for the alleviation of acute anxiety and fear associated with transportation and veterinary visits in cats [51]. Its efficacy is demonstrated in prospective, placebo-controlled clinical field studies [51]. These data provide direct clinical support for α2δ calcium-channel ligands in feline situational anxiety and fear; however, this evidence should not be extrapolated to chronic or generalized anxiety-related conditions. GABAergic agents and α2δ calcium-channel ligands may provide useful support for selected acute or situational behavioral indications; however, they should be integrated into broader behavioral and environmental management frameworks rather than used as sole long-term interventions.
Table 2. Comparative Clinical Evidence by Species, Study Design, and Indication.
| Drug/Class | Primary Target | Dogs: Clinical Evidence | Cats: Clinical Evidence |
|---|---|---|---|
| Fluoxetine (SSRI) | SERT inhibition | 2 RCTs: separation anxiety [ 29 ] and compulsive disorder ( n = 63) [ 19 ] (Category A) | 1 RCT: urine spraying ( n = 17) [ 24 ] (Category A) |
| Clomipramine (TCA) | 5-HT and NE reuptake inhibition | 1 multicenter RCT: separation anxiety ( n = 95) [ 20 ] (Category A) | 1 multicenter RCT: urine spraying ( n = 67) [ 25 ] (Category A) |
| Trazodone | 5-HT2 antagonism and SERT inhibition | 1 randomized, double-blind, placebo-controlled crossover trial: veterinary-visit stress ( n = 20) [ 21 ] (Category A) | 1 randomized, double-blind, placebo-controlled crossover trial: pre-visit/transport anxiety ( n = 10) [ 22 ] (Category A) |
| Imepitoin | GABA-A receptor modulation | 1 randomized, double-blind, placebo-controlled clinical trial: noise-related fear/anxiety ( n = 238) [ 46 ] (Category A); authorized indication in the EU | No established direct clinical evidence for behavioral indications |
| Dexmedetomidine | α2-adrenoceptor agonism | 1 randomized, double-blind, placebo-controlled clinical trial: noise-related fear/anxiety ( n = 182) [ 32 ] (Category A) | No comparable controlled clinical trial identified for behavioral indications; evidence remains limited/indirect (Category C–D) |
| Tasipimidine | α2-adrenoceptor agonism | 2 pivotal randomized, double-blind, vehicle-controlled regulatory field studies: noise aversion ( n = 160) and separation anxiety ( n = 224) [ 34 ], plus 1 published randomized, double-blind, placebo-controlled crossover pilot study of owner-departure anxiety (Category A) | No established clinical evidence |
| Gabapentin | α2δ subunit of voltage-gated calcium channels | 1 double-blind, placebo-controlled clinical trial: veterinary-visit stress (Category A); 1 retrospective clinical study: broader behavioral disorders (Category C) | 1 randomized, blinded, placebo-controlled crossover trial: pre-visit/transport stress ( n = 20) [ 48 ] (Category A) |
| Pregabalin | α 2 δ subunit of voltage-gated calcium channels | No established direct clinical evidence for behavioral indications | Placebo-controlled clinical field evidence: acute anxiety and fear associated with transportation and veterinary visits ( n = 209) [ 51 ]; FDA-approved and authorized in the EU for this indication (Category A) |
| Selegiline | MAO-B inhibition | 1 large prospective open-label clinical study: canine cognitive dysfunction ( n = 641) [ 52 ], with additional experimental/behavioral studies (Category B) | No established direct clinical evidence for behavioral indications (Category D) |
| Benzodiazepines (e.g., alprazolam, diazepam) | GABA-A receptor positive allosteric modulation | Category B–C (situational fear/anxiety; evidence varies by agent and indication) | Category C–D; oral diazepam carries a risk of idiosyncratic acute hepatic necrosis |
3.4. Dopaminergic System
Dopaminergic pathways, particularly mesolimbic circuits projecting from the ventral tegmental area to the nucleus accumbens and prefrontal cortex, affect motivation, reward processing, and repetitive behaviors. In human psychiatry, dopaminergic pathways are associated with impulse-control disorders and certain repetitive behavioral phenotypes. In veterinary medicine, dopaminergic modulation has mostly been studied in the context of canine cognitive dysfunction syndrome (CCD).
In the U.S., selegiline hydrochloride oral tablets (Anipryl®) are FDA-approved for the control of clinical signs associated with canine cognitive dysfunction syndrome (CDS). Clinical improvement has been reported in affected dogs, although the available evidence should be interpreted in light of the limitations of the underlying studies [52]. Improvements in cognitive and behavioral parameters have been reported; however, limitations in the study designs and variability in the reported outcomes suggest only moderate overall strength of evidence [53]. Dopaminergic contributions to compulsive behaviors and select impulsive aggression phenotypes remain mechanistically plausible but are frequently intertwined with serotonergic pathways. Consequently, attributing compulsive behaviors solely to dopaminergic imbalances oversimplifies the complexity of the relevant circuit interactions. A circuit-level model incorporating serotonergic–dopaminergic interplay could better reflect current neurobiological understanding [54].
3.5. Glutamatergic Pathways and Emerging Targets
Glutamatergic neurotransmission plays a critical role in synaptic plasticity, learning, and the extinction of conditioned fear responses. In human psychiatry, the modulation of N-methyl-D-aspartate (NMDA) receptors and related glutamatergic pathways has been explored in anxiety disorders and trauma-related conditions [55]. In veterinary behavioral medicine, direct clinical trials targeting glutamatergic systems are rare.
Nevertheless, mechanistic insights from translational neuroscience suggest that glutamatergic modulation enhances the efficacy of exposure-based behavioral interventions by facilitating fear extinction processes [56]. Currently, glutamatergic strategies, including NMDA receptor modulation, mGluR modulation, and riluzole, should be considered preclinical or exploratory concepts in veterinary behavioral medicine rather than established clinical treatment options for dogs and cats. Their inclusion here is intended to highlight potential directions for translational research and should not be interpreted as supporting their routine clinical use. The comparative clinical evidence for the principal pharmacological agents discussed above is summarized by the species and study-design category in Table 2.
3.6. Endocannabinoid System and Cannabidiol
The endocannabinoid system is increasingly being investigated as a potential modulator of stress- and anxiety-related behaviors in veterinary medicine. Cannabidiol (CBD) has complex pharmacological actions that extend beyond classical cannabinoid receptors and may affect serotonergic signaling, endocannabinoid tone, and stress-related neurobiological pathways. In dogs, controlled studies have examined CBD in models of noise-induced fear, separation-related stress, and car travel, although findings remain inconsistent [57,58,59]. A placebo-controlled study using a fireworks model did not demonstrate a clear anxiolytic effect of CBD [57], whereas a subsequent blinded study reported attenuation of selected behavioral and physiological stress measures following a single 4 mg/kg dose during separation and car travel [58]. More recent crossover data also suggest that effects may vary based on the dose, formulation, and concurrent ingredients [60]. Therefore, CBD should currently be regarded as an emerging rather than established pharmacological option for the treatment of canine behavioral disorders. Evidence regarding optimal dosing, long-term behavioral efficacy, and clinical effectiveness across behavioral phenotypes remains limited. A recent randomized, single-blind clinical trial involving 100 cats with owner-directed aggression reported reductions in aggression scores following cannabidiol (CBD) treatment, with no statistically significant differences among the active treatment groups, including fluoxetine [61]. However, these preliminary findings do not establish therapeutic equivalence or support the routine clinical use of CBD for feline behavioral disorders.
4. Translational Boundaries in Comparative Psychopharmacology
The central objective of comparative veterinary psychopharmacology is to delineate the boundary between mechanistic translatability and diagnostic overextension. Accordingly, translational interpretation should distinguish conservation of molecular targets and broad neural functions from experimental-model evidence, direct clinical evidence in dogs and cats, similarity of observable behavioral phenotypes, and diagnostic equivalence. While mammalian neurotransmitter systems exhibit substantial evolutionary conservation, the interpretive frameworks used to define psychiatric disorders differ fundamentally between humans and non-verbal species. This distinction has theoretical and practical implications in rational pharmacological decision-making. The principal translational boundaries between human psychiatry and veterinary behavioral medicine are summarized in Table 3.
At the mechanistic level, cross-species homology supports translational inferences. Major neurotransmitter systems are evolutionarily conserved across mammalian central nervous systems and have broadly comparable receptor families and circuit architecture [62,63,64]. These conserved elements justify hypothesis-driven therapeutic extrapolation, particularly when targeting receptor-level pharmacodynamics or neurotransmitter reuptake mechanisms. Such biological continuity forms the basis of translational psychopharmacology.
However, diagnostic equivalence does not follow from mechanistic similarity. Human psychiatric diagnoses rely heavily on subjective internal experiences, which are typically assessed using structured clinical interviews and self-report measures [65]. In veterinary medicine, behavioral syndromes are defined based on observable behavior patterns and caregiver-reported changes rather than subjective internal experiences [66]. Observable behaviors may reflect multiple underlying states, including fear, frustration, pain, cognitive decline, environmental conflicts, or learned responses. The absence of introspective reporting introduces inherent diagnostic ambiguity and limits direct categorical mapping to Diagnostic and Statistical Manual of Mental Disorders (DSM)-based constructs [67].
This distinction is particularly important because many human psychiatric categories incorporate subjective phenomena, such as intrusive thoughts, delusions, persistent worry, or alterations in thought content, which cannot be directly assessed in non-verbal veterinary patients. In dogs and cats, clinical assessment must instead rely primarily on observable phenotypes, including motor patterns, posture, vocalization, elimination behavior, avoidance, and autonomic arousal, together with contextual and caregiver-reported information. Consequently, human diagnostic labels such as post-traumatic stress disorder or generalized anxiety disorder should not be assumed to represent diagnostically equivalent conditions in companion animals. Phenotype-based descriptions of observable behavior and context provide a more defensible basis for clinical assessment and pharmacological decision-making.
Accordingly, strict transplantation of human psychiatric labels into veterinary behavioral medicine risks conceptual oversimplification. While the “anxiety spectrum” model may translate conceptually, discrete DSM diagnostic categories cannot be implemented equivalently in dogs and cats [10]. For example, a diagnosis of separation anxiety in a dog does not imply phenomenological equivalence with human separation anxiety disorder; rather, it reflects a pattern of context-specific distress behaviors observed in the caregiver’s absence. This distinction is critical when interpreting treatment response expectations and communicating prognoses to caregivers.
A circuit-level framework offers a more defensible translational model than categorical diagnostic alignment [68]. Behavioral phenotypes in veterinary patients may be interpreted in relation to multiple putative neurobiological contributors and plausible pharmacological targets, including serotonergic, noradrenergic, dopaminergic, and inhibitory neurotransmitter systems. These associations should not be interpreted as evidence that dysfunction of a single neurotransmitter system constitutes the underlying cause of a given behavioral phenotype. This circuit-informed approach reduces the risk of overgeneralization and aligns therapeutic selection with mechanistic plausibility rather than diagnostic analogy.
Furthermore, translational boundaries are not static. As objective behavioral phenotyping tools, wearable sensory devices, and standardized scoring systems evolve, veterinary behavioral diagnostics may become more granular and biologically anchored [69,70]. However, until such tools are validated across species and contexts, clinical translation must remain cautious and explicitly acknowledge areas in which mechanistic conservation does not imply diagnostic equivalence.
In summary, the most defensible translational strategy prioritizes conserved receptor and circuit mechanisms, applies phenotype-oriented interpretation, and explicitly avoids the direct replication of human psychiatric taxonomies. This calibrated framework enhances scientific rigor, while supporting rational, species-aware therapeutic adaptations.
5. Species-Specific Pharmacokinetics and Clinical Implications
Pharmacokinetic variability is an important translational consideration in veterinary psychopharmacology. Even when receptor-level pharmacodynamics are conserved, pharmacokinetic differences may affect drug exposure, dosing intervals, accumulation, washout periods, and the risk of adverse effects or drug interactions. Importantly, these differences are drug- and pathway-specific and should not be generalized across all psychotropic agents. Available drug-specific pharmacokinetic characteristics and their clinical implications in dogs and cats are summarized in Table 4. A feline pharmacokinetic study of compounded oral trazodone, administered alone or with gabapentin, further illustrates the importance of formulation- and combination-specific evidence when interpreting sedative effects and potential drug interactions [71].
Dogs and cats may differ in hepatic biotransformation pathways, including glucuronidation and cytochrome P450-mediated metabolism; however, the clinical relevance of these differences is drug- and pathway-specific [90,91,92]. Therefore, reduced glucuronidation capacity in cats should not be interpreted as implying uniformly slower clearance or a universal requirement for lower dosing of all psychotropic drugs. Where feline-specific pharmacokinetic data are inadequate, dosing and monitoring decisions should be based on the pharmacokinetic characteristics and therapeutic margin of the individual drug rather than on a generalized species-wide rule.
Inter-individual variability further complicates prescription. Even within species, absorption kinetics, protein binding, and metabolic rates may vary substantially. Age-related physiological changes, including reduced hepatic perfusion, reduced renal clearance, altered body composition, and polypharmacy exposure, are especially relevant in geriatric patients, who constitute a significant proportion of behavioral medicine cases [93,94,95]. However, much of the evidence regarding age-related pharmacokinetic changes is derived from human medicine, and direct pharmacokinetic data in geriatric dogs and cats remain scant; therefore, these considerations should be regarded as indirect rather than established species-specific evidence. Cognitive dysfunction syndrome, chronic anxiety, and compulsive disorders frequently occur in aging animals, highlighting the importance of pharmacokinetic vigilance.
Washout planning is an important consideration when transitioning between psychotropic drugs, particularly when monoamine oxidase inhibitors or serotonergic agents are involved [28]. Contraindicated combinations should be distinguished from drug combinations that require caution or enhanced monitoring. Appropriate washout periods are drug-specific and depend on factors including the drugs involved, active metabolites, pharmacodynamic effects, and elimination characteristics; therefore, a single washout interval should not be applied to all drug transitions. For example, when transitioning from fluoxetine to the MAOI selegiline, an extended washout period is required because of the prolonged elimination of fluoxetine and its active metabolite, norfluoxetine. At least 5 weeks should elapse between the discontinuation of fluoxetine and initiation of selegiline [96].
Polypharmacy amplifies pharmacokinetic complexity. Patients with behavioral disorders often receive concurrent medications for dermatological, endocrine, neurological, or orthopedic conditions. Cytochrome-mediated interactions, protein-binding displacement, and additive sedative effects should be carefully considered [97]. Recent canine studies have directly evaluated the concurrent administration of tasipimidine with clomipramine and fluoxetine, providing drug-combination-specific evidence that is more directly relevant to veterinary practice than predictions based solely on pharmacological mechanisms [72,88]. In feline patients, for whom interaction data are scarce, the minimization of unnecessary pharmacological layering is particularly important.
The regulatory status also intersects with pharmacokinetic interpretation. Approved indications typically reflect species-specific dose validation and safety evaluations, whereas off-label prescriptions often rely on extrapolated data and clinical experience. Off-label use is common in veterinary behavioral medicine given the limited availability of species-specific approvals. Therefore, transparent risk–benefit assessments, careful documentation, and ongoing monitoring are essential components of responsible prescription.
Ultimately, pharmacokinetic awareness transforms psychopharmacological prescription from a receptor-target exercise into a species-calibrated clinical process. Rational decision-making requires the integration of mechanistic understanding with metabolic variability, comorbidity context, age-related physiology, and practical monitoring constraints. Dose initiation, titration, and monitoring should be individualized based on the pharmacokinetic profile, therapeutic margin, indication, and available species-specific evidence for each drug.
6. Phenotype-Oriented Clinical Integration
A phenotype-oriented clinical decision framework integrating differential diagnoses, the intended role and duration of pharmacotherapy, species-specific evidence, adverse effects, monitoring requirements, and concurrent behavioral and environmental management is presented in Table 5.
Clinical phenotypes in this review are defined by observable behavioral patterns, their context, persistence, and functional impact rather than by direct equivalence to human psychiatric diagnoses. Separation-related anxiety/distress refers to signs of distress occurring in association with owner absence or separation, which may include vocalization, pacing, destructive behavior, inappropriate elimination, or inability to settle. Noise-related fear/anxiety is used in this review as the general descriptive term for fear- or anxiety-related behavioral responses elicited by specific acoustic stimuli, such as thunderstorms or fireworks. Terms such as “noise phobia” and “noise aversion” are retained only when they reflect the terminology used in the original study or an approved regulatory indication and should not be interpreted as interchangeable diagnostic categories. Situational fear or stress refers to context-dependent responses associated with identifiable events, including transportation or veterinary visits. Compulsive or repetitive behaviors refer to repetitive, relatively invariant behaviors that are excessive or interfere with normal function after relevant medical and environmental causes have been considered. More generalized anxiety-related presentations are used descriptively for persistent or recurrent anxiety across multiple contexts rather than as direct equivalents of human generalized anxiety disorder. In all cases, medical conditions, pain, environmental factors, and other behavioral diagnoses should be considered as potential differential or contributing factors.
6.1. Distinguishing Anxiolysis from Sedation and Reduced Behavioral Expression
In studies of situational stress, reduced behavioral expression should not necessarily be interpreted as equivalent to anxiolysis. Sedation, motor impairment, or reduced arousal may reduce movement, vocalization, resistance, or other observable behaviors without demonstrating a corresponding reduction in the animal’s fear- or anxiety-related state. This distinction is particularly relevant to alpha-2 adrenergic agonists, benzodiazepines, trazodone, and gabapentin. Accordingly, behavioral outcomes should be interpreted together with assessments of alertness or sedation, observer blinding, physiological measures when available, and the specific outcome measures used in each study. For example, the randomized trial of oromucosal dexmedetomidine for the treatment of noise-associated fear in dogs incorporated a functional alertness assessment and excluded observations associated with clinically relevant sedation from selected efficacy analyses. In the canine trazodone veterinary-visit trial, behavioral assessments were complemented by physiological measures, although not all physiological outcomes differed between trazodone and the placebo. In the feline gabapentin pre-visit study, reduced owner-assessed stress and improved veterinary compliance were reported, but sedation was also a common treatment effect. Thus, easier handling or reduced behavioral activity should not, in isolation, be interpreted as evidence of anxiolysis. Where pharmacotherapy was evaluated together with a structured behavior-modification or environmental-management program, the observed treatment outcome should be interpreted as evidence for the combined intervention rather than as the isolated effect of the drug.
6.2. Anxiety Spectrum Disorders
Chronic anxiety-related conditions, including separation anxiety and other anxiety-related phenotypes, may involve serotonergic pathways that represent plausible pharmacological targets. First-line pharmacotherapy for chronic separation anxiety typically involves SSRIs or tricyclic antidepressants [20,29]. Adjunctive agents may be used during treatment initiation or anticipated stress exposure. Behavioral modification remains an essential co-intervention for achieving durable improvement.
In cats, the evidence should be interpreted more narrowly. Controlled studies of fluoxetine and clomipramine have primarily evaluated urine spraying, whereas controlled studies of trazodone and gabapentin have focused mainly on acute transport- or veterinary-visit-related stress. Improvement in these specific outcomes should not be interpreted as establishing efficacy in the treatment of generalized chronic anxiety or compulsive disorders in cats.
6.3. Compulsive Disorders
Compulsive behaviors such as tail chasing, flank sucking, and excessive grooming are generally addressed using serotonergic agents, with controlled clinical evidence supporting selected compulsive disorders in dogs, and evidence in cats remaining limited [19,98]. Environmental modifications and behavioral redirection strategies are critical adjuncts.
6.4. Aggression
Aggression is best conceptualized as a behavioral manifestation rather than a single diagnostic entity. Clinically relevant presentations may include fear-related aggression, pain-related aggression, resource-related aggression, frustration-related aggression, and aggression associated with neurological or cognitive disease. These presentations may differ in their triggers, context, persistence, and associated motivational factors, and relevant medical and behavioral differential diagnoses should therefore be evaluated before pharmacological intervention. In particular, pain, neurological disease, cognitive dysfunction, and other medical conditions may contribute to or alter aggressive behavior. Medical assessment should extend beyond localized pain and musculoskeletal disease to consider systemic inflammatory, infectious, neurological, and endocrine conditions that may contribute to altered arousal, irritability, or behavioral reactivity [99,100]. Such conditions should be evaluated as potential contributors or confounders before attributing aggression solely to a primary behavioral disorder. Aggressive behavior should also be characterized according to its social target and situational context, including owner-directed, stranger-directed, conspecific-directed, and handling-related aggression [101,102,103]. These phenotypic distinctions may inform behavioral assessment and individualized management; however, evidence supporting specific pharmacological regimens for each aggression subtype remains limited.
Pharmacotherapy should not be considered a treatment for “aggression” as a unitary condition. Rather, medication may be used to address contributing processes such as fear or anxiety, hyperarousal, pain, impaired impulse control, or cognitive dysfunction when clinically appropriate. Therefore, treatment should be individualized based on behavioral and medical assessment and integrated with environmental management, behavior modification, and appropriate safety measures. Evidence supporting pharmacological intervention for aggression-related presentations remains limited and heterogeneous.
6.5. Cognitive Dysfunction Syndrome
Cognitive dysfunction in aging dogs shows a moderate response to dopaminergic modulation by selegiline [52]. The adjunctive management of anxiety, sleep disturbance, and environmental enrichment further supports cognitive stabilization.
7. Discussion
This review proposes a structured comparative framework for veterinary psychopharmacology that separates mechanistic translatability from diagnostic over-translation and incorporates species-specific pharmacokinetic constraints into clinical decision-making. Across neurotransmitter systems, mechanistic conservation provides a rational basis for therapeutic selection; however, the usefulness of this translation depends on the strength of evidence, phenotype validity, and safety implications of interspecies variability. Several crosscutting themes that are particularly relevant to contemporary veterinary behavioral practice and the design of future research have emerged from this comparative review.
A major limitation of the current evidence base is its marked imbalance between canine and feline studies. Controlled clinical evidence is available for selected canine indications, whereas feline evidence is more limited and indication-specific, with controlled trials concentrated in a smaller number of clinical scenarios. Consequently, extrapolation across species should remain provisional and should not be treated as equivalent evidence of efficacy or safety.
The second critical theme is the reality of polypharmacy in behavioral medicine. Long-term serotonergic agents typically require several weeks to achieve maximal clinical effect [104]. Consequently, adjunctive agents may be introduced during acute behavioral crises that require immediate risk mitigation. Situational anxiolytics, sedatives, or medications targeting comorbidities are thus often incorporated into multimodal strategies.
Although combination therapy may be rational in selected cases, it increases the complexity of causal attribution when adverse effects occur and amplifies the risk of drug–drug interactions, particularly among serotonergic agents and sedative combinations [105,106]. Polypharmacy is further complicated by concurrent medical conditions and geriatric physiology [107].
These realities underscore the clinical value of an explicit framework that links phenotypes to potentially relevant neurobiological circuits, clarifies the intended role of each agent (foundational versus adjunctive), and emphasizes washout planning and monitoring strategies. Without such a structure, prescription may drift toward incremental additions rather than a coherent regimen design, increasing the likelihood of avoidable adverse outcomes.
Aggression highlights the need for phenotype-specific clinical assessment and standardized outcome measures. Distinguishing aggression by social target, situational context, and contributing medical conditions may improve the interpretation of treatment outcomes. However, clinical evidence supporting pharmacotherapy for specific aggression subtypes remains limited, with available studies often involving small samples and selected aggression phenotypes [108,109].
This review also highlights the risk of translational misinterpretation when human psychiatric frameworks are applied to veterinary patients without explicit boundary setting. Mechanistic similarities at the receptor and transporter level can foster confidence in cross-species applicability; however, diagnostic categories and subjective symptom constructs do not translate directly [110,111]. In veterinary behavioral medicine, clinical syndromes are inferred through observable behavior patterns and caregiver reports, which can be affected by household dynamics, caregiver expectations, and contextual variability. Therefore, an overreliance on human diagnostic labels may bias clinical reasoning and lead to mismatched therapeutic targets or unrealistic expectations regarding responses. A more robust translational stance acknowledges that transferability is strongest at the mechanistic and circuit level, while phenotype definition and outcome assessment remain species- and context-specific. This distinction is particularly relevant when considering emerging targets, such as glutamatergic modulation [112]. While mechanistic plausibility is supported by human clinical data on glutamatergic modulation in treatment-resistant depression [113], direct randomized clinical trial evidence in veterinary behavioral medicine remains scarce. Thus, therapeutic implications should be framed as hypothesis-generating and situated within future research directions rather than as established clinical recommendations.
Finally, biomarker development and precision medicine approaches represent promising avenues to reduce uncertainty in psychopharmacological decision-making but require careful calibration in veterinary settings. Objective behavioral phenotyping, including quantitative measures derived from wearable devices and activity metrics, has increasingly been used to characterize psychiatric conditions and may facilitate more objective outcome assessment in clinical research [114]. Physiological or biochemical markers, such as stress-associated endocrine measures or autonomic indices, could support treatment monitoring or stratify responders versus non-responders [115]. In parallel, pharmacogenomic or metabolizer-status approaches are conceptually attractive for addressing interindividual variability and adverse event risk, particularly in cats, where pharmacokinetic data and evidence depth are limited [90,116]. However, translation of precision approaches without robust validation should be avoided and should focus on pragmatic tools that meaningfully improve decision-making rather than adding complexity without demonstrated benefits.
Overall, the available literature supports the clinical relevance of psychopharmacology for selected canine and feline behavioral indications, but the strength and generalizability of evidence vary substantially by species, drug, and phenotype. These limitations should be considered when interpreting the comparative framework presented in this review and highlight the need for more rigorous and clinically informative veterinary trials.
8. Future Directions
Future research in veterinary psychopharmacology should prioritize several foundational evidence gaps before more speculative precision-medicine approaches are pursued. First, standardized and clinically meaningful phenotype definitions are needed to distinguish between heterogeneous behavioral presentations and improve comparability across studies. Second, validated and species-appropriate behavioral outcome measures should be developed, with greater incorporation of blinded assessment and objective measures where feasible. Third, additional controlled clinical trials are particularly needed in cats, for which the evidence remains limited and indication-specific.
Dopaminergic and glutamatergic pathways also warrant further investigation as potential targets for behavioral disorders that respond incompletely to established pharmacotherapies. Glutamatergic modulation may be particularly relevant as an adjunct to behavioral interventions by facilitating fear-extinction learning during exposure-based protocols [117]. Dopaminergic mechanisms may also merit further investigation in compulsive/repetitive behaviors and impulsive aggression, although direct evidence supporting dopamine-targeted treatment in companion animals remains limited. However, these applications remain exploratory in companion animals and require controlled clinical validation before therapeutic recommendations can be established.
Drug-specific pharmacokinetic studies should also be expanded in both species, including repeated-dose studies and investigations in clinically relevant populations such as geriatric animals and patients with comorbidities. Longer-term studies are needed to characterize the durability of response, adverse effects, treatment discontinuation, and partial or non-response. Pragmatic studies of real-world polypharmacy should be used to evaluate commonly used drug combinations and potential pharmacokinetic and pharmacodynamic interactions. Finally, direct comparative or head-to-head trials between commonly used treatments are needed to inform relative efficacy, tolerability, and treatment selection.
Wearable devices, biomarkers, pharmacogenomics, and precision-medicine approaches may ultimately complement these priorities, but their clinical value has not yet been established. At present, these approaches should be considered exploratory research directions requiring validation rather than tools ready for routine clinical implementation.
9. Conclusions
Comparative veterinary psychopharmacology could benefit from this structured framework that integrates neurotransmitter targets, translational boundaries, and species-specific pharmacokinetics. Mechanistic conservation supports rational cross-species inference; however, diagnostic non-equivalence and pharmacokinetic variability necessitate cautious, calibrated application. By aligning pharmacological selection with evidence grading, circuit-level understanding, and species-aware interpretation, clinicians could improve therapeutic precision, while minimizing risks.